Human & Experimental

http://het.sagepub.com/
Toxicology

Metals and female reproductive toxicity

P Sengupta, R Banerjee, S Nath, S Das and S Banerjee
Hum Exp Toxicol published online 25 November 2014
DOI: 10.1177/0960327114559611

The online version of this article can be found at:

http://het.sagepub.com/content/early/2014/11/21/0960327114559611

Published by:

http://www.sagepublications.com

Additional services and information for Human & Experimental Toxicology can be found at:

Email Alerts: http://het.sagepub.com/cgi/alerts

Subscriptions: http://het.sagepub.com/subscriptions

Reprints: http://www.sagepub.com/journalsReprints.nav

Permissions: http://www.sagepub.com/journalsPermissions.nav

>> OnlineFirst Version of Record - Nov 25, 2014

What is This?

Downloaded from het.sagepub.com by guest on December 1, 2014

Article
Human and Experimental Toxicology
1–19
Metals and female reproductive toxicity ª The Author(s) 2014
Reprints and permission:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0960327114559611
het.sagepub.com

P Sengupta1, R Banerjee2, S Nath3, S Das2 and S Banerjee2

Abstract
Research into occupational exposure of metals and consequences of reproductive systems has made imperative
scientific offerings in the preceding few decades. Early research works focused on possible effects on the repro-
ductive functions rather than the complete reproductive health of the woman. Later, it was realized that metals,
as reproductive toxins, may also induce hormonal changes affecting other facets of reproductive health such as
the menstrual cycle, ovulation, and fertility. Concern is now shifting from considerations for the pregnant woman
to the entire spectrum of occupational health threats and thus reproductive health among women.

Keywords
Arsenic, cadmium, fertility, lead, zinc

Introduction such as sampling time and the matrix (maternal or

Effects of metals on female reproduction may arise
from their action in several stages beginning in fetal
life, during early development or maturity, and
include indicators such as subfertility, infertility,
intrauterine growth retardation, spontaneous abor-
tions, malformations, birth defects, postnatal death,
learning and behavior deficits, and premature aging.
Because it is difficult to obtain detailed information
regarding effects on the reproductive system in
humans, the evidence is usually limited to animal data
or studies on fertility and spontaneous abortions. Preg-
nancy loss is the end point most frequently used to
monitor effects on female reproductive function, start-
ing from early losses, which contain a large proportion
of chromosomal abnormalities and may represent 35–
40% of human pregnancies. The remaining 10–15%
later abortions are clinically manifested, and some
have been linked to environmental factors.1 Thus, there
seems to be a remarkably high background rate of fetal
loss in humans. The clinical and epidemiological find-
ings related to metal-induced effects on female repro-
duction are often difficult to interpret because many
other factors may influence the outcome such as age,
ovarian reserve, hormonal imbalance, behavior, genet-
ics, male fertility factors, or sexually transmitted dis-
eases. In addition, timing, duration, and intensity of
exposure are important in assessing reproductive
adverse effects. Ernhart and Greene2 pointed out some
critical aspects in measuring the dose indicators,
fetal blood, cord blood, or placenta) in which indica-
tors of prenatal exposure should be determined. To
better assess early exposure to metals and the trend
of absorption through pregnancy, at least one sample
should be taken during the first trimester and another
during the last 6 weeks of the pregnancy. This will
facilitate the assessment of effects on the various
stages of development and organogenesis.
Knowledge about pathogenetic mechanisms of
female reproductive damage is limited. Effects may
be direct, when environmental or occupational metals
interact with specific reproductive target organs, or
indirect, when metals act on endocrine or other sys-
tems. The ovaries and ova are susceptible to direct
damage by metals for an extended period of time, from
meiosis through ovulation. Some experimental studies
suggest an increased risk of miscarriage, fetal mal-
formation, placental insufficiency, and premature
1
Department of Physiology, Vidyasagar College for Women,
University of Calcutta
2
Department of Physiology, University of Calcutta, Kolkata, West
Bengal, India
3
Department of Genetics, University of Calcutta, Kolkata, West
Bengal, India
Corresponding author:
P Sengupta, Department of Physiology, Vidyasagar College for
Women, University of Calcutta.
Email: pallav_cu@yahoo.com

