Anisimov Et Al

Neuroendocrinology Letters Volume 27 Nos.
12 February-April 2006
Light pollution, reproductive function and cancer risk

Vladimir N. A
Correspondence to:
Vladimir N. Anisimov
Department of Carcinogenesis and Oncogerontology,
N.N. Petrov Research Institute of Oncology,
Pesochny-2, St.Petersburg 197758, RUSSIA
PHONE : +7 (812) 596-8697; FAX : +7 (812) 596-8947
EMAIL : aging@mail.ru
Submitted: December 1, 2005

Key words:
Accepted: December 15, 2005
light-at-night; shift work; circadian rhythm; anovulation; carcinogenesis;

melatonin; life span
Neuroendocrinol Lett 2006; 27(1-2):3552 PMID: 16648818
Abstract
NEL271206R01 Neuroendocrinology Letters www.nel.edu
Introduction
The alternation of the day and night circadian
cycle is a most important regulator of a wide variety of physiological rhythms in living organisms,
including humans (Young and Kay 2001; Reppert
and Weaver 2002; Roenneberg and Merrow 2003;
Bell-Pedersen et al 2005). Due to the introduction
of electricity and artificial light about hundred years
ago the pattern and duration of human exposure to
light has changed dramatically, and thus light-atnight has become an increasing and essential part of
modern lifestyle. Light exposure at night seems associated with a number of serious behavioral as well as
health problems, including cardiovascular diseases
and cancer (Reiter 2002; Anisimov et al. 2002, 2003;
Knutsson 2003; Ha and Park 2005). According to
the circadian disruption hypothesis, light-at-night
might disrupt the endogenous circadian rhythm,
and that specifically suppress nocturnal production
in the pineal gland of indole hormone melatonin

and its secretion in blood (Stevens 2005).
As reported by the International Agency for
Research on Cancer (Parkin et al. 2001), breast cancer constituted a huge disease burden in developed
countries in the year 2000. It is the most common
cancer in women with an estimated 999,000 new
cases of breast cancer each year (about 22% of cancers in women) resulting in some 375,000 deaths.
More than half of all cases are registered in industrialized countries: about 335,000 in Europe and
195,000 in North America. The disease is not yet
as common among women in developing countries
although proliferation is increasing. Risk of breast
cancer incidence had been associated with higher
socio-economic status such as income, education,
housing, etc. as they were related to such health factors as age at menstruation and menopause, obesity,
To cite this article: Neuro Endocrinol Lett 2006; 27(1-2):3552
A R T I C L E
At present, light pollution (exposure to light-at-night) both in the form of occupational exposure during night work and as a personal choice and life style, is
experienced by numerous night-active members of our society. Disruption of the
circadian rhythms induced by light pollution has been associated with cancer in
humans. There are epidemiological evidences of increased breast and colon cancer
risk in shift workers. An inhibition of the pineal gland function with exposure to
the constant light (LL) regimen promoted carcinogenesis whereas the light deprivation inhibits the carcinogenesis. Treatment with pineal indole hormone melatonin
inhibits carcinogenesis in pinealectomized rats or animals kept at the standard
light/dark regimen (LD) or at the LL regimen. These observations might lead to use
melatonin for cancer prevention in groups of humans at risk of light pollution.
R E V I E W
Department of Carcinogenesis and Oncogerontology, N.N. Petrov Research Institute of Oncology,

Pesochny-2, St.Petersburg 197758, Russia.
35
height, alcohol consumption, late age at first birth, low

parity, estrogen replacement therapy, some diet habits,
etc. Another rapidly growing cancer incidence in the
developed countries is colon cancer (Parkin et al. 2001;
Napalkov 2004). There are an estimated 943 000 new
cases in 2000. The risk of colon cancer also has been
associated with higher socio-economical status, obesity,
alcohol consumption, diet habits, etc. Some epidemiological evidence suggests that the increasing exposure to
light pollution might be responsible for the increase in
the incidence of both breast and colon cancer in humans
(Hansen 2001; Davis et al. 2001; Schernhammer et al.
2001; 2003; Schernhammer and Schulmeister 2004;
Stevens 2005).
It was initially believed that light of at least 2500 lux
was sufficient to regulate melatonin secretion from the
human pineal gland. Carefully designed studies have
shown, however, that illumination as low as 1.3 lux of
monochromatic blue light at 460 nm or 100 lux of broadband white light can significantly suppress melatonin
production (Brainard et al. 2001; Brainard and Hanifin
2005). A profound reduction of melatonin level was
observed in humans exposed during 2 weeks to intermittent exposure to light at night (Zeitzer et al. 2000; Graham and Cooks 2001). It worth to note that attribution
any detrimental effects of light-at-night directly to loss
of melatonin is overspeculative (Arendt 2005). Arendt
(2005) stressed that that light-at-night has numerous
other effects. Most important, light directly influences
the expression of the clock gene feedback loops driving
circadian rhythms (Reppert and Weaver 2002).
Both the disruption of circadian regulation by bilateral electrolytic lesions of hypothalamic suprachiasmatic
nuclei (SCN) or the exposure to jet lag accelerated growth
of transplantable malignant tumors in mice (Filipski et
al. 2002, 2003, 2005). Mutation in the Period2 (per2)
gene in mice leads to the increase in spontaneous tumor
incidence and to the increase in susceptibility to carcinogenic effect of -radiation in mice (Fu et al. 2002; Lee
2005). However, knockout Cry1/Cry2 mice failed shown
increased susceptibility to spontaneous or -irradiation
induced carcinogenesis (Gauger and Sancar 2005). In
humans, there were revealed disturbances in the expression of the three period genes (PER1, PER2 and PER3) in
most (<95%) of the breast cancerous cells in comparison
with the nearby non-cancerous cells (Chen et al. 2005). It
was shown that the variant Per3 genotype (heterozygous
+ homozygous 5-repeat alleles) was associated with an
increased risk of breast cancer among premenopausal
women (Zhu et al. 2005). These preliminary studies will
require confirmation in larger numbers of observations.
In this review, we focus on the role of light pollution
in development of cancer. The special attention is paid
to the effect of light pollution on cancer risk in shift
workers and on spontaneous and induced carcinogenesis
in rodents. Rodents seem to be an adequate model for
studying the carcinogenic effect of light pollution in
humans (Anisimov et al. 2005). We will also evaluate the
36
data on effect of light deprivation and anti-carcinogenic

potential of melatonin.
Circadian rhythms regulation and eects of

light-at-night
The circadian system comprises three key components: (1) endogenous oscillators (clocks) generating
a circadian rhythm; (2) input pathways entraining the
circadian rhythm to the astrophysical day; and (3) output
pathways distributing signals from the oscillator to the
periphery (Korf et al. 2003). In year 2002 a previously
unknown function for retinal ganglion cells has been
discovered (Berson 2002). In mammals, these cells play
a key role in the regulation of nonvisual photic responses,
such as behavioral responses to light, pineal melatonin
synthesis, and sleep latency (Panda et al. 2005). It was
shown that axons of retinal ganglion cells connect to
the circadian oscillator suprachiasmatic nuclei (SCN)
in the hypothalamus. The molecular clockwork in the
SCN is composed of interacting positive and negative
feedback loops of several (at least nine) core circadian
clock genes (Reppert and Weaver 2002; Korf et al. 2003;
Reddy et al. 2005). These genes regulate cell functions
by controlling the expression of key cell-cycle checkpoint
genes and genes of apoptosis (Fu and Lee, 2003). Light
information from the retina is conveyed to the SCN via
the retinohypothalamic tract, a subdivision of the optic
tract that terminated in the core of the SCN.
In mice, light appears to affect the mammalian circadian network via the induction of three genes: Per1,
Per2 and Dec1 (Roenneberg and Merrow 2003). Light
received via retinal photoreceptors is transmitted to the
SCN via two pathways: directly via retino-hypothalamic
tract, using glutamate and pituitary adenuclate cyclase
activating polypeptide (PACAP) as principle neurotransmitters; and indirectly, via the intergeniculate leaflet
and the midbrain, using amino butyric acid (GABA),
neuropeptide Y, and serotonin as transmitters (Reppert
and Weaver 2002). All three light-induced clock genes
are responsive only at specific circadian times. Dec1 is
light-induced throughout the subjective night; Per1 both
at the beginning and the end of the subjective night; and
Per2 only in the early subjective night (Roenneberg and
Merrow 2003). The intracellular transduction pathways
appear to involve Ca2+-mediated phosphorylation of
CREB, which binds to CREs in the promoters of Per1
and Per2 (Anisimov and Popovic 2004). Some data on
mammalian circadian rhythm genes are presented in the
Table 1.
Under LL conditions, mPer1, mPer2, mCry1, and
mCry2 messages in SCN remained rhythmic, although
the waveform of mCry2 was altered compared with to DD
(Munoz et al., 2005). In LL, mPER1, mCRY1, and mCRY2
protein levels were also rhythmic and comparable to the
patterns observed in DD. However, mPER2 was elevated
and contitutively expressed under LL regime (Munoz et
al. 2005). These findings suggest that mPER2 is important for the generation of phase delays in the molecular
Neuroendocrinology Letters Vol.27 Nos.12, Feb-Apr 2006 Copyright Neuroendocrinology Letters ISSN 0172780X www.nel.edu

Table 1. Mammalian circadian rhythm genes
Gene names
Properties
Period1 (Per1)
Period2 (Per2)
Period3 (Per3)
Mutations alter rhythmicity in rodents and humans. Physical association Tei et al. (1997) ;
with CRY and among PER proteins. Positive regulator of Bmal1.
Takumi et al. (1998)
Cryptochrome 1 (Cry 1)
Cryptochrome 2 (Cry 2)
Mutations alter rhythmicity in rodents. Physically associates with and

stabilizes PER. Negative regulator of Per and Cry transcription.
Circadian locomotor output cycles

kaput (Clock)
References
Mutations alter rhythmicity in rodents. Constitutively expressed.

Physically associates with BMAL1. Binds to E-boxes in and promotes
transcription of Per and Cry.
Brain and muscle aryl hydrocaerbon Mutations alter rhythmicity in rodents. Rhythmically expressed.
receptor nuclear translocator
Physically associates with CLOCK. Binds to E-boxes in and promotes
[ARNT]-like protein 1 (Bmal1/Mop3) transcription of Per and Cry.
Casein kinase 1 (CK1)
Mutations alter rhythmicity in rodents. Affected by hamster mutation
tau. Protein kinase. Physically associates with and phosphorylates PER.
Affect PER stability and nuclear localization.
Dec1 (Stra13/Sharp2 /BHLHB2); Dec2 Basic helix-loop-helix transcription factors, repressed Clock. Bmal1(Sharp1/BHLHB3)
induced transactivation of the mouse Per1 promoter through direct
protein-protein interactions with Bmal1 and/or completion for E-box
elements.
Timeless (mTim)
Knockdown of dTim disrupted SCN neuronal activity rhythms, and
altered levels of core clock elements. Associates with PER in oscillating
SCN cells.
clockwork. Exposure to light at night markedly reduced

Per1 and Cry2 gene expression in the pineal gland of rats,
but not that of Per3 and Cry1 (Simonneaux et al. 2004),
whereas the Per2 might not essential to drive a spontaneous arylalkylamine-N-acethyltransferase rhythmically
(Isobe et al. 2004).
One of the best studied output pathways of the SCN is
the neuronal circuit that controls the rhythmic production of melatonin in the pineal galand (Korf et al. 2003).
This pathway comprises SCN projection to neuronas of
the hypothalamic paraventricular nucleus which send
their axons to the preganglionic sympathetic neurons
in the upper thoracic spinal cord. These preganglionic
neurones provide synaptic input to the superior cervical ganglia, giving rise to noradrenergic postgnaglionic
nerve fibers that terminate in the pineal gland. SCN
oscillator controls the biosynthesis of the main pineal
hormone melatonin. In all mammals, the production
of melatonin is maximal at night time and minimal at
day time (Arendt, 1995).
Discussing relation between light and melatonin
in humans, Stevens and Rea (2001) stressed, that the
effect of light on pineal function in humans has several
features that are relevant to potential long-term health
effects: (1) the exposure to light at night (~ 2500 lux)
completely suppresses melatonin prudiction in radents
and humans; (2) some people are much more sensitive
to light-at-night (~200 lux) than other; (3) blue-green
(~ 500 nm) light-at-night more effective suppreses melat
onin production; (4) there appears to be a dose-response
to light-at-night; (5) light quality during the day appears
to affect nocturnal melatonin production as well as the
human circadian pacemaker; (6) women may be more
sensitive to the suppressive effects of light-at-night than
are men. In C3H mice with hereditary retinal degenera-
Van der Horst et al.(1999);

Thresher et al. (1998)
Vilaterna et al. (1994); King
et al. (1997) ;
Gekakis et al. (1998)
Ralph and Menaker (1998) ;

Toh et al. (2001) ;
Honma et al. (2002)
Barnes et al. (2003)
tion the threshold of light sensitivity to suppress pineal

melatonin content was between 0.14 and 0.017 lux,
whereas that in normal CBA mice was between 0.0021
and 0.00026 lux (Goto and Ebihara 1990).
Light-at-night and reproductive function

The prolonged exposure to continuous light (LL)
systematically induced complete suppression of body
temperature and locomotor activity circadian rhythms
in rats (Depres-Brummer et al. 1995) and disturbances
of estrous function (Hoffmann 1968). There is evidence
that light controls the course of the estrous cycle only via
the suprachiasmatic nucleus (SCN) of the hypothalamus
(Barbacka-Surowiak et al. 2003). Artificial increase in
the length of light phase of the day (by 24 hours) as
usual followed by the increase in the duration of estrous
cycle and in some cases to it disturbances. If the light
will be switched-on for 24 hours per day the majority of
female mice and rats in a short period revealed the persistent estrus syndrome. In physiological circumstances,
this syndrome naturally develops at some age (in rats, as
usual between 15th and 18th months) and proceeds to
the anestrous (Ashheim 1976), being the physiological
equivalent of climacteric syndrome and climacteric in
women. The ovaries of persistent-estrus rats content
follicular cysts and hyperplasia theca-tissue, whereas the
corpora lutea are absent (Ird 1966; Lazarev et al. 1976;
Prata Lima et al. 2004). Instead of cyclic production of
gonadotropins, prolactin, estrogens and progesterone
characteristic for normal reproductive period of life,
these hormones secrete acyclically that followed by
hyperplastic processes in mammary gland and uterus
(Ird 1966; Anisimov 1971, 1987).
37
The continuous illumination of 2-month-old Wistar

rats during 1, 2 or 6 months resulted in the appearance
of persistent estrus in 24, 61 and 100% of animals,
respectively (Klochkov and Beliaev 1977). In 15 weeks
after the start of the experiment at the age of 2 month,
follicular cysts in the ovaries had 92% of outbred rats in
the LL groups and no cases of the ovarian cysts development were observed in the control LD group (Lazarev
et al.1976). It is very important that the follicular cysts
in the ovaries and the persistent estrus is not stopped if
rats were placed then in the room with the standard LD
regimen (Lazarev et al. 1976). Chernova (2005) observed
earlier appearance of long cycles and high incidence of
irregular estrous cycles in female LIO rats exposed to the
LL regimen from the age of 1 month as compared to the
LD regimen.
In our studies, the effect of the LL regimen on estrous
function in female transgenic HER-2/neu and female
CBA mice was evaluated (Baturin et al. 2001; Anisimov
et al. 2004). The age-related changes in the length of the
estrous cycle and the rate of long estrous cycles developed
earlier in both strains of mice maintained at LL regimen
from the age of 2 months as compared with those kept
at the LD regimen. Fifty percent of HER-2/neu mice of
the control (LD) group revealed irregular estrous cycles
at the age of 9 months however 76% in the LL group.
In CBA mice, the fast rise of the irregular estrous cycle
rate was observed in the LL group as compared to the LD
group. Treatment with melatonin prevents age-related
alterations in estrous cycles in mice both in the LD and
LL groups. It is worthy to note that among surgically
blinded HER-2/neu mice the rate of irregular estrous
cycles was also less than that in the LD controls (Baturin
et al. 2004).
Lin et al. (1990) have show that light-at-night shortened menstrual cycle length in women with cycles of
33 days or longer at baseline. According to the report
of Chung et al. (2005), 60% of the nurses with regular
menstrual cycles and fixed night shifts had a menstrual
cycle length of less than 25 days. Around 70% of nurses
complained of occasional or frequent dysmenorrhea in
this study. There are limited evidence that women with
short menstrual cycles have increasing risk of breast
cancer whereas long cycles associated with reduced risk
(Harlow and Ephross 1995).
There are data on the decrease in the level of dopamine
and noradrenalin in the hypothalamus of rats exposed to
the LL regimen (Ivanisevich-Milovanovic et al. 1995). The
level of folliculostimulating hormone (FSH) is increases
and the level of luteinizing hormone (LH) is decreased in
the pituitary of rats maintained at the LL regimen.
The decrease of tolerance to glucose and of the
sensitivity to insulin has been observed in rats with the
persistent-estrus (Anisimov 1987). We have found that
the exposure to the LL regimen leads to the increase of
the threshold of sensitivity of the hypothalamus to the
feedback inhibition by estrogens in female rats (Dilman
and Anisimov 1979). This mechanism is a key mechanism
in the aging of reproductive system in female rats as well
38
as in women (Dilman and Anismov 1979; Dilman 1994;

Rossmanith, 1996; Wise et al. 2005). There are data on
the decrease in the concentration of estrogen receptors in
mammary epithelium in rats exposed to the LL regimen
(Sechardi et al. 1992).
Thus, exposure to light-at-night leads to anovulation
and acceleration of age-related switching-off of reproductive function in rodents and dysmenorrea in women.
It is worthy to note that the exposure to constant
light increases lipid peroxidation in animal tissues
and decreases their total antioxidative and superoxide
dismutase activity, whereas an administration of
melatonin caused a decrease in lipid peroxidation, especially in the brain (Benot et al. 1998; Albarran et al 2001;
Baydas et al 2001; Ilyukha et al. 2005). These data are in
agreement with the free radical theory of aging (Harman
1994).
Shift work and cancer: epidemiological

evidence
The number of shift workers has increased in some
branches of industry, especially manufacturing. The total
number of night shift and other types of shft workers
is 20% in the United States (Monk 2000) and ranged
from 15 to 20% of the total workforce in most European
Community countries (Tenkane et al. 1997). Prominent
health problems among shift workers include sleep
disorders, gastrointestinal diseases, increased incidence
of cardiovascular diseases, metabolic disorders, intolerance to glucose, and possibly, an increase in late-onset
diabetes (Steenland and Fine 1996; Tenkane et al. 1997;
Rajaratnam and Arendt 2001; Di Lorenzo et al. 2003; Ha
and Park 2005). It was shown that obesity, high triglicerides and low concentration of high-density lipoprotein
(HDL) cholesterol appear to cluster together more
often in shift workers than in day workers (Knutsson
and Boggild 2000). On the other hand, there is strong
evidence showing that the metabolic syndrome, which
is composed of obesity, high triglicerides and low HDL
cholesterol level, hypertension, low fibrinolytic activity
and often impaired glucose tolerance, is a risk factor not
only for cardiovascular disease, but also for cancer (Dilman 1994).
Taylor and Pocock (1972) have reported an increase
in number of death from all neoplasms in shift workers
which had employed for not less that 10 years in period
between 1956 and 1968 as compared with day workers. A
large case-control study (over 7000 cases and 7000 population controls) have shown that night-work occupation
singificantly increases the risk of breast cancer in women
age 30 to 54 years in Denmark (Hansen, 2001). The overall
estimate of the odds ratio (OR) was 1.5 (95% confidence
interval (CI) = 1.31.7). The largest job entailing work
at night was restaurant waiter (300 cases) with the same
odds ratio estimate of 1.5 (CI=1.2 1.7). In another nightwork occupation group of 54 flight attendants an odds
ratio was 1.9 (CI=1.23.0). The similar estimation was
reported for a cohort study on breast cancer risk in flight
attendants in Finland (1.9; CI=1.12.2) (Pukkala et al.

1995). Compared to the general population, female breast
cancer incidence was over 30% higher than expected, and
malignant melanoma incidence was roughly twice that
expected in California flight attendants (Reunolds et al.
2002). In recent case-control study, was received no clear
evidence that occupation factors affected breast cancer
risk among Finnish flight attendants (Kojo et al. 2005).
Davis et al. (2001) reported the results of a case-control study of women age 20 to 74 years in the Seattle area.
There were 3 surrogates for exposure: shift work occupation, self-reported ambient light levels; in the bedroom at
night, and degree of nonpeak sleep (awake between 1 and
2 AM). There was a modest increased breast carcinoma
risk associated with shift work (OR= 1.6) and with nonpeak sleep (OR= 1.4). For self-reported ambient bedroom
light level, the odds ratio for the highest of 3 light-level
categories compared with the lowest was 1.4.
The report from Schernhammer et al. (2001) relied on
the 1988 Nurses Health Study questionaire, asking how
many years the nurse had worked rotating night shifts
in addition to days and evening shifts. Among nurses
who reported working 30 or more years of rotating
shifts, the relative risk of breast carcinomas was 1.36 (CI
= 1.041.78) compared with nurses who had no history
of rotating shift work. It was found reduced melatonin
and elevated estrogen levels in nurses with a long history of rotating night work (Schernhammer et al. 2004;
Schernhammer and Hankinson 2005). Megdal et al.
(2005) conducted a systemic review and meta-analysis
of observational studies on effect of night work on breast
cancer risk. Based on 13 studies, including seven studies
of airline cabin crew and six studies on other night shift
workers, the agregate estimate for all studies combined
was 1.48 (CI=1.36 1.61), with a similar significant
elevation of breast cancer risk among airline cabin crew
and female night workers.
Thynes et al. (1996) report an increased risk of colon
(1.3; 95% confidence interval =0.62.6) and rectum (1.8;
95% confidence interval = 0.73.9) cancer in their cohort
of female radio and telegraph workers. Schernhammer
et al. (2003) reviewed data from the Harvard Nurses
Health Study of 78,586 women. The authors found a
higher incidence of colorectal cancer as high as 35%
among shift workers who worked a rotating night shift
at least three nights per month for 15 or more years. The
elevated risk for malignancies of lymphatic system was
described among the female Iceland flight attendants
(Rafnsson et al. 2001). A slight increase in risk of prostate
cancer with increasing number of long distance flights in
Nordic airline pilots was reported as well (Pukkala et al.
2002). It is worthy to note that the mechanisms underlying the increased risk of cancer among night workers
and flight crew are not yet known. The possible impact
of disturbances in circadian rhythms and light-induced
decrease in the normal nocturnal secretion of melatonin
as the likely underlying biological mediator of increased
cancer risk are most acknowledged hypotheses (Fu and
Lee 2003; Pauley 2004; Stevens 2005).
Light-at-night and spontaneous

carcinogenesis in rodents
In 1964, Johle reported that the occurrence of spontaneous mammary tumors and death resulting from the
tumor growth were significantly accelerated in C3H-A
mice exposed to constant illumination. In suffered from
retinal degeneration C3H-HeJ mice the exposure to the
constant illumination delayed onset of mammary tumors
and elongated tumor growth.
The development of hyperplastic processes and the
mastopathy was registered in 7888% of outbred female
rats in 7 months after the start of the exposure to the LL
regimen (Smirnova 1966). First cases of the mastopathy
have been registered in 4.5 6 months after the start of
the exposure to the LL. The development of mammary
fibroadenomas and adenocarcinomas was registered
in the LL group. The cystic-adenomatous hyperplasia
and fibrous polyps of endometrium developed also in
the rats in the LL group. No cases of mastopathy were
registered in rats of the control (LD) group at the 7th
month after start of the observation. Follicular ovarian
cysts were obligatory observed in each rat with registered
mastopathy. The level of FSH was increased and the level
of LH decreased in the pituitary of rats in the LL group as
compared to the LD group (Smirnova 1966).
The survival of female LIO rats exposed to the LL
regimen from the age of 1 month was 54.3% and spontaneous tumor incidence of tumors was 30% at the age
of 18 months as compared with 86% of survivors and
16% of tumor-bearing rats in rats maintained at the LD
regimen (Vinogradova and Shevchenko, 2005).
The exposure to the LL regimen failed to change the
incidence of spontaneous mammary adenocarcinoma
development, the size of mammary tumors, as well as
the incidence and size of lung metastases in transgenic
HER-2/neu female mice. However, the number of tumors
per mouse was significantly increased in the LL group as
compared to the LD group. The number of mice bearing
4 and more tumors was higher in the LL group than in
the LD group, whereas the number of mice bearing 1 to
3 tumors was lower in the LL group in comparison with
the LD group (Baturin et al. 2001). It is worthy of note
that the effect of the LL regimen was proportional to the
intensity of the light exposure.
Female BDII/Han rats showed extremely high (up
to 90%) incidence of the spontaneous development of
endometrial adenocarcinomas. The exposure to the LL
regimen started at the age of 30 days was followed by
significant shortening of animals life span, due to acceleration of tumorigenesis (Bartsch and Bartsch 1999).
However, the exposure to the LL started at the age of 50
days was not effective.
In our experiments the effect of LL conditions on
the development of spontaneous tumors in female CBA
mice was investigated (Anisimov et al. 2004). Fifty female
CBA mice starting from the age of 2 months were kept
under standard LD and 50 CBA mice of similar age were
kept under LL (2500 lux). Exposure to the LL regimen
39
decreased food consumption but did not influence body

weight, significantly accelerated age-related disturbances
in estrous function, and was followed by a significant
increase in spontaneous tumor incidence in female
CBA mice. Tumor incidence as well as the number of
total or malignant tumors was significantly increased
in the LL group compared to the LD group (p<0.001).
The incidence of lung adenocarcinomas, leukemias and
hepatocarcinomas was 7/50; 6/50 and 4/50 in the LL
group and 1/50; 0/50 and 0/50 in the LD group. Mice
from the LL groups had shorter life spans then those
from the LD group. The data demonstrated that exposure
to constant illumination was followed by increase in the
incidence of spontaneous lung carcinomas, leukemia and
hepatocarcinoma in female CBA mice.
Thus, exposure to continuous illumination increases
incidence of mammary and endometrial adenocarcinomas in rats and leukemia, lung and liver carcinoma in
mice.
Light-at-night and chemically-induced

carcinogenesis
Khaetsky (1964,1965) firstly reported the effect of
exposure to LL regimen on DMBA-induced mammary
carcinogenesis in outbred rats. Female rats were kept at
LD regimen or at the LL regimen during 7 weeks and
then were exposed to 5 weekly intravenous injections of
DMBA in a single dose 1.5 mg/rat. Mammary tumors
developed in 40% LD and in 29% LL rats. Granulesa-cell
ovarian tumors developed in 24% LL rats, but not in the
LD group. In another set of experiments female rats were
administered intravenously with DMBA and in 4 weeks
after the last injection of the carcinogen were exposed
to LL. In this condition the significant stimulation of
mammary carcinogenesis has been observed: the number of mammary carcinomas per rat as well as their rate
of growth was increased whereas the latent period was
reduced as compared with the LD group.
A single intragastric administration of 50 mg DMBA
to Sprague-Dawley rats at the age of 50 days induced
mammary carcinomas, whereas the same dose of the
carcinogen given to rats exposed to the LL from the age
of 43 days was followed by the development secreting
mammary fibroadenomas (Hamilton and Sneddon 1968;
Hamilton, 1969). Ovaries of these rats were very susceptible to carcinogenic effect of DMBA and the increased
conversion of androstendione into estradiol-17 was
observed in them as well (Bell et al. 1968; Smyth et al.
1968).
The incidence of mammary carcinomas in rats
exposed to oral dose 20 mg DMBA at the age of 55 days
was 60% at the LD regimen and 95% when animals were
kept at the LL regimen from the birth (Kothari, 1988).
The number of the tumors per tumor-bearing rats was
2.26 and 1.13, and a tumor latency 60 3.2 days and 94
8.3 days, in the LL and the LD groups, respectively, p
< 0.001. Administration of melatonin inhibited development of DMBA-induced tumors in both groups.
40
Virgin female Sprague-Dawley rats were kept at the LL