Downloaded from het.sagepub.com by guest on December 1, 2014

2 Human and Experimental Toxicology
birth because of metal exposure.3 Metals such as lead
(Pb) may interfere with the hypothalamic–pituitary–
ovarian axis at different levels by modifying the secre-
tion of prolactin, adrenocortical steroids, or thyroid
hormones; vascular effects on the placenta have also
been suggested.4,5
Current evidence provides warning signals; the
female reproductive system is vulnerable to toxic
agents, and the number of working women poten-
tially exposed to metals is increasing worldwide. It
is estimated that most of the working women are in
reproductive age; about half of working women are
exposed during pregnancy, and about 20% are
exposed to chemicals of potential concern.6 Reviews
on female reproductive effects include Gold and
Tomich,7 Gardella and Hill,8 Foster,9 and Kumar.10
Metals as EDCs and female
reproduction
The ability of endocrine-disrupting chemicals (EDCs)
to alter reproductive function in females has been
clearly demonstrated by the consequences of syn-
thetic estrogen use and environmental or occupational
exposure of metals in women. They are reported to
have decreased fertility11 and early menopause.12
Many of these disorders have been replicated in
laboratory animals treated with EDCs during different
phases of reproductive age.13–15 As earlier studies
point out the lessons learned from several years of
EDCs research in humans and animals are that the
female fetus is susceptible to environmentally
induced reproductive abnormalities, that gonadal
organogenesis is sensitive to synthetic hormones and
hormone mimics during critical exposure windows,
and that reproductive disease may not appear until
decades after exposures.
Proper development of ovarian follicles in the fetus is
dependent on estrogen exposure during critical periods
of development. For instance, mice treated with different
metals and other EDCs on postnatal day 1 to 5 develop
multioocytic follicles as adults.16 Disturbances in hor-
mone signaling resulting from chemical exposures dur-
ing developmental periods could contribute to ovarian
disorders and declining conception rates in human popu-
lations.17 While the mechanisms by which EDCs alter
follicle development are not fully understood, there is
evidence that these chemicals are contributing to
increased rates of aneuploidy, polycyctic ovarian syn-
drome,18 premature ovarian failure,19 and altered cycli-
city and fecundity.20 In humans, altered cyclicity has
Downloaded from het.sagepub.com by guest on December 1, 2014
been reported in individuals exposed to metals and pes-
ticides. Indeed, cycle irregularities have been noted in
women whose mothers were exposed in utero to EDC.13
Uterine fibroids (or leiomyomas) are the most
common tumor of the female reproductive system,21
occurring in 25–50% of all women. The risk of the
development of uterine fibroids increases with age
during premenopausal years, but tumors typically
regress with the onset of menopause.22 Studies have
shown that exposure to metals increases the incidence
of fibroids in these animals.23 The potential for EDCs
to cause uterine fibroids in humans is less clear.
In summary, both animal and human studies sug-
gest a role of environmental metals and other EDCs
in altering female reproductive development. Data
from animal experiments show that EDC exposure
during critical periods of development, both prenatal
and neonatal, can induce functional changes that
appear later in life. There are data gaps in under-
standing the mechanisms by which EDCs carry out
their action, but it is clear that to reduce the risk of
reproductive disorders we must take action to reduce
exposure to these chemicals.
Arsenic
The effect of arsenic (As) on female reproductive
function has not been studied sufficiently and is not
clear. The effect on human reproduction of As was
investigated in females exposed by means of air or
drinking water. Tabacova et al.24 examined the rela-
tionship between As exposure from a copper smelter
area in Bulgaria and oxidative damage during preg-
nancy. Placental levels of As were highest in areas
with the highest environmental contamination, and
exposed pregnant women were at higher risk of oxi-
dative damage during pregnancy. Aschengrau et al.25
investigated the relationship between community
drinking water quality and spontaneous abortion.
Type and concentration of trace elements were gath-