or at the DD regimens and were given with a single dose
of DMBA (20 mg/rat) (Jull 1966). In the LL group the
vaginal smears revealed a persistent estrus syndrome. In
6 months, progressively growing mammary carcinomas
developed in 82% of rats in the LL group and in 87% of
rats in the DD group. Additionally, 42% of the LL rats
developed fibroadenomas of mammary gland whereas
only 3% of the DD rats developed these tumors.
The incidence of DMBA-induced mammary adenocarcinoma was 95% in female Hotlzman rats exposed
to LL regimen from the birth in contrast to that (60%)
observed in control animals maintained on a light/dark
(10/14 h) schedule (Kothari et al. 1982). The latency
period of tumor appearance in the LL group was found
to be significantly shorter than that seen in the LD group.
Shah et al. (1984) and Mhatre et al. (1984) exposed the
female Holtzman rats to LL from before birth, through
the length of the study. They reported that LL regimen
increased DMBA-induced carcinogenesis in mammary
gland of rats.
In our experiments (Anisimov et al. 1994) outbred
Wistar-derived female rats were kept at the LD or the
LL regimen from the age of 1 month. Starting in 2 weeks
after this (at the age 45 days) rats of both groups were
exposed to 3 weekly intravenous injections of NMU at
a single dose of 50 mg/kg. The experiment was finished
in 15 months after a start. Administration of NMU to
the LD rats was followed by development of mammary
adenocarcinomas in 55% of rats. The constant light
exposure significantly promoted mammary carcinogenesis increasing the incidence and decreasing the latent
period of development of mammary carcinomas. Rats
exposed to the LL had much elevated night serum level
of prolactin and decreased level of melatonin as compared with the LD rats. Our data are in agreement with
observations on promoting effect of the constant light on
mammary carcinogenesis induced by DMBA (for review
see Brainard et al. 1999; Blask, 2001).
Female Sprague-Dawley rats were given a single
intragastric dose of DMBA (20 mg) at the age of 55 days
and thereafter kept under LD or LL regimens (Cos et al.
2005). The animals exposed to LL showed significantly
higher rates of tumor growth than animals under LD
photoperiod. The night excretion of the melatonin
metabolite 6-sulfatoxymelatonin under LL regimen was
significantly decreased as compared with LD control rats.
It is important that similar results were observed also in
rats exposed to constant dim light (0.21 lx) during darkness or to short (30 min) applying light at the half-way
throughout the period of darkness (Cos et al. 2005).
There are two studies failed to observe promotion
effect of LL regimen on mammary carcinogenesis.
Anderson et al. (2000) kept Sprague-Dawley female rats
at LL conditions since the age of 26 day and administered
8 mg of DMBA orally at the age of 52 days. The incidence
and multiplicity of mammary adenocarcinomas were
decreased in LL as compared to the LD group. Travlos
et al. (2001) have shown no effect on the development
NMU-induced mammary tumors in female Fischer 344

rats exposed at night to intermittent light exposure, which
effectively suppressed nocturnal melatonin level. It is
worthy of note that in this experiment the pinealectomy
also was failed to promote DMBA-induced mammary
carcinogenesis. The reasons of these contradictions are
still unclear.
The hypothesis that light-induced circadian clock
suppression exerts a promoting effect on liver carcinogenesis was investigated in rats (van der Heiligenberg et
al. 1999). Male Wistar rats were given diethylnitrosamine
(DEN, 10 mg/kg/day p.o.) for 6 weeks and were randomized into 3 groups. Rats from group 1 received DEN only.
Rats from group 2 also received phenobarbital (pheno,
30 mg/rat/day p.o.) for 4 weeks as a promoting agent and
rats from group 3 were exposed to LL. Three months after
starting DEN treatment, urinary 6-sulfatoxymelatonin
(MT6s) excretion, a marker of circadian clock function,
had lost its circadian rhythmicity in the LL group, with a
4-fold lower 24 h mean than that found in the LDpheno
and LD groups. Laparotomy was then performed. The
proportion of rats with macroscopic nodules on liver
surface was 72% (LD group), 89% (LDpheno group) and
95% (LL group) (p from 2 = 0.1). Nodules were more
numerous and larger both in the LL group and in the
LDpheno one as compared to the LD group (p from 2
<0.05). All the rats died with hepatocellular carcinomas,
with a median survival of 5 months, similar in all 3
groups. Exposure to LL produced a 4-fold decrease in
urinary 6-sulfatoxymelatonin concentration, which
reflected the so called functional pinealectomy. In addition , light-induced circadian clock suppression exerted a
promoting effect similar to that caused by phenobarbital
in this model, yet through different effects on circadian

system function (van der Heiligenberg et al. 1999).
In our experiment the effect of LL regimen on transplacental carcinogenesis has been studied (Beniashvili et
al. 2000). Pregnant females were randomly subdivided
into three groups (24 rats per group) and kept at the LD
(group 1) or at the LL (24 h a day, group 2) or at the continuous darkness (group 3). N-nitrosoethylurea (NEU)
has been injected into the tail vein of all rats (80 mg/kg)
on the 1819th day of the pregnancy. After the delivery
the lacting dams and their progeny during the lactation
period (1 month after delivery) were kept also at the
three different light/dark regimens. Then all offspring
from each group was kept at the LD regimen, males and
females separately, and were observed until natural death.
The exposure to constant light significantly promoted
the transplacental carcinogenesis. The incidence of total
tumors, tumors of both a peripheral nervous system and
kidney was 2.6; 2.5 and 8.5 times higher, and survival
significantly shorter, correspondingly, in rats from the
group 2 exposed to the LL regimen as compared to the
group 1 (LD) (P<0.05). Thus, our data firstly have shown
the promoting effect of LL regimen on the realization
of the transplacental carcinogenesis induced by NEU in
rats (Beniashvili et al. 2000).
Panchenko (2005) observed a significant increase
of multiplicity of adenocarcinomas in ascending and
descending colon of rats exposed to 1,2-dimethylhydrazine (DMH) and the LL as compared to rats treated with
DMH and maintained at LD conditions.
Thus, exposition to the LL regimen has a promoting
effect on chemically induced carcinogenesis in rodents
(Table 2). It worthy of notes that surgical pinealectomy
Table 2. Reports on the acceleration of tumor development in rodents exposed to constant illumination
Species
Strain
Carcinogen
Tumor site and type
References
Mouse
C3H-A
Spontaneous
Mammary adenocarcinoma
Johle (1964)
CBA
Spontaneous
Anisimov et al. (2004)
FVB/N
HER-2/neu*
Lung adenocarcinoma;
Leukemia; hepatocarcinoma
Baturin et al. (2001)
Outbred
Spontaneous
BDII/Han
Spontaneous
Mammary adenocarcinoma and fibroadenoma;

fibrous polyps of endometrium
Endometrial adenocarcinoma
Smirnova (1966);
Lazarev et al. (1976)
Bartsch et al. (1999)
LIO
Spontaneous
Outbred
DMBA
Vinogradova and Shevchenko

(2005)
Khaetsky (1964,1965)
Sprague-Dawley DMBA

fibrous polyps of endometrium
Mammary adenocarcinoma;
granulesa-cell ovarian tumors
ovarian tumors
Holtzman
DMBA
Wistar
NMU
Kotahri et al. (1982); Kothari

(1987)
Wistar
DENA
Hepatocellular carcinoma
Van der Heiligenberg et al. (1999)
Wistar
NEU trans-placentally Nervous system tumors, kidney mesenchymal

tumors
Rat
Sprague-Dawley DMBA
Hamilton (1979); Jull (1966)

Kothari (1988); Cos et al. (2005)
Beniashvili et al. (2000)
* Transgenic HER-2/neu mice.

41
or cervical ganglionectomy also inhibits DMBA-induced

mammary carcinogenesis in rats (Aubert et al. 1980;
Shah et al. 1984; Tamarkin et al. 1981).
Light-at-night and growth of transplanable

tumors
The exposure to LL regimen (300 lux or 0.2 lux)
reduced nocturnal melatonin levels and increased the
growth rate of transplantable hepatoma 7288CTC cells
in rats (Dauchy et al. 1997,1999). When darkness was
interrupted by 300 lux of constant white LL, rats with
transplanted human MCF-7 breast carcinoma xenografts
had lower nocturnal melatonin, and grew faster than rats
kept at a normal day-night environment (LD) (Blask et
al. 2003). Alternating the photoperiod of LD 14:10 and
DL 10:14 every 3 days in Ehrlich carcinoma or sarcoma180 inoculated mice was followed by the reduction of
survival time, acceleration of tumor growth and depression of the immune system as compared with animals
kept a constant photoperiod of LD 12:12 of LD 14:10 (Li
and Xu 1997).
Eect of light deprivation on carcinogenesis

In a series of experiments, Kuralasov (1979, 1990)
studied effect of light deprivation on growth and
development of transplantable and DMBA-induced
mammary tumors. Animals were kept in dark room (0
to 0.5 lux/cm2) (DD) or under standard light-dark regimen (LD). The trasplantability of rat RMK-1 mammary
carcinoma was 89.5% in the LD and only 58.6% in DD
rats (p < 0,05). The mean doubling time of the tumor size
was 82.3 hours in the LD group and 138 hours in the DD
group. Administration of DMBA (2 mg x 4, i.v. weekly)
induced mammary adenocarcinomas in 49% of the LD
rats and in 5% of the DD rats. Number of tumors per
tumor-bearing rat was 3.15 and 1.01 and latent period
was 91 6.5 day and 135 10.5 days in the LD and in the
DD group, respectively. Survival of tumor-bearing rats
in the DD group was 54.7% longer than that in the LD
group. The exposure to the DD regimen was followed by
the decrease in serum levels of FSH, estradiol-17 and
11-oxycorticosteroids and by the decrease in 131I uptake
by thyroid gland in comparison to the LD rats (Kuralasov
1990).
Administration of synestrol (0.2 mg/day) inhibited the
growth of transplantable RMK-1 mammary carcinoma
by 30.7% in the LD rats whereas by 88% in the DD rats
(Kuralasov 1979). In the last group 36% of all tumors
totally regressed, however no cases of total regression of
the tumor were observed in the LD group. The exposure
to the DD regimen potentiated the anti-tumor effect
of some cytostatics and anti-cancer drugs (tamoxifen,
androgens, tio-TEPA, cyclophosphamide, CMF, tioTEPA+synestrol) (Kuralasov 1990).
This approach has been used for treatment of breast
cancer patients (T2-4 N2-3 M0) (Kuralasov 1990). There
are 138 patients under observation. Some of them (54
42
patients) were treated with polychemotherapy (modified

Coopers protocol + hormonotherapy). Forty-six patients
were exposed to radiotherapy and 38 to radiotherapy
+ chemotherapy. Premenopausal breast cancer patients
revealed the decrease in the serum level of estradiol-17
(by 7-fold) and in the level of FSH, whereas the level of
testosterone and progesterone increased as compared with
the indices of the hormones in the same patients before
the exposure to the constant dark regimen. In postmenopausal women, these changes were less expressed than
that in premenopausal ones. The dexamethasone test was
negative in 62.5% of breast cancer patients kept in standard light/dark regimen and only in 9.5% of the patients
kept in the darkness. Full or partial (> 50%) regression of
breast carcinoma has been observed in 32.4% of patients
of the control group and 78.6% in the group kept in darkness. The index of operability was 36% and 88% in the
LD and DD groups, respectively (Kuralasov 1990).
Pinealectomy abolished the effects of the light deprivation on growth and function of hormone-dependent
tissues of reproductive system (Arendt 1995). Blask et
al. (1988) administered DMBA into Sprague-Dawley
rats and 3 weeks later rats were surgically blinded. The
progressive tumor growth revealed 68% blinded and
88% of control rats (p <0.05). Pinealectomy abolished
the inhibitory effect of blinding on mammary carcinoma
growth. Forty six percent of rats bearing DMBA-induced
mammary tumors subjected to the surgical blinding and
to an excision of olfactory bulbs revealed regression of
mammary tumors whereas in control group no such cases
have been observed (Blask, 1984). If rats were subjected
to the same surgery during the stage of initiation of the
carcinogenesis, the inhibitory effect was much more
expressed. Pinealectomy abolished the positive effect
of blinding and anosmia (Blask, 1984). Similar result
were obtained by Sanchez-Barcelo et al. (1988) in rats
exposed to blinding plus anosmya before administration
of DMBA or to this surgery after tumor development (1
cm in diameter).
In our experiments (Anisimov et al. 1994) female rats
were kept at the LD or DD regimens from the age of 1
month. Two weeks later rats were exposed to 3 weekly
injections of NMU at a single dose 50 mg/kg. The
exposure to the DD regimen practically totally inhibited
mammary carcinogenesis. There was only one mammary
adenocarcinoma and 5 fibroadenomas developed among
50 female rats exposed to NMU at DD regimen, whereas
7 cases of mammary adenocarcinomas and 6 cases of
fribroadenomas were observed among 30 exposed to
NMU rats maintained at the LD regimen.
In another experiment, female rats were subjected
to light deprivation by surgical optical enucleation at
the age of 1 month and exposed to a single i.v. injection
of 50 mg/kg NMU at the age of 55 days. The incidence
of NMU-induced malignant tumors in blind rats was
significantly decreased (38% vs. 78% in the sighted
controls), with latency being longer as compared with
controls (Zhukova and Anisimov 1994). The frequency
of mammary carcinoma, leukemia and adenoma of the

Table 3. Light deprivation and breast cancer risk in women
Visual impairment rate
Breast cancer risk
Total blindness
0.82 (0.47 1.34)
Partly blindness
1.06 (0.92 1.21)
Moderate low vision
1.05 (0.84 1.30)
Severe low vision
0.96 (0.59 1.46)
Profound low vision
0.79 (0.44-1.29)
References
Feyting et al. (1998)
Verkasalo et al. (1999)
Near-total blindness
0.66 (0.24-1.44)
Total blindness
0.47 (0.01-2.63)
Total blindness
0.57 (0.35 0.92)
Hahn (1998)
Total blindness
0.64 (0.21-1.49)
Kliukiene et al. (2001)
Note: In brackets are 0.95% confidential intervals.
pituitary and thyroid gland in blind rats was significantly

lower in blind females. Blindness failed to affect the
growth of transplantable mammary carcinoma-755 in
C57BL mice and Pliss lymphosarcoma in rats, however,
the growth of Lewis lung carcinoma (LLC) in blind
C57Bl mice and Walker-256 carcinoma in blind rats was
inhibited as compared with sighted controls. The mitotic
index of LLC tumor as well as Walker-256 carcinoma
was reduced by 36.9% and 59.4% in blind animals as
compared to sighted controls (Anisimov et al. 1995).
Twenty five female HER-2/neu transgenic mice aged
2 months, were surgically deprived of lighting; 30 intact
transgenic mice, kept under standard conditions, were in
control. The light deprivation was followed by decreasing
of food intake, decreased body weight and delayed ageassociated estrous disorders, as compared with control.
The mean survival rate among experimental mice was
higher by 13.5% than in control (p<0.001). The mean life
span among the last surviving 10% of the experimental
mice was longer than in control by 21.5% while maximum life span by 21%. Although the number of tumor
bearers under 7 months in the light deprivation group
was twice less than that in the control (p<0.05), they had
almost equalized by the end of the experiment (Baturin
et al. 2004).
The exposure to the DD regimen during the pregnancy and the lactation period significantly inhibited
the transplacental carcinogenesis in the offspring of rats
treated with NEU (Beniashvili et al. 2000). The incidence
of total tumors, tumors of a peripheral nervous system
was by 2.4 and 2.7 times less, and survival was longer,
respectively, in exposed to the darkness rats as compared
to the group LD.
Panchenko (2005) exposed male LIO rats to 5 weekly
s.c injection of DMH and maintained animals at LD or
DD regimens and observed the decrease in the incidence
and the multiplicity of colon adenocarcinoma development under DD regimen as compared to LD regimen.
Thus, experiments with rodents give evidences of
inhibitory effect of light deprivation on spontaneous and
induced carcinogenesis.
Cancer risk in blind humans

There are some epidemiological data supporting
these findings. Hahn (1991) analyzed over 100,000
hospital discharge records published by the National
Hospital Discharge Survey. Risk of breast carcinoma
was twice less in primary blinded women as compared
with sighted ones. In Sweden cohort study, Feychtyng et
al. (1998) found risk of cancer to be lower among blind
persons, and this reduced risk was also held true specifically for breast cancer in women. Pukkala et al. (1999)
and then Verkasalo et al. (1999) observed the decrease
of breast cancer risk in women with visual impairment
(categorized from moderate low vision to total blindness)
in Finland. Breast cancer was investigated in a cohort of
15412 Norwegian visually impaired women (Kliukiene
et al. 2001). The risk among totally blind women was
0.64 (95% confidence interval (CI) = + 0.211.49) and
for those who became blind before age of 65, the SIR was
0.51 (95% CI = 0.111.49). Kerenyi (2002) reported that
workers who, every day, worked for 67 hours in darkness, producing films at the Canadian Kodak factory,
had a reduced risk of breast cancer and of malignant
melanoma compared with workers in administration
or other manufacturing areas. The relative risk of breast
cancer was significantly decreased among the photo
laboratory workers compared with other employees (OR
= 0.4; CI = 0.2 to 0.9) (Hansen 2002). Thus, blindness
decreases the cancer risk in humans (Table 3).
Eect of genetic or surgical disruption of

circadian rhythm on tumor growth
Mice with germinal Per2 null mutation, displayed
disrupted circadian clock function and displayed an
increased susceptibility to develop lymphoma following exposure to -radiation (Fu et al. 2002). It was
shown also that these mPer2m/m mice are more prone
to spontaneous tumorigenesis as compared with wildtype controls. The increased incidence of lymphomas
and higher mortality rate were ascribed in part to the
elevated c-Myc and in part to a general dysregulation of
ecll cycle genes as a result of clock disruption (Fu et al.,
43
2002). In Cry1-/-Cry2-/- mice, in contrast to Per2 mutant

mice, -irradiation did not influence both the mortality
and spontaneous lymphoma incidence as compared to
irradiated wild type control mice (Gauger and Sancar
2005). The Cry1-/-Cry2-/- mutant fibroblasts were indistinguishable from the wild-type controls with respect to
their sensitivity to ionizing irradiation and UV radiationinduced DNA damage checkpoint response. The authors
suggest that disruption of the circadian clock in itself not
compromise mammalian DNA repair and DNA damage
checkpoints and does not predispose Cry1-/-Cry2-/- mice
to spontaneous and ionizing radiation-induced cancers
(Gauger and Sancar 2005). It seems there is not a great
contradiction between the results of these two studies. The Period (Per1-3) genes encode individualized
PER-ARNT-SIm (PAS) domain proteins that function
in the nucleus (Reppert and Weaver 2002). Analysis of
the rhythms in mRNA levels of individual clock genes
showed that only the increase in the mPer1 mRNA level
is temporally linked to an up-regulated norepinephrine
release from sympathetic pinealopetal nerves and mPer1
is the only clock gene, which is cyclic AMP-inducible,
thus playing a central role in clockwork oscillation in the
mouse pineal gland (Karolczak et al. 2004). Thus, difference in the combination of knockouted pineal and SCN
clock genes might leads to some variations in the effects
on cell cycle checkpoints and apoptosis.
It is worthy to note that homozygous Clock mutant mice
have displayed hyperphagy and obesity, and developed a
metabolic syndrome of hyperleptinemia, hyperlipidemia,
hepatic steatosis, hyperglycemia, and hypoinsulinemia
(Turek et al. 2005). Clock mutant females have extended,
irregular estrous cycles, lack a coordinated lutinizing
hormone surge on the day of proestrus and a decrease
of fertility (Miller et al 2004). There are reports that the
clock geners Clok/Bmal1 are directly associated with the
circadian expression of peroxisome proliferator-activated
receptor (PPAR) response element-controlled target
genes, which involved in lipid metabolism and oxidative
stress (Inoue et al. 2005).
The Glasgow osteosarcoma (GOS) or pancreatic
adenocarcinoma P03 were transplanted into intact male
B6DF1 mice or mice with the SCN destroyed by bilateral
electrolytic lesions (Filipski et al. 2002, 2003). Tumor
growth was faster in lesioned than in sham operated mice
bearing either GOS or P03 tumors. SCN destruction
caused a major diruption of circadian temporal structure
of the corticosterone and lymphocyte count rhythm in
these mice.
The exposure to chronic jet lag accelerated growth of
Glasgow osteosarcoma rate mostly between the 8th and
11th day after tumor inoculation (Filipski et al. 2004,
2005). The authors failed to observe and significant effect
of exposure to LL or DD regimens on tumor growth or
survival of tumor-bearing mice. Both of these conditions
altered the period length of the circadian rhythms in
activity and body temperature, which maintained their
physiologic phase relations, however. It have been shown
also that chronic jet lag severely altered the circadian
44
rhythms in the clock protein mPER1 expression in SCN,

and mRNA expression of clock genes mPer2 and mReverb in liver and tumor in GOS-bearing mice (Filipski et
al. 2004, 2005). The integrity of circadian coordination
has been known to persist in mice exposed to constant
light or constant darkness (Haus et al. 1967). However, in
the experiments of Filipski et al. (2004, 2005) the effect
of LL and DD regimen on locomotor activity and body
temperature rhythms as well as on the expression of clock
genes was not studied. It was shown that the circadian
clock regulates angiogenesis (Koyanagi et al. 2003), that
can facilitate energy supply to the tumor. It is worth to
note that marked 24-hour activity rhythm was associated
with longer survival in patients with metastatic colorectal
cancer (Mormont et al. 2000).
It was shown recently that there are disturbances in
the expression of three period (PER) genes in most (<
95%) of the breast cancerous cell in comparison with the
nearby non-cancerous cells in women (Zhu et al., 2005).
This may result in the disruption of the control of the
normal circadian clock, thus benefiting the survival of
cancer cells and promoting carcinogenesis. Murine and
human data have indicated that tumors and tumor-bearing hosts may exhibit markedly altered circadian rhythms
(Mormont and Levi 2003; Canaple et al. 2003; Shephton
and Spiegel 2003; Reddy et al. 2005). We observed the
significant disturbances in circadian rhythms of serum
melatonin (Anisimov et al. 1999), of pinealocytes activity
(Sibarov et al. 2000) and hypothalamic suprachiasmatic
nuclei and preoptic area content of biogenic amines in
rats during colon carcinogenesis induced by 1,2-dimethylhydrazine in rats (Arutjunyan et al. 2001).
Currently, it is not clear whether mPer2 is unique in
its tumor suppressor attributes, or whether other clock
genes have similar anti-tumor function in vivo (Reddy
et al. 2005). The mechanism of this suppression is also
unclear but an important observation is that cancer
tissues express clock genes. Environmental and genetic
factors that damage systemic and/or local circadian
function may compromise temporal regulation of cell
division (Matsuo et al. 2003) and thereby promote tumor
progression (Fu and Lee 2003; Reddy et al. 2005).
Eect of melatonin on carcinogenesis

Administration of melatonin (50 or 100 g/rat daily)
was followed by normalization of the estrous function
and by the prevention of follicular ovarian cysts and
mammary hyperplastic processes and mastopathy in
rats kept during 8 month under the LL regimen. The
preventive effect of melatonin was proportional to it dose
(Lazarev et al. 1976).
Administration of melatonin to BDII/Han rats inhibited the development of endometrial adenocarcinomas,
but was less effective being started at the age 50 days and
was absolutely non-effective when was started at the age
of 6 months (Bartsch and Bartsch 1999). The evidence
of oncostatic action of melatonin on mammary tumor
growth was obtained both in in vitro and in vivo experi-
ments. MCF-7 human breast cancer cell line mostly used

as a model for study of melatonin effect in vitro (Cos
and Sanchez-Barcelo 1995, 2000, 2001). This cell lines
originated from the pleural effusion of women with
metastatic breast carcinoma, and contains both estrogen
and progesterone receptors. It was shown that a growth
of MCF-7 cells is estrogen dependent and estrogens
regulate the levels of some RNAs and proteins in them
(Cos and Sanchez-Barcelo 2001). The inhibitory effect
of melatonin on MCF-7 cells was firstly observed by
Blask and Hill (1986). A lot of experiments on effect of
melatonin on MCF-7 cell growth was reviewed recently
by Cos and Sanchez-Barcelo (1995,2001). It was shown
that melatonin, at physiological concentration in a culture medium, inhibits cell proliferation and invasiveness
of the cells, suppress mitotic activity of estradiol-17 and
EGF, thus blocks proliferation at stage G0/G1 of mitotic
cycle. Only those lines of MCF-7 and other breasts carcinoma cell lines which have estrogen receptors (T47D,
ZR75-1) have been shown susceptible to inhibitory effect
of melatonin (Cos and Sanchez-Barcelo 2000, 2001;
LHermite-Baleriaux and de Launoit 1992; Molis et al.
1993). Lemus-Wilson et al. (1995) observed inhibitory
effect of melatonin on proliferative effect of prolactin
and human growth hormone on MCF-7 cells. There are
suggestion that melatonin could suppress autocrine and
paracrine secretion of some growth factors (EGF, TGF-,
insulin, IGF-I and II (Haus et al. 2001).
Anisimov et al. (1973) has shown inhibitory effect of
melatonin on transplantable mammary carcinoma RSM
in female 3 mice. Melatonin was given subcutaneously in a daily dose of 50 g/mouse and 51% decrease
of tumor size have been observed.
According Hamilton and Sneddon (1968), morning
administration of melatonin to rats was followed by
the increase in the incidence of mammary carcinomas
induced by DMBA in female rats. However in a number
of subsequent experiments it was shown that the evening
treatment with melatonin inhibits DMBA-induced
mammary carcinogenesis (Aubert et al. 1980; Shah et al.
1984; Kothari 1987; Kothari et al. 1995, 1997; Blask et al.
1986; Subramanian and Kothari 1991). Melatonin also
attenuated the stimulating mammary carcinogenesis
effect of pinealectomy (Tamarkin ET al.1981). Another
mammary carcinogen, N-nitrosomethylurea (NMU) was
also used in experiments with melatonin. This model
has some advantages in comparison to DMBA-induced
carcinogenesis. In contrast to DMBA-induced mammary adenocarcinoma susceptible mostly to prolactin,
the growth of NMU-induced mammary carcinoma is
more depends on the levels of estrogens, that is more
relevant to human breast carcinoma (Welsch 1985). In
several studies it has been observed inhibitory effect of
melatonin on NMU-induced carcinogenesis in mammary gland of rats (Kothari et al. 1995; Blask et al. 1991;
Musatov et al. 1999). It is interesting that melatonin
failed reveal the dose-dependent inhibitory effect in this
model. The effect of melatonin was similar to those of
estrogen antagonist tamoxifen (Blask et al. 1991).
Subramanian and Kothari (1991) reported a suppressive effect of melatonin on the development of
spontaneous mammary carcinomas in female C3H/Jax
mice treated from the age of 3 weeks until the age of
12 months. In female CBA mice, administration of
melatonin with night drinking water from the age of
6 months failed change the incidence of spontaneous
mammary adenocarcinomas (Anisimov et al. 2001).
The oncostatic effects of melatonin on the mammary
gland have been studied in transgenic mice carrying the
N-ras proto-oncogene under the control of the MMTVLTR (Mediavilla et al. 1997). Female (4-week-old) virgin
mice with positive transgenic pedigrees were injected
with melatonin or vehicle late in the evening. After 5
months of treatment, animals were sacrificed and the
mammary glands were dissected for whole mounts,
histology, and immunohistochemical analysis with a
mouse monoclonal antibody specific for N-ras protein.
Mammary glands of control transgenic mice showed different densities of hyperplastic alveolar nodules (HANs)
consisting primarily of dysplastic epithelial cells with
nuclear atypia and prominent nucleoli. The epithelial
cells of HANs showed a high expression of N-ras while
no immunostaining was detected in the unaffected
mammary parenchyma. Only one (10%) of the control
transgenic mice presented an infiltrating ductal carcinoma with the neoplastic cells overexpressing N-ras
protein. The mammary glands of melatonin treated mice
had a lower density of HANs, absence of epithelial dysplastic cells, and weak immunostaining of N-ras protein
in comparison to the vehicle-treated group. None of the
melatonin treated animals developed mammary carcinomas during the observation period. The lymph nodes of
the inguinal mammary glands of all the vehicle-treated
transgenic mice presented hyperplasia and two animals
even had lymphomas, whereas in melatonin-treated animals there was less hyperplasia (two cases were atrophic)
and a lack of lymphomas. Authors conclude that in the
mammary glands of -LTR/N-ras transgenic female virgin
mice, melatonin reduces the incidence of HANs and the
expression of N-ras protein in focal hyperplastic lesions,
completely prevents the development of epithelial cell
atypia and mammary adenocarcinomas, and also reduces
the hyperplasia of the mammary lymphoid tissue and
prevents the development of lymphomas.
Four-week-old TG.NK female mice with MMTV/cneu oncogene were given melatonin at 50, 100 or 200
mg/kg dissolved in corn oil (Rao et al. 2000). Melatonin
delayed the appearance of palpable mammary tumors
and the growth of tumors with a dose-related statistically
significant negative trend for the incidence of tumors.
The administration of melatonin during the nighttime significantly decreased the incidence of mammary
adenocarcinomas in FVB/N female mice transgenic for
oncogene HER-2/neu in the LD group and, in a lower
manner, in the LL group (Baturin et al. 2001). The mean
number of tumors per tumor-bearing mouse was not
changed by the melatonin treatment in both light regimens. However, at the LL regimen the number of mice
45
Table 4. Summary on anti-carcinogenic effect of melatonin in rodents
Target tissue
Tumor type
Strain
Carcinogen
References
Adenocarcinoma
SHR
C3H/Jax
Spontaneous
MMTV
ras-MMTV-LTR
MMTV/c-neu
HER-2/neu
DMBA
Anisimov et al. (2003b)