ered from routine analyses of public tap water supplies
of areas where the women resided during pregnancy.
After adjustment for potential confounders, an increase
in the frequency of spontaneous abortion was asso-
ciated with high levels of As. In a case-control study
of stillbirths, Ihrig et al.26 included the assessment
of environmental As exposures and analysis of con-
founders (race, ethnicity, maternal age, median
income, and parity). There was a statistically signif-
icant increase in the risk of stillbirth in the group
with the highest exposure to As. Further analysis
Sengupta et al.
showed that the increase was limited to Hispanic
people, possibly because of a genetic impairment
in folate metabolism. However, this study had a
small number of cases in the high-exposure group,
lacked data on smoking, and did not consider poten-
tial confounding exposures to other chemicals. As a
whole, the studies on As reproductive effects have
been criticized because they did not adequately mea-
sure exposure to As and other metals and did not
evaluate other potential confounding factors.27 In the
3
studies have revealed the involvement of boron in
the synthesis of estrogens, vitamin D, and other ster-
oid hormones, it being essential in the process of
hydroxyl group addition in steroid biosynthesis. The
presence of hydroxyl groups can lead to large differ-
ences of hormonal activity, the difference between
testosterone and estrogen, for example, being due
to the presence or absence of a single hydroxyl
group. In some studies, it has been reported that post-
menopausal women supplemented with about 3 mg
multigenerational experimental study by Schroeder
and Mitchener, female rats continuously exposed to
arsenate in drinking water did not show decreased
fertility.28 Two other studies demonstrated that
reproductive functions (included precoital interval,
mating index, and fertility index) were not affected
in female rats orally exposed to trivalent As by
gavage from 14 days before mating through gesta-
tion.29 Some effects were demonstrated in female
mice exposed to monomethyl arsenic acid before
mating and during pregnancy with production of
fewer litters than normal, but this effect was attribu-
table mainly to decreased fertility of the males.30
Also rats treated with As by daily gavage (before
mating and continuing through gestation) had signif-
icantly reduced fetal body weights and significantly
increased skeletal malformations that the researchers
considered to be consequences of growth retarda-
tion. In mice treated with As acid, there was a signif-
icant increase in the number of resorptions per litter
and significant decreases in the number of live pups
per litter and mean fetal weight. However, overt
maternal toxicity (including death) was found at the
same or lower doses as those leading to developmen-
tal effects.31
Boron
Boron is found abundantly in nature, though only in
compounds and in combination with sodium and
oxygen. Examples of compounds containing boron
are borax (Na2B4O710H2O) and boric acid.32,33
Relatively little is known about the occurrence of
boron in the food chain and hence a biomarker that
reflects its intake is required.34 Boron complexes
with organic compounds containing hydroxyl groups
and those with more than two hydroxyl groups react
more strongly. The simplest hydrogen compounds of
boron act as mild reducing agent, readily reducing
aldehydes, ketones, and acid chlorides; some of them
are derived from lipid peroxidation.34 Previous
Downloaded from het.sagepub.com by guest on December 1, 2014
of boron/day had a significant increase in 17- estra-
diol and concentration of testosterone; precursor of
estradiol was also reported to get increased.34,35
Conversely, it was shown experimentally that boron
affects the development of human fetus. Fetal toxicity of
boron was observed in mice, rats, and rabbits. The
reported developmental toxicities occurring after boron
exposure include high prenatal mortality and reduced
fetal body weight. Placenta-crossing ability of boron
is still unknown.32 In some other animal studies, boron
was also found to cause a reduction in ovulation in
female rats.32 Whorton et al.36 showed a statistically sig-
nificant increase in fertility as measured by live births
among the employees of the inorganic borate facility.
Boron does not appear to be causing any decrease in fer-