Subramanian and Kothari (1991)
Mediavilla et al. (1997)
Rao et al. (2000)
Baturin et al. (2001); Anisimov et al. (2003a)
Benzo[a]pyrene
+ croton oil
Kumar and Das (2000)
Mice
Mammary gland
Uterine cervix and Squamous-cell papilloma

vagina
and carcinoma
Skin
Papilloma
Subcutaneous
tissue
Lung
Sarcoma
TG.NK
FVB/N
CBA
Swiss
SHR
Adenoma
A/J
SHR
Mastopathy
Fibroadenoma and
adenocarcinoma
Adenocarcinoma
Outbred
LIO
Vesnushkin et al. (2005)

Benzo[a]pyrene
Urethane
Weisburger et al. (2003)

Vesnushkin et al. (2005a)
Rats
Mammary gland
Endometrium
Colon
Adenocarcinoma
Adenocarcinoma
Foci of aberrant crypts
Sprague-Dawley, DMBA
Holzman
Sprague-Dawley;
LIO
Wistar:Han
BDII/Han
LIO
F344
bearing 4 and more tumors was reduced by melatonin

more significantly than that in mice kept at LD regimen.
Melatonin administration decreased the size of mammary adenocarcinomas and the incidence of lung
metastases at the LD regimen, but not at the LL regimen
as compared with the LD and LL groups not exposed to
melatonin, respectively. In order to evaluate whether the
decreased incidence of mammary tumors observed in
mice kept in standard light/dark regimen was due to an
effect of melatonin on mammary gland, we performed
RT-PCR analysis for HER-2/neu gene expression in the
mammary tumors from mice of the LD group. mRNA of
HER-2/neu gene was a greatly expressed in saline treated
mouse whereas it was significantly (2.5-fold) decreased
in animals chronically treated with melatonin (Baturin
et al. 2001).
Thus, treatment with melatonin inhibits spontaneous
and induced carcinogenesis in rodents (Table 4).
Forty patients with failed metastatic breast cancer
were randomly assigned to receive tamoxifen alone or
tamoxifen plus 20 mg of melatonin per os, at 8 p.m. At
1 year, 12 from 19 melatonin-treated patients were alive
(63.2%) compared to 5 from 21 patients treated with
tamoxifen alone (23.8%, p < 0.01) (Lissoni et al., 1995,
2001; Hrushesky, 2001).
46
Spontaneous
Spontaneous
NMU
Gamma-rays + DMBA
Spontaneous
DMH
Azoxymethane
Lazarev et al. (1976)

Vinogradova and Shevchenko (2005)
Aubert et al. (1980); Tamarkin et al. (1981);
Shah et al. (1984); Matre et al. (1984); Kothari
et al. (1985); Blask et al. (1986);
Kothari (1988); Lenoir et al. (2005);
Kubatka et al. (2002)
Blask et al. (1991); Musatov et al. (1999);
Kubatka et al. (2002); Melancon et al. (2005)
Mockova et al. (2000)
Bartsch and Bartsch (1999)
Anisimov et al. (1987, 2000)
Weisburger et al. (2003)
Mechanisms of anti-carcinogenic eects of

melatonin
In rats exposed to a single intragastric dose of DMBA
at the age of 51 days nocturnal plasma melatonin was
found to be significantly depressed both 2 and 7 days after
the carcinogen administration (37% and 31%, p <0.05),
whereas the main periferal metabolite of melatonin,
6-sulfatoxymelatonin (MT6s), did not differ compared
to controls, indicating an increased degradation of the
pineal hormone due to DMBA (Bartsch et al. 1990). Later
it was shown that the hepatic micorosomal monoxygenases of the cytochrome P450 system catalyzing the 6hydroxylation of melatonin are also enhanced by DMBA
treatment (Praast et al. 1995). Comprehensive review on
the melatonin level and rhythm in breast cancer patients
has been recently published by Bartsch et al. (2001). In
brief, nocturnal circulating melatonin is diminished in
patients with breast cancer. The most prominent depletion
is found among patients with advanced localized primary
tumors leading to a negative correlation between circulating melatonin level and tumor size. As it was reviewed
earlier, exogenous melatonin can prevent development
of mammary cancer. The mechanisms of the inhibitory
effect of melatonin on mammary carcinogenesis include

Table 5. Mechanisms involved in inhibitory effect of melatonin on mammary tumor development
Parameters
Gonadotropins (FSH and LH) level
Prolactin level
Growth hormone, IGF-I
Insulin level
Estrogen level
Estrogen receptor expression
Aromatase activity in tumor tissue
Mutagenic effect of chemical carcinogens and irradiation
Clastogenic effect of chemical carcinogens
DNA adduct formation
Proliferative activity
Apoptosis
Angiogenesis (VEGF, vascular endothelial growth factor)
ROS formation
Antioxidative defence system
Linoleic acid uptake
Immune surveillance
Gene expresion of immunomodulating cytokines
Activity of telomerase
p53 and p21WAF1 expression
HER-2/neu expression
ras expression
Endothelin-1
Bcl-3 expression
the variety possibilities, discussed in several reviews

(Blask 2001; Vijayalaxmi et al. 2002; Reiter 2004). In the
Table 5 most important mechanisms are summarized.
It is clear that the majority of the listed factors in the
more or less degree might be involved in the inhibitory
effect of melatonin on the development of mammary
carcinoma.
Conclusion
Data reviewed show the important role of the pineal
gland in development of cancer. Inhibition of pineal
function with the pinealectomy or with exposure to
the constant light regimen stimulates carcinogenesis,
whereas light deprivation inhibits the carcinogenesis.
Epidemiological observations on increased risk of breast
and colon cancer in night shift workers, on the decreased
risk in blind women are in accordance with the results
of experiments in rodents. Treatment with pineal
indole hormone melatonin inhibits carcinogenesis in
pinealectomized rats or animals kept at the LD or the
LL regimens.
Acknowledgments
This article was supported in part by grant # NSh5054.2006.4 from the President of Russian Federation.
Effect

References
Reiter (1980)
Anisimov et al. (1994); Shah et al. (1984)
Rao et al. (2000)
Wolden-Hanson et al. (2000)
Hill et al. (2001)
Hill et al. (2001)
Cos et al., 2005
Musatov et al. (1998); Vijayalaxmi et al. (1998)
Musatov et al. (1998)
Reiter (2001)
Blask (2001)
Eck-Enriques et al. (2000)
Lissoni et al. (2001)
Reiter (2001)
Reiter (2001)
Blask et al. (2003)
Maestroni (2001)
Liu et al. (2001)
Leon-Blanco et al. (2003, 2004)
Mediavilla et al.(1999)
Baturine et al. (2001)
Mediavilla et al. (1997)
Kilic et al. (2004)
REFERENCES
Abarran MT. Lopez-Burillo S., Pablos MI, et al. 2001. Endogenous
rhythms of melatonin, total antioxidant status and superoxide
dismutase activity in several tissues of chick and their inhibition
by light. J Pineal Res 30:227233.
Anderson LE, Morris JE, Sasser LB, Stevens RG. 2000. Effect of constant light on DMBA mammary tumorigenesis in rats. Cancer
Lett 148:121126.
Anisimov SV, Popovic N. 2004. Genetic aspects of melatonin biology. Rev Neurosci 15: 209230.
Anisimov SV, Boheler KR, Anisimov VN. 2002. Microarray technology
in studying the effect of melatonin on gene expression in the
mouse heart. Dokl Biol Sci 383:9095.
Anisimov VN. 1971. Blastomogenesis in persistent-estrous rats. Vopr
Onkol 8:6775.
Anisimov VN. 1987. Carcinogenesis and Aging. Vol 2. Boca Raton:
CRC Press.
Anisimov VN. 2002. The light-dark regimen and cancer development. Neuroendocrinol Lett 23 (Suppl):2836.
Anisimov VN. 2003. The role of pineal gland in breast cancer development. Crit Rev Oncol Hematol 46:221234.
Anisimov VN, Morozov VG, Khavinson VKh, Dilman VM. 1973. Correlation of anti-tumor activity of pineal and hypothalamic extracts,
melatonin and sygetin in mouse transplantable mammary tumor. Vopr Onkol 10:99101.
Anisimov VN, Zhukova OV, Beniashvili DSh, Bilanishivili VG, Menabde MZ. 1994. Light deprivation, electromagnetic fields and
mammary carcinogenesis. Adv Pineal Res 7:229234.
Anisimov VN, Zhukova OV, Labunets IF, Bartsch H, Bartsch C. 1995.
The inhibitory effect of light deprivation on N-nitrosomethylurea-induced carcinogenesis and on the growth of transplanted
tumors in rodents: possible involvement of the pineal gland and
the immune system. Exp Oncol 17(1):4754.
47
Anisimov VN, Popovich IG, Zabezhinski MA. 1997. Melatonin and colon carcinogenesis: I. Inhibitory effects of melatonin on development of intestinal tumors induced by 1,2-dimethylhydrazine in
rats. Carcinogenesis 18:15491553.
Anisimov VN, Kvetnoy IM, Chumakova NK, Kvetnaya TV, Molotkov
AO, Pogudina NA, et al. 1999. Melatonin and colon carcinogenesis. II. Intestinal melatonin-containing cells and serum melatonin
levels in rats with 1,2-dimethylhydrazine-induced colon tumors.
Exp Toxicol Pathol 51:4752.
Anisimov VN, Zabezhinski MA, Popovich IG, Musatov SA, Andre V,
Godard F, Sichel F. 2000. Inhibitory effect of melatonin on 7,12
dimethylbenz[a]anthracene-induced carcinogenesis of the uterine cervix and vagina in mice and mutagenesis in vitro. Cancer
Lett 156:199205.
Anisimov VN, Zavarzina NY, Zabezhinski MA, Popovich IG, Zimina
OA, Shtylick AV, et al. 2001. Melatonin increases both life span
and tumor incidence in female CBA mice. J Gerontol Biol Sci 56A:
B311B323.
Anisimov VN, Alimova IN, Baturin DA, Popovich IG, Zabezhinski MA,
Manton KG, et al. 2003a. The effect of melatonin treatment regimen on mammary adenocarcinoma development in HER-2/neu
transgenic mice. Int J Cancer 103:300305.
Anisimov VN, Alimova IN, Baturin DA, Popovich IG, Zabezhinsri MA,
Rosenfeld SV, et al.2003b. Dose-dependent effect of melatonin
on life span and spontaneous tumor incidence in female SHR
mice. Exp Gerontol 38:449461.
Anisimov VN, Baturin DA, Popovich IG, Zabezhinski MA, Mantron KG,
Semenchenko AV, et al. 2004. Effect of exposure to light-at-night
on life span and spontaneous carcinogenesis in female CBA mice.
Int J Cancer 111:475479.
Anisimov VN, Ukraintseva SV, Yashin AI, 2005. Cancer in rodents:
does it tell us about cancer in humans? Nat Rev Cancer 5:807
819.
Arendt J. 1995 Melatonin and the Mammalian Pineal Gland. London:
Chapman & Hall.
Arendt J. 2005. Melatonin: characteristics, concerns, and prospects. J
Biol Rhythms 20: 291303.
Arutjunyan AV, Kerkeshko GO, Anisimov VN, Stepanov MG, Prokopenko VM, Pozdeev NV, et al. 2001. Disturbances of diurnal
rhythms of biogenic amines contents in hypothalamic nuclei as
an evidence of neurotropic effects of enterotropic carcinogen
1,2-dimethylhydrazyine. Neuroendocrinol Lett 22:229237.
Aschheim P. 1976. Aging in the hypothalamic-hypophyseal-ovarian
axis in the rat. In: Everitt AV, Burgess JA, eds. Springfield: Charles
C Tomas, pp. 376392.
Aubert C, Janiaud P, Lecalvez J. 1980. Effect of pinealectomy and
melatonin on mammary tumor growth in Sprague-Dawley
rats under different conditions of lighting. J Neural Transmiss
47:121130.
Barbacka-Surowiak G, Surowiak J, Stoklosowa S. 2003. The involvement of the suprahiasmatic nuclei in the regulation of estrous
cycles in rodents. Reproduct Biol 3:99129.
Barnes JW, Tischkau SA, Barnes JA, Mitchell JW, Burgoon PW, Hickok
JR, Gillette MU. 2003. Requirement of mammalian Timeless for
circadian rhythmicity. Science 302: 439442.
Bartsch C, Bartsch H, Gupta D. 1990. Pineal melatonin synthesis and
secretion during induction and growth of mammary cancer in female rats. In: Neuroendocrinology: New Froniters. Gupta D, Wollmann HA, Ranke MB, eds. London and Tubingen: Brain Research
Promotion, pp. 326332.
Bartsch C, Bartsch H. 1999. Effects of melatonin and constant light
on the development of spontaneous endometrial carcinomas in
aging BDII/Han rats appear to be exerted by modulatinf maturation of the reproductive system. Z Gerontol Geriatrie 32 (Suppl
2): II/5.
Bartsch H, Bartsch C, Mecke D. 2001. The modulation of melatonin
in tumor-bearing animals: underlying mechanisms and possible
significance for prognosis. In: Bartsch C, Bartsch H, Blask DE, Cardinali DP, Hrushesky WJM, Mecke D, eds. The Pineal Gland and
Cancer. Neuroimmunoendocrine Mechanisms in Malignancy.
Berlin: Springer, pp.197209.
Baturin DA, Alimova IN, Anisimov VN, Popovich IG, Zabezhinski MA,
Provinciali M, Mancini R, Franceschi C. 2001. Effect of light regime and melatonin on the development of spontaneous mammary tumors in HER-2/neu transgenic mice is related to a downNeuroendocrinology Letters Vol.27 Nos.12, Feb-Apr 2006
48
regulation of HER-2/neu gene expression. Neuroendocr Lett

22:439445.
Baturin DA, Alimova IN, Popovich IG, Zabezhinskii MA, Semenchenko
AV, Yashin AI, et al. 2004. Effect of light deprivation on homeostasis, life span and development of spontaneous tumors in HER-2/
neu transgenic mice. Vopr Onkol 50:332338.
Baydas G, Ercel E, Canatan H, Donder E, Akyol A. 2001. Effect of
melatonin on oxidative status of rat brain, liver and kidney tissues under constant light exposure. Cell Biochem Funct 19:37
41.
Bell JA, Sneddon A, Hamilton T. 1968. Influence of light and 9,10dimethylbenz(a) anthracene on rat ovarian steroidogenesis: neutral steroids. Biochem J 110:29p30p.
Bell-Pedersen D, Cassone VM, Earnest DJ, Golden SS, Hardin PE,
Thomas TL, Zoran MJ. 2005. Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat Rev Genet Advance
online publ. 10 June 2005; doi:10.1038/nrd1633.
Beniashvili DS, Benjamin S, Baturin DA, Anisimov VN. 2001. Effect of
light/dark regimen on N-nitrosoethylurea-induced transplacental carcinogenesis in rats. Cancer Lett 163:5157.
Benot S, Molinero P, Soutto M, Goberna R, Guirrero JM. 1998. Circadian variation in the rat serum total antioxidant status: correlation with melatonin levels. J Pineal Res 25:14.
Berson DM, Dunn FA, Takao M. 2002. Phototrsansduction by retinal
ganglion cells that set the circadian clock. Science 295:1070
1073.
Blask DE. 1984.The pineal: an oncostatic gland. In: Reiter RJ, ed. The
Pineal Gland. New York: Raven Press, pp. 253284.
Blask DE. 2001. An overview on the neuroendocrine regulation of
experimental tumor growth by melatonin and its analogues
and the therapeutic use of melatonin in oncology. In: Bartsch C,
Bartsch H, Blask DE, Cardinali DP, Hrushesky WJM, Mecke D, eds.
The Pineal Gland and Cancer. Neuroimmunoendocrine Mechanisms in Malignancy. Berlin: Springer, pp. 309342.
Blask DE, Hill SM. 1986. Effects of melatonin on cancer: studies on
MCF-7 human breast cancer cells in culture. J Neural Transm
(Suppl)21:433449.
Blask DE, Hill SM, Orstead KM, Massa JS. 1986. Inhibitory effects of
the pineal hormone melatonin and underfeeding during the
promotion phase of 7,12-dimethylbenz[a]-anthracene-(DMBA)induced mammary tumorigenesis. J Neural Transm 67:125138.
Blask DE, Hill SM, Pelletier DB. 1988. Oncostatic sygnaling by the
pineal gland and melatonin in the control of breast cancer. In:
Gupta D, Attanasio A, Reiter RJ, eds. The Pineal Gland and Cancer.
London: Brain Research Promotion, pp. 221232.
Blask DE, Pelletier DB, Hill SM, Lemus-Wilson A, Grosso DS, Wilson
ST, et al. 1991. Pineal melatonin inhibition of tumor promotion
in the N-nitroso-N-methylurea model of mammary carcinogenesis: potential involvement of antiestrogenic mechanisms in vivo.
J Cancer Res Clin Oncol 117:526532.
Blask DE, Dauchy RT, Sauer LA, Krause JA, Brainard GC. 2003. Growth
and fatty acid metabolism of human breast cancer (MCF-7) xenografts in nude rats: impact of constant light-induced nocturnal
melatonin suppression. Breast Cancer Res Treat 79:313320.
Brainard GC, Hanifin JP. 2005. Photons, clocks, and consciousness. J
Biol Rhythms 20: 314325.
Brainard GC, Kaver R, Kheifets LI. 1999. The relationship between
electromagnetic field and light exposure to melatonin and
breast cancer risk: a review of the relevant literature. J Pineal Res
26:65100.
Brainard GC, Hanifin JP, Greeson J, Byrne N, Glickman G, Gerner E, et
al. 2001. Action spectrum of melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci 21: 6405
6412.
Canaple L, Kakizawa T, Laudet V. 2003. The days and nights of cancer
cells. Cancer Res 63:75457552.
Chen ST, Choo KB, Hou MF, Yeh KT, Kuo SJ, Chang JG. 2005. Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 26:12411246.
Chernova IV. 2005. Light regimens and estrous cycle in rats. Med
Acad J 3, Suppl. 7:4546.
Chung FF, Yao CC, Wan GH. 2005. The associations between menstrual function and life style/working conditions among nurses
in Taiwan. J Occup Health 47:149156.
Copyright Neuroendocrinology Letters ISSN 0172780X www.nel.edu

Cos S, Sanchez-Barcel EJ. 1995. Melatonin inhibition of MCF-7 huGoto M, Ebihara S. 1990. The influence of different light intensiman breast cancer cell growth: influence on cell proliferation
ties on pineal melatonin content in the retina; degenerate C3H
rate. Cancer Lett 93:207212.
mouse and the normal CBA mouse. Neucrosci Lett 108:267272.
Cos S, Sanchez-Barcel EJ. 2000. Melatonin and mammary pathologiGraham C, Cook MR. 2001. Examination of the melatonin hypothcal growth. Front Neuroendocrinol 21:133170.
esis in women exposed at night to EMF or bright light. Environ
Cos S, Sanchez-Barcelo EJ. 2001. In vitro effects of melatonin on
Health Perspect 109:501507.
tumor cells. In: Bartsch C, Bartsch H, Blask DE, Cardinali DP,
Ha M, Park J. 2005. Shiftwork and metabolic risk factors of cardioHrushesky WJM, Mecke D, eds. The Pineal Gland and Cancer.
vascular disease. J Occup Health 47:8995.
Neuroimmunoendocrine Mechanisms in Malignancy. Berlin:
Hahn RA. 1991. Profound bilateral blindness and the incidence of
Springer, pp. 221239.
breast cancer. Epidemiology 2:108210.
Cos S, Mediavilla D, Martinez-Campa C, Gonzalez A, Laonso-GonHamilton T. 1969. Influence of environmental light and melatonin
zalez C, Sanchez-Barcelo EJ. 2006. Exposure to ligh-at-night inupon mammary tumour induction. Br J Surg 56:764766.
creases the growth of DMBA-induced mammary adenocarcinoHamilton T, Sneddon A. 1968. Environmental light and DMBA- inmas in rats. Cancer Lett 235:266-271.
duced rat mammary tumours. Br J Surg 55:71 76.
Cos S, Gonzalez A, Guezmes A, Mediavilla MD, Martinez-Campa C,
Hansen J. 2001. Increased breast cancer risk among women who
Alonso-Gonzalez C, et al. 2006. Melatonin inhibits the growth of
work predominantly at night. Ann Epidemiology 12:7477.
DMBA-induced mammary tumors by decreasibg the local bioHansen J. 2002. Re: Night shift work, light at night, and risk of breast
syhthesis of estrogens through the modulation of aromatase accancer. J Natl Cancer Inst 97:533534.
tivity. Int J Cancer 118:274-278.
Harlow SD, Ephross SA. 1995. Epidemiology of menstruation and its
Dauchy RT, Blask DE, Sauer LA, Brainard JC, Krause JA. 1999. Dim
relevance to wimens health. Epidemiol Rev 17: 265286.
light during darkness stimulates tumor progression by enHarman D. 1994. Free-radical theory of aging: increasing the funchancing tumor fatty acid uptake and metabolism. Cancer Lett
tional life span. Ann NY Acad Sci 717:257266.
144:131-136.
Haus E, Lakatua D, Halberg F. 1967. The internal timing of several cirDauchy RT, Sauer LA, Blask DE, Vaughan GM. 1997. Light contaminacadian rhythms in the blinded mouse. Exp Med Surg 25:745.
tion during the dark phase in photoperiodically controlled aniHaus E, Dumitriu L, Nicolau GY, Bologa S, Sackett-Lundeen L. 2001.
mal rooms: effect on tumor growth and metabolism in rats. Lab
Circadian rhythms of basic fibroblast growth factor (bFGF), epiAnim Sci 47:511518.
dermal growth factor (EGF), insulin-like growth factor-1 (IGFDavis S, Kaune WT, Mirick DK, Chen C, Stevens RG. 2001. Residental
1), insulin-like growth factor binding protein-3 (IGFBP-3), cortimagnetic fields, light-at-night, and nocturnal urinary 6-sulfatoxsol, and melatonin in women with breast cancer. Chronobiol Int
ymelatonin concentration in women. Am J Epidemiol 154:591
18:709727.
600.
Hill SM, Kiefer T, Teplitzky S, Spriggs LL, Ram PT. 2001. ModulaDavis S, Mirick DK, Stevens RG. 2001a. Night shift work, light at
tion of the estrogen response pathway in human breast cancer
night, and risk of breast cancer. J Natl Cancer Inst 93:15571562.
cells by melatonin. In: Bartsch C, Bartsch H, Blask DE, Cardinali
Depres-Brummer P, Levi F, Metzger G, Touitou Y. 1995. Light-inDP, Hrushesky WJM, Mecke D, eds. The Pineal Gland and Canduced suppression of the rat circadian system. Am J Physiol 268:
cer. Neuroimmunoendocrine Mechanisms in Malignancy. Berlin:
R1111R1116.
Dilman VM. 1994. Development, Aging and Disease. A New RatioHoffmann JC. 1968. Effect of photoperios on estrous cycle length in
nale for an Intervention Strategy. Chur: Harwood Acad Publ.
the rat. Endocrinology 83:13551357.
Dilman VM, Anisimov VN. 1979. Hypothalamic mechanisms of ageHonma S., Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato
ing and of specific age pathology - I. Sensitivity threshold of hyY, Honma K. 2002. Dec1 and Dec2 are regulators of the mammapothalamo-pituitary complex to homeostatic stimuli in the relian molecular clock. Nature 419:841844.
productive system. Exp Gerontol 14:161174.
Hrushesky WJM. 2001. Melatonin cancer therapy. Bartsch C, Bartsch
Di Lorenzo L, De Pergola G, Zocchetti C, LAbbate N, Basso A, PanH, Blask DE, Cardinali DP, Hrushesky WJM, Mecke D, eds. The Pinacciulli N, et al. 2003. Effect of shift work on body mass index:
neal Gland and Cancer. Neuroimmunoendocrine Mechanisms in
results of a study performed in 319 glucose-tolerant men workMalignancy. Berlin: Springer, pp.476508.
ing in a Southern Italian industry. Int J Obes Relat Metab Disord
Ilyukha VA, Vinogradova IA, Fedorova AS, Velb AN. 2005. Effect of
27:13531358.
light regimens, pineal hormones and age on antioxidant system
Eck-Enriquez K, Kiefer TL, Spriggs LL, Hill SM. 2000. Pathways
of rats. Med Acad J 3, Suppl 7:2930.
through which a regimen of melatonin and retinoic acid induced
Inoue I, Shinoda Y, Ikeda M, Hayashi K, Kanazawa K, Nomura M, et al.
apoptosis in MCF-7 human breast caancer cells. Breast Cancer
2005. CLOCK/BMAL1 is involved in lipid metabolism via transacRse Treat 61:229239.
tivation of the peroxisome proliferator-activated receptor (PPAR)
Feychting M, Oosterlund B, Ahlbom A.1998. Reduced cancer inciresponse element. J Atherosclerosis Thromb 12:169174.
dence among the blind. Epidemiology 9:490494.
Ird EA. 1966. Follicular Cysts of the Ovary and Dyshormonal Tumors.
Filipski E, King VM, Li XM, Granda TG, Mormont MC, Liu XH, et
Leningrad: Meditsina.
al.2002. Host circadian clock as a control point in tumor progresIsobe Y, Nishino H. 2004. Signal transmission from the suprachiassion. J Natl Cancer Inst 94:690697.
matic nucleus to the pineal gland via the paraventricular nucleus:
Filipski E, King VM, Li XM, Granda TG, Mormont MC, Claustrat B, et
analysed from arg-vasopressin peptide, rPer2 mRNA and AVP
al. 2003. Disruption of circadian coordination accelerates maligmRNA changes and pineal AA-NAT mRNA after the melatonin innant growth in mice. Pathologie Biologie 51:216219.
jection during light and dark periods. Brain Res 1013:204211.
Filipski E, Dellaunay F, King VM, Wu MW, Claustrat B, Grechez-CasIvanisevic-Milovanocic OK, Demajo M, Karakasevic A, Pantic C.
siau A, et al. 2004. Effects of chronic jet lag on tumor progression
1995. The effect of constant light on the concentration of
in mice. Cancer Res 64:78797885.
catecholamines of the hypothalamus and asdrenal glands, circuFilipski E, Innominato PF, Wu MW, Li XM, Iacobelli S, Xiam LJ, et al.
latory adrenocorticotropin hormone and progesterone. J Endocr
2005. Effects of light and food schedules on liver and tumor moInvest 18:378383.
lecular clocks in mice. J Natl Cancer Inst. 97:507517.
Johle W. 1964. Trends in photophysiologic concept. Ann NY Acad Sci
Fu L, Lee CC. 2003. The circadian clock: pacemaker and tumour sup11:88104.
pressor. Nature Rev Cancer 3:350361.
Jull JW. 1966. The effect of infection, hormonal environment, and
Fu L, Pelicano H, Liu J, Huang P, Lee CC. 2002. The circadian gene
genetic constitution on mammary tumor induction in rats by
Period2 plays an importnat role in tumor suppression and DNA
7,12-dimethylbenz(a)anthracene. Cancer Res 26:23682373.
damage response in vivo. Cell 111: 4150.
Karolczak M., Burbach GJ, Sties G, Korf HW, Stehle JH. 2004. Clock
Gauger MA, Sancar A. 2005. Cryptochrome, circadian cycle, cell cygene mRNA and protein rhythms in the pineal gland of mice. Eur
cle checkpoints, and cancer. Cancer Res 65:68286834.
J Neurosci 19:33823388.
Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP,
Kerenyi N. 2002. Re: Night shift work, light at night, and risk of breast
Takahashi JS, Weitz CJ. 1998. Role of the CLOCK protein in the
cancer. J Natl Cancer Inst 97:531532.
mammalian circadian mechanism. Science 280:15641569.
49
Khaetski IK. 1964. Carcinogenic effect of DMBA at neuroendocrine
disturbances. In: Tumor and Organism. Abstracts of the Symposium. North-Western Book Publisher, pp. 7274.
Khaetski IK. 1965. Effect of hypothalamo-pituitary lesions induced
by constant illumination on development of induced mammary
tumors in rats. Vopr Exp Oncol (Kiev) 1:8793.
Kilic E, Kilic U, Reiter RJ, Bassetti CI, Hermann DM. 2004. Prophylactic use of melatonin protects against focal cerebral ischemia
in mice: role of endothelin converting enzyme-1. J Pineal Res
37:247251.
King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Antoch MP,
Steeves TD, et al. 1997. Positional cloning of the mouse circadian
clock gene. Cell 89:641653.
Kliukiene J, Tynes T, Anderson A. 2001. Risk of breast cancer among
Norvegian women with visual impairment. Br J Cancer 84:397
399.
Klochkov DV, Beliaev DK. 1977. Effect of continuous illumination on
the reproductive function in rats. Aftereffects. Ontogenez 8:487
496.
Knutsson A. 2003. Health disorders of shift workers. Occupat Med
53:103108.
Knutsson A, Boggild H. 2000. Shiftwork, risk factors and cardiovascular disease: review of disease mechanisms. Rev Environ Health
15:359372.
Kojo K, Pukkala E, Auvinen A. 2005. Breast cancer risk among Finnish cabon attendants: a nested case-control study. Occup Environ Med 62:488493.
Korf HW, Von Gall C, Stehle J. 2003. The circadian system and melatoni: lessons from rats and mice. Chronobiol Int 20:697710.
Kothari L. 1987. Influence of chronic melatonin on 9,10-dimethyl-1,2benzanthrazene-induced mammary tumors in female Holtzman
rats exposed to continuous light. Oncology 44:6466.
Kothari L. 1988. Effect of melatonin on the mammary gland morphology, DNA synthesis, hormone profiles and incidence of
mammary cancer in rats. In: Gupta D, Attanasio A, Reiter RJ, eds.
The Pineal Gland and Cancer. London: Brain Research Promotion,
pp. 210219.
Kothari L, Shah PN, Mhatre MC. 1982. Effect of continuous light on
the incidence of 9,10-dimethyl-1,2-benzanthracene induced
mammary tumors in female Holtzman rats Cancer Lett 16:313
317.
Kothari A, Borges A, Kothari L. 1995. Chemoprevention by melatonin
and combined melatonin-tamoxifen therapy of second generation nitroso-methylurea-induced mammary tumour in rats. Eur J
Cancer Prev 4:497500.
Kothari A, Borges A, Ingle A, Kothari L. 1997. Combination of
melatonin and tamoxifen as a chemoprophylaxis against N-nitroso-N-methylurea-induced rat mammary tumors. Cancer Lett
111:5966.
Koyanagi S, Kuramoto Y, Nagasawa H, Aramaki H, Ohdo S, Soeda S,
Shimeno H. 2003. A molecular mechanism regulating circadian
expression of vascular endothelial gorwth factos in tumor cells.
Cancer Res 63:72777283.
Kubatka P, Kalicka K, Chamilova M, Ahlersova E, Ahlers I, Bojkova
B, et al. 2002. Nimesulide and melatonin in mammary carcinogenesis prevention in female Sprague-Dawley rats. Neoplasma
49:255259.
Kumar CA, Das UN. 2000. Effect of melatonin on two stage skin carcinogenesis in Swiss mcie. Med Sci Monit 6:471475.
Kuralasov AK. 1979. Effect of dark adaptation on carcinogenesis and
efficacy of treatment DMBA-induced mammary tumor. Proc Acad
Sci Kazakh SSR, Ser Biol 4:7982.
Kuralasov AK. 1990. Experimental Bases for Use of Artificial Photoregimen for Breast Cancer Treatment in Kazakhstan. Diss Doctor Med Sci. Moscow: All-Union Cancer Center.
LHermite-Baleriaux M., de Launoit Y. 1992. Is melatonin really an in
vitro inhibtor of human breast cancer cell proliferation in vitro.
Cell Dev Biol 28A:583584.
Lazarev NI, Ird IO, Smirnova IO. 1976. Experimental Models of Endocrine Gynecological Diseases. Moscow: Meditsina.
Lee CC. 2005. The circadian clock and tumors suppression by mammalian Period genes. Methods in Enzymology 393:852861.
Lemus-Wilson A, Kelly PA, Blask DE. 1995. Melatonin blocks the stimulatory effects of prolactin on human bresast cancer cell growth
in culture. Br J Cancer 72:14351440.
Neuroendocrinology Letters Vol.27 Nos.12, Feb-Apr 2006
50
Lenoir V, de Jonage-Canonico MBY, Perrin MH, Martin A, Scholler R,