tility. A nonstatistically significant increase was
detected in the percentage of female offspring. Accord-
ing to Whorton et al. Na2B4O710H2O miners had a non-
significant excess of births compared to the general
population and a nonsignificant excess of female births
compared to males.32,33 According to earlier studies,
plasma oestradiol increases in peri-menopausal women
supplemented with 2.5 mg boron/day for 60 days. In ani-
mal study, boron compounds have moderate acute toxi-
city, with lethal doses and developmental toxicity being
reported, following administration of boron to pregnant
rats and rabbits. There is a marked decrease in weight of
ovaries with the increasing dose of boron.33 In some
other studies, no evidence was found to suggest that
boron interferes with human fertility and reproduction
and no adverse effects were reported on fertility over
three generations. Exposure to inorganic borates does
not affect fertility adversely. Boron-caused infertility
are only supported by animal toxicity studies, which
employ higher concentrations of boron than the levels
of environmental or occupational human exposure.32
Cadmium
Few data are available on the effects of cadmium on
human female reproductive function. Epidemiological
4 Human and Experimental Toxicology
studies have not revealed reproductive effects in con-
trast to experimental evidence in animals. Studies are
needed to determine whether cadmium at low doses
may act as reproductive and developmental toxicant
and whether the fetal toxicity is related to placental
defects or to accumulation of cadmium in the fetus.
In vitro studies have shown effects on calcium and
oxytocin activities in myometrial strips from term
pregnant women37 and on steroidogenesis in granulosa
cells obtained from ovarian follicular aspirates.38
However, the lowest cadmium concentration that
reduced progesterone production was about 3.5 times
higher than levels reported in the ovary of a female
smoker. After acute and at high-dose administration
in rats, cadmium has been shown to affect various
female reproductive end points, resulting in hemorrha-
gic changes in the ovary and uterus or in persistent
estrous and ovulation; these effects can be prevented
by coadministration of selenium.39 The effects of
cadmium vary according to the sensitivity of early
embryos, and studies on cadmium acetate exposure
indicate no effects on fertilization but only at the blas-
tocyst stage or in vitro reduction of development to the
morula stage.40 Exposure of experimental animals to
cadmium increased uterus weight accompanied by
proliferation of the endometrium and induction of pro-
gesterone receptors, mimicking the effects of estro-
gens. Female offspring experienced an earlier onset
of puberty and growth of the mammary gland. In rats,
exposure to cadmium oxide dusts increased the dura-
tion of the estrous cycle, decreased the preovulatory
luteinizing hormone levels in blood, and inhibited
ovulation. These effects were generally observed
after high-dose, acute exposures and, therefore, pro-
vide little information for current human exposures.41
Cadmium given before mating may lead to sterility in
a dose-dependent fashion, because of anovulation
resulting from reversible pituitary dysfunction. How-
ever, animals may develop tolerance and remain fer-
tile despite cadmium treatment, with normal fetal
outcome and postnatal development.38 Piasek and
Laskey42 evaluated the direct effects of in vitro cad-
mium exposure on steroidogenesis in Sprague Daw-
ley rat ovaries; production of progesterone and
testosterone was affected in proestrous rats and preg-
nant dams, whereas estradiol was not affected. They
concluded that cadmium interferes with the ovarian
steroidogenic pathway at more than one site. These
effects may be mediated by interference with DNA-
binding zinc in steroidogenesis or by estrogen-like
activity.43,44
Downloaded from het.sagepub.com by guest on December 1, 2014
Chromium
Few studies in human females have addressed potential
adverse effects of chromium and chromium compounds.
The effect of chromium (VI) on human pregnancy out-
comes was examined in females working in manufac-
turing facilities in Russia.45 Complications during
pregnancy and childbirth were reported in women with
higher levels of chromium in blood and urine than the
control group. However, the quality of the data and
reporting limits their interpretation regarding the poten-