Kerdelhue B. 2005. Preventive and curative effect of melatonin
on mammary carcinogenesis induced by dimethylbenz[a]anth
racene in the female Sprague-Dawley rat. Breast Cancer Res 7:
R470R476.
Leon-Blanco M, Guerriero JM, Reiter RJ, Calvo JR, Pozo D. 2003.
Melatonin inhibits telomerase activity in the MCF7 tumor cell
line both in vivo and in vitro. J Pineal Res 35:204211.
Leon-Blanco M, Guerriero JM, Reiter RJ, Pozo D. 2004. RNA expression of human telomerase subunits TR and TERT is differentially
affected by melatonin receptor agonists in the MCF7 tumor cell
line. Cancer Lett 216:7380.
Li JC, Xu F. 1997. Influence of light-dark shifting on immune system,,
tumor growth and life span of rats, mice and fruit flies as well as
on the counteraction of melatonin. Biol Signals 6:7789.
Lin MC, Kripke DF, Parry BL, Berga SL. 1990. Night light alters menstrual cycles. Psychiatry Res 33:135138.
Lissoni P. 2001. Efficacy of melatonin in the immunotherapy of cancer using interleukin-2. In: Bartsch C, Bartsch H, Blask DE, Cardinali DP, Hrushesky WJM, Mecke D, eds. The Pineal Gland and Cancer. Neuroimmunoendocrine Mechanisms in Malignancy. Berlin:
Lissoni P, Barni S, Meregalli S, Fossati V, Cazzanga M, Espositi D, et al.
1995. Modulation of cancer endocrine therapy by melatonin: a
phase II study of tamoxifen plus melatonin in metastatic breast
cancer patients progressing under tamoxifen alone. Br J Cancer
71:854856.
Liu F, Ng TB, Fung MC. 2001. Pineal indoles stimulate the gene expression of immunomodulating cytokines. J Neural Transm
108:397405.
Maestroni GJM. 2001. Melatonin and the immune system: therapeutic potential in cancer, viral diseases, and immunodeficiency states. In: Bartsch C, Bartsch H, Blask DE, Cardinali DP,
Hrushesky WJM, Mecke D, eds. The Pineal Gland and Cancer.
Neuroimmunoendocrine Mechanisms in Malignancy. Berlin:
Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okahamura H.
2003. Control mechanism of the circadian clock for timing of cell
division in vio. Science 302:255259.
Mediavilla MD, Guezmez A, Ramos S, Kothari L, Garijo F, SanchezBarcelo EJ. 1997. Effect of melatonin on mammary gland lesions
in transgenic mice overexpressing N-ras proto-oncogene. J Pineals Res 22:8694.
Megdal SP, Kroenke CH, Laden F, Pukkala E, Schernhammer ES. 2005.
Night work and breast cancer risk: a systemic review and metaanalysis. Eur J Cancer 41:2023-2032.
Melancon K, Cheng Q, Kiefer TL, Dai J, Dong C, Yan L, Collins A, Thiyagarajah A, Long S, Hill SM. 2005. Regression of NMU-induced
mammary tumors with the combination of melatonin and 9-cisretinoic acid. Cancer Lett 227:3948.
Mhatre MC, Shah PN, Juneja HS. 1984. Effect of various photoperiods
on mammary morphology, DNA synthesis, and hormone profile
in female rats. J Natl Cancer Inst 72: 14111416.
Miller BH, Olson SL, Turek FW, Levine JE, Horton TH, Takahashi JS.
2004. Circadian Clock mutation disrupt estrous cyclicity and
mainenance of pregnacy. Curr Biol 14:13671373.
Mockova K, Mnichova M, Kubatka P, Bojkova B, Ahlers I, Ahlersova
E. 2000. Mammary carcinogenesis induced in Wistar:Han rats by
the combination of ionizing radiation and dimethylbenzanthracene: prevention with melatonin. Neoplasma 47:227229.
Molis T, Walters MR, Hill SM. 1993. Melatonin modulation of estrogen receptor expression in MCF-7 human breast cells. Int J Oncol
3:687694.
Monk TH. 2000. Shift work. In: Kryger MH, Roth T, Dement WC, eds.
Principles and Practice of Sleep Medicine, 2nd ed. Philadelphia:
WB. Saunders Company, pp. 471476.
Mormont MC, Levi F. 1997. Circadian-system alterations during cancer processes: a review. Int J Cancer 70:241247.
Mormont MC, Waterhouse J, Bleuzen P, Giachetti S, Jami A, Bogdan
A, et al. 2000. Marked 24-h rest/activity rhythms are associated
with better quality of life, better respo0nse, and longer survival
in patinets with metastatic colorectal cancer and good performance status. Clin Cancer Res 6:30383045.
Munoz M, Peirson SN, Hankins MW, Foster RG. 2005. Long-term constant light constitutive elevated expression of mPER2 protein
Copyright Neuroendocrinology Letters ISSN 0172780X www.nel.edu

in the murine SCN: a molecular basis for Aschoffs rule? J Biol
Rossmanith WG. 1996. Gonadotropin secretion during aging in
Rhythms 20:314.
women: review article. Exp Gerontol 30:369381.
Musatov SA, Anisimov VN, Andre V, Vigreux C, Godard T, Gauduchon
Sanchez-BarceloEJ, Cos S, Mediavilla MD. 1988. Influence of pineal
P, et al. 1998. Modulatory effects of melatonin on genotoxic refunction on the initiation and growth of hormone-dependent
sponse of reference mutagens in the Ames test and the comet
breast tumors. Possible mechanisms. In: Gupta D, Attanasio A,
assay. Mutat Res 417:7584.
Reiter RJ, eds. The Pineal Gland and Cancer. London: Brain ReMusatov SV, Anisimov VN, Andre V, Vigreuz C, Godard T, Sichel F.
search Promotion, pp. 221232.
1999. Effects of melatonin on N-nitroso-N-methylurea-induced
Schernhammer ES, Hankinson SE. 2005. Urinary melatonin levels
carcinogenesis in rats and mutagenesis in vitro (Ames test and
and breast cancer risk. J Natl Cancer Inst 97:10841087.
COMET assay). Cancer Lett 138:3744.
Schernhammer ES, Schulmeister K. 2004. Melatonin and cancer risk:
Napalkov NP. 2004. Cancer and demographic transition. Vopr Onkol
does light at night compormise physiologic cancer protection
50:127144.
by lowering serum melatonin levels? Br J Cancer 90:941943.
Oster H, Baeriswyl S, van der Horst GTJ, Albrecht U. 2003. Loss of
Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawacircadian rhythmicity in aging mPer1-/- mCry2-/- mutant mice.
chi I, et al. 2001. Rotating night shifts and risk of breast cancer in
Genes Dev 17:13661379.
women participating in the nurses health study. J Natl Cancer
Panchenko AV. 2005. Colon carcinogenesis in rats maintained at varInst 93:15631568.
ious light regimens. Med Acad J 3, Suppl 7:3233.
Schernhammer ES, Laden F, Spezer FE, Willett WC, Hunter DJ, KawaPanda S, Nayak SK, Campo B, Walzer JR, Hogenesch JB, Jegla T. 2005.
chi I, et al. 2003. Night-shift work and risk of colorectal cancer in
Illumination of the melanopsin signaling pathway. Science
the Nurses Health Study. J Natl Cancer Inst 95:825828.
307:600604.
Schernhammer ES, Rosner B, Willett WC, Laden F, Coldiz GA, HankinParkin DM, Bray FI, Deseva SS. 2001. Cancer burden in the year 2000.
son SE. 2004. Epidemiology of urinary melatonin in women and
The global picture. Eur J Cancer 37:S4S66.
its relation to other hormones and night work. Cancer Epidemiol
Pauley SM. 2004. Ligthing for the human circadian clock: recent reBiomarkers Prev 13:936943.
search indicates that lighting has become a public health issue.
Seshardi R, Subramnanian A, Kothari L. 1992. Effect of neonatal piMedical Hypotheses 63:588596
neal ablation on estradiol receptors in mammary glands of rats
Praast G, Bartsch C, Bartsch H, Mecke D, Lippert TH. 1995. Hepatic
housed under varying photoperiods. Indian J Exp Biol 30:162
hydroxylation of melatonin in the rat is induced by phenoobar164.
bital and 7,12-dimethylbenz[a]anthracene - implications for canShah PN, Mhatre MC, Kothari L. 1984. Effect of melatonin on mamcer etiology. Experientia 51:349355.
mary carcinogenesis in intact and pinealectomized rats in varyPrata Lima MF, Baracat EC, Simones MJ. 2004. Effects of melatonin
ing photoperiods. Cancer Res 44:34033407.
on the ovarian response to pinealectomy or continuous ligh in
Shephton S, Spiegel D. 2003. Circadian disruption in cancer: a
gfemale rats: similarity with polycystic ovary syndrome. Brazil J
neuroendocrine-immune pathway from stress to disease? Brain
Med Biol Res 37:987995.
Behav Immun 17:321328.
Pukkala E, Auvinen H., Wahlberg G. 1995. Incidence of cancer among
Sibarov DA, Kovalenko RI, Nozdrachev AD, Anisimov VN. 2000. DayFinnish arline cabin attendants, 196792. Br Med J 311:649652.
time pineal gland activation in rats with colon tumors induced
Pukkala E, Verkasalo PK, Ojamo M, Rudanko SL. 1999. Visual impairby 1,2-dimethylhydrazine. Neuroendocrinol Lett 21:307312.
ment and cancer: a population-based cohort study in Finfland.
Simmonneaux V, Poirel VJ, Garidou ML, Nguen D, Diaz-Rodriguez E,
Cancer Causes Control 10:1320.
Pevet P. 2004. Daily rhythm and regulation of clock gene expresPukkala E, Aspholm R, Auvinen A, Eliasch H, Gundestrup M, Halsion in the rat pineal gland. Mol Brain Res 120:164172.
dorsen T, et al. 2002. Incidence of cancer among Nordic airSmirnova IO. 1966. Experimental Bases of Treatment of Mastopathy
line pilots over five decades: occupational cohort study. BMJ
with Iodine Microdoses. PhD Thesis. Moscow: All-Union Cancer
325:567571.
Center.
Rajaratnam SMW, Arendt J. 2001. Health in a 24-h society. Lancet
Smyth BJ, Sneddon A, Hamilton T. 1968. Influence of light and 9,10358:9991005.
dimethylbenz(a)anthracene on rat ovarian steroidogenesis: pheRafnsson V, Tulinius H, Jonasson J, Hrafnkelsson J. 2001. Risk of
nolic steroids. Biochem J 110:28p29p.
breast cancer in female flight attendants: a population-based
Steenland K, Fine L. 1996. Shift work, shift change, and risk of death
study (Iseland).Cancer Cause Control 12:95101.
from heart disease at work. Am J Industr Med 29:278281.
Rao GN, Ney E, Herbert RA. 2000. Effect of melatonin and linolenic
Stevens RG. 2005. Circadian disruption and breast cancer. From
acid on mammary cancer in transgenic mice with cneu breast
melatonin to clock genes. Epidemiology 16:254258.
cancer oncogene. Breast Cancer Res Treatment 64:287296.
Stevens RG, Rea MS. 2001. Light in the built environment: potential
Ralph MR, Menaker MA. 1988. A mutation of the circadian system in
role of circadian disruption in endocrine disruption and breast
golden hamsters. Science 241:12251227.
cancer. Cancer Causes Control 12:279287.
Reddy AK, Wong GKY, ONeill J, Maywood ES, Hastings MH. 2005. CirSubramanian A, Kothari L. 1991. Melatonin, a suppressor of spontacadioan clocks: neural and peripheral pacemakers that impact
neous murine mammary tumors. J Pineal Res 10:136140.
upun the cell division cycle. Mutat Res 574:7691.
Subramanian A, Kothari L. 1991a. Suppressive effect by melatonin
Reiter RJ. 1980. The pineal and its hormones in the control of reproon different phases of 9,10-dimethyl-1,2-benzathracene (DMBA)duction in mammals. Endocrin Rev 1:109131.
induced rat mammary gland carcinogenesis. Anticancer Drugs
Reiter RJ. 2001. Reactive oxygen species, DNA damage, and carci2:297303.
nogenesis: intervention with melatonin. In: Bartsch C, Bartsch H,
Takumi T, Taguchi K, Miyake S, Sakakida Y, Takashima N, Matsubara
Blask DE, Cardinali DP, Hrushesky WJM, Mecke D, eds. The Pineal
C, et al. 1998. A light-independent oscillatory gene mPer3 in
Gland and Cancer. Neuroimmunoendocrine Mechanisms in Mamouse SCN and OVLT. EMBO J 17:47534759.
lignancy. Berlin: Springer, pp. 442455.
Tamarkin L, Cohen D, Roselle C, Reichert M. 1981. Melatonin inhiReiter RJ. 2002. Potential biological consequences of excessive light
bition and pinealectomy enhancement of 7,12-dimethylbenz[
exposure: melatonin suppression, DNA damage, cancer and
a]anthracene-induced mammary tumors in the rat. Cancer Res
neurodegenerativr diseases. Neuroendocrinol Lett 23, Suppl 2:
41:44324436.
913.
Taylor PJ, Pocock SJ. 1972. Mortality of shift and day workers 1956
Reiter R. 2004. Mechanisms of cancer inhibition by melatonin. J Pi68. Brit J Industr Med 29:201207.
neal Res 37:213214.
Tei H, Okamura H, Shigeyoshi Y, Fukuhara C, Ozawa R, Hirose M,
Reppert SM, Weaver DR. 2002. Coordination of circadian timing in
Sakaki Y. 1997. Circadian oscillation of a mammalian homologue
mammals. Nature 418:935941.
of the Drosophila period gene. Nature 389:512516.
Reynolds P, Cone J, Layefsky M, Goldberg DE, Hurley S. 2002. Cancer
Tenkane L, Sjoblom T, Kalino T, Alikoski T, Harma M. 1997. Shift work,
incidence in California flight attendants (United States). Cancer
occupation and coronary heart disease over a 6-years of folCauses Control 13:317324.
low up in the Helsinki Heart Study. Scand J Work Environ Health
Roenneberg T, Merrow M. 2003. The network of time: understand23:257265.
ing the molecular circadian system. Curr Biol 13:R198R207.
51
Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptacek LJ, Fu YH.
2001. An hPer2 phoshorylation site mutation in familiall advanced sleep ohase syndrome. Science 291:10401043.
Travlos GS, Wilson RE, Murrell JA, Chignell CF, Boorman GA. 2001. The
effect of short intermittent light exposure on the melatonin circadian rhythm and NMU-induced breast cancer in female F344/N
rats. Toxicol Pathol 29:126136.
Thresher RJ, Vitaterna MH, Miyamoto Y, Kazantsev A, Hsu DS, Petit C,
et al. 1998. Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282:14901494.
Turek FW, Joshu C, Kohsaka A, Lin E., Ivanova G., McDearmon E, et al.
2005. Obesity and metabolic syndrome in circadian Clock mutant
mice. Science 308:10431045.
Tynes T, Hannevik M, Andersen A, Vistnes Aim Haldorsen T. 1996.
Incidence of breast cancer in Norwegian female radio and telegraph operators. Cancer Causes Control 7:197204.
Van den Heilignerberg S, Depres-Brummer P, Barbason H, Claustrat
B, Reynes M, Levi F. 1999. The tumor promoting effect of constant
light exposure on diethylnitrosamine-induced hepatocarcinogenesis in rats. Life Sci 64:25232534.
Van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao
M, de Wit J, Verkerk A, Eker AP, van Leenen D, Buijs R, Bootsma
D, Hoeijmakers JH, Yasui A. 1999. Mammalian Cry1 and Cry2 are
essential for maintenance of circadian rhythms. Nature 398:627
630.
Verkasalo PK, Pukkala E, Stevens RG, Ojamo M, Rudanko SL. 1999. Inverse association between breast cancer incidence and degree of
visual impairment in Finland. Br J Cancer 80:14591460.
Vesnishkin GM, Plotnikova NA, Semenchenko AV, Anisimov VN. 2005.
Melatonin inhibits carcinogenesis induced by benzo(a)pyrene in
mice. J Exp Clin Cancer Res, submitted.
Vesnishkin GM, Plotnikova NA, Semenchenko AV, Anisimov VN. 2006.
Melatonin inhibits lung carcinogenesis induced by urethane in
mice. Vopr Onkol 52:164-168.
Vijayalaxmi, Reiter RJ, Meltz ML. 1998. Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes. Mutat Res 397:203208.
Vijayalaxmi, Thomas CR, Reiter RJ, Herman TS. 2002. Melatonin: from
basic research to cancer treatment clinics. J Clin Oncol 20:2575
2601.
52
Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, Dove WF, Pinto LH, Turek FW, Takahashi JS. 1994. Mutagenesis and mapping of a mouse gene, Cl ock, essential for circadian behavior. Science 264:719725.
Vinogradova IA, Shevchenko AI. 2005. Effect of light regimen on indices of biological age and age-related pathology. Med Acad J 3;
Suppl 7:1820.
Van Gall C, Weaver DR, Moek J, Jilg A, Stehle JH, Korf HW. 2005.
Melatonin plays a crucial role in the regulation of rhythmic clock
gene expression in the mouse pars tuberalis. Ann NYAcad Sci
1040:508511.
Weisburger JH, Rivenson A, Choi CI, Reinhardt J, Pittman B, Zang E.
2003. Inhibition of lung, mammary gland and colon tumors by
melatonin. Proc Am Assoc Cancer Res, Abstract #5694; 44(2nd
ed):11331134.
Welsch CW. 1985. Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles
Benton Huggins. Cancer Res 45: 34153443.
Wise PM, Gerhold LM, Cashion AB. 2005. Neuroendocrine modulation of menopause: evolution of our thinhking. In: Hormones,
Age and Cancer. Berstein LM (Ed). St.Petersburg, Nauka, pp. 94
111.
Wolden-Hanson T, Mitton DR, McCants RL, Yellon SM, Wilkinson CW,
Matsumoto AM, et al. 2000. Daily melatonin administration to
middle-aged male rats suppresses body weight, intraabdominal
adiposity, and plasma leptin and insulin independent of food intake and total body fat. Endocrinology 141:487497.
Young MW, Kay SA. 2001. Time zones: a comparative genetics of circadian clocks. Nat Rev Genet 2:702715.
Zeitzer JM, Dijk DJ, Kronauer R, Brown E, Czeisler C. 2000. Sensitivity
of the human circadian pacemaker to nocturnal light: melatonin
phase resetting and suppression. J Physiol 526:695702.
Zhu Y, Brown HN, Zhang Y, Stevens RG, Zheng T. 2005. Period3 structural variation: a circadian biomarker associated with breast cancer in young women. Cancer Epidemiol Biomarkers Prev 14:268
270.
Zhukova OV, Anisimov VN. 1994. Effect of light deprivation on carcinogenesis induced by N-nitrosomethylurea in female rats. Vopr.
Onkol 40(1-3):71-75.

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Neuroendocrinology Letters Volume 27 Nos.

Light pollution, reproductive function and cancer risk

Submitted: December 1, 2005

Accepted: December 15, 2005

light-at-night; shift work; circadian rhythm; anovulation; carcinogenesis;

Neuroendocrinol Lett 2006; 27(1-2):3552 PMID: 16648818

NEL271206R01 Neuroendocrinology Letters www.nel.edu

in the pineal gland of indole hormone melatonin

Department of Carcinogenesis and Oncogerontology, N.N. Petrov Research Institute of Oncology,

height, alcohol consumption, late age at first birth, low

data on effect of light deprivation and anti-carcinogenic

Circadian rhythms regulation and eects of

Light pollution, reproductive function and cancer risk

Mutations alter rhythmicity in rodents. Physically associates with and

Circadian locomotor output cycles

Mutations alter rhythmicity in rodents. Constitutively expressed.

clockwork. Exposure to light at night markedly reduced

Van der Horst et al.(1999);

Ralph and Menaker (1998) ;

Barnes et al. (2003)

tion the threshold of light sensitivity to suppress pineal

Light-at-night and reproductive function

The continuous illumination of 2-month-old Wistar

as in women (Dilman and Anismov 1979; Dilman 1994;

Shift work and cancer: epidemiological

Light pollution, reproductive function and cancer risk

attendants in Finland (1.9; CI=1.12.2) (Pukkala et al.

Light-at-night and spontaneous

decreased food consumption but did not influence body

Light-at-night and chemically-induced

Virgin female Sprague-Dawley rats were kept at the LL

Light pollution, reproductive function and cancer risk

NMU-induced mammary tumors in female Fischer 344

in this model, yet through different effects on circadian

Tumor site and type

Anisimov et al. (2004)

Baturin et al. (2001)

Mammary adenocarcinoma and fibroadenoma;

Vinogradova and Shevchenko

Mammary adenocarcinoma and fibroadenoma;

Kotahri et al. (1982); Kothari

Van der Heiligenberg et al. (1999)

NEU trans-placentally Nervous system tumors, kidney mesenchymal

Hamilton (1979); Jull (1966)

Beniashvili et al. (2000)

* Transgenic HER-2/neu mice.

or cervical ganglionectomy also inhibits DMBA-induced

Light-at-night and growth of transplanable

Eect of light deprivation on carcinogenesis

patients) were treated with polychemotherapy (modified

Light pollution, reproductive function and cancer risk

Breast cancer risk

0.82 (0.47 1.34)

1.06 (0.92 1.21)

Moderate low vision

1.05 (0.84 1.30)

Severe low vision

0.96 (0.59 1.46)

Profound low vision

0.57 (0.35 0.92)

Kliukiene et al. (2001)

Note: In brackets are 0.95% confidential intervals.

pituitary and thyroid gland in blind rats was significantly

Cancer risk in blind humans