tial ability of chromium to produce reproductive effects.
Bonde46 studied the spouses of stainless steel welders
exposed to chromium (VI) for spontaneous abortions
and congenital malformations. The author concluded
that the weak indications of an increased risk of sponta-
neous abortion among partners of stainless steel welders
(odds ratio (OR), 1.9; 95% confidence interval (CI),
1.1–3.2) needed to be corroborated. In a subsequent
investigation of a similar population by Hjollund
et al.,47 information was collected on exposure and out-
comes for 245 clinically recognized pregnancies. Male
welding of stainless steel was associated with an
increased risk of spontaneous abortion in spouses
(adjusted relative risk, 3.5; 95% CI, 1.3–9.1). The muta-
genic effect of chromium (VI) previously found in both
somatic and germ cells could be responsible for the
abortions, which in this case would be a male-
mediated effect. In an earlier study, the same group
examined outcomes in 2520 pregnancies of spouses of
Danish metal workers exposed to chromium (VI) from
1977 to 1987.47 The number of spontaneous abortions
was not higher for pregnant women whose spouses
worked in the stainless steel welding industry compared
with controls (OR, 0.78; 95% CI, 0.55–1.1). At present,
the effects of chromium on female reproductive func-
tion in humans remain unclear. Reproductive effects
have been observed in the offspring of mice exposed
to chromium (III) after oral maternal exposure. Signifi-
cant decreases in the relative weights of reproductive
tissues (ovaries and uterus) were observed in the off-
spring of exposed BALB/c mice. A significant delay
in timing of vaginal opening was also noted.48 Cultured
mouse embryos were sensitive to chromium (VI) expo-
sure in vitro; incubation of blastocysts with potassium
dichromate inhibited inner cell mass growth and
differentiation, whereas hatching, attachment, and tro-
phoblast outgrowth were not affected.49 Murthy
et al.50 reported a number of reproductive effects
(reduced number of follicles at different stages of
maturation, reduced number of ova/mice, increased
Sengupta et al.
estrous cycle duration, and histological alterations) in
the ovaries of female mice exposed to potassium dichro-
mate in drinking water for 20 days. The severity of the
reproductive effects seemed to be dose related. Other
experimental studies reported increased preimplanta-
tion losses and resorptions in rats and mice exposed
to chromium (VI).51 A decrease in the number of
pregnant females was observed after the mating of
unexposed females with male mice exposed to chro-
mium chloride, whereas an increase in relative ovar-
ian weight was observed in female mice exposed to
potassium dichromate. Impaired fertility was
observed in females exposed to chromium (III) mated
with unexposed males. In females of different species
fed with potassium dichromate (VI), microscopic exam-
ination of the ovaries revealed no treatment-related
effects.52 Additional studies were carried out in rats to
assess reproductive effects from exposure to potassium
dichromate in drinking water. At the highest level of
exposure, there were a decreased number of implanta-
tion sites, number of live fetuses, and fetal weight. There
were also increases in the number of resorptions and the
number of preimplantation and postimplantation losses.
There was also a significant reduction in ossification of
fetal bones.53 In a second study, female rats were
exposed to potassium dichromate for 20 days before
mating.51 Similar effects were observed on gestational
weight, postimplantation loss, number of live fetuses,
and fetal ossification (in fetal caudal bones). In a third
study, female rats were exposed to potassium dichromate
for 3 months premating.51 Reduced maternal gestational
weight gain, increased preimplantation and postimplan-
tation loss, reduced fetal weight, fetal subdermal hemor-
rhagic thoracic and abdominal patches, and increased
incidences of reduced ossification in fetal caudal bones
were observed in all treatment groups. In addition, the
highest dose group exhibited increased resorptions,
reduced numbers of corpora lutea and fetuses per litter,
reduced implantations, reduced placental weight, and
reduced fetal length. No treatment-related gross visceral
abnormalities were seen in these studies.
Cobalt
Cobalt (Co) has important role in many processes,
including female reproduction54; it is an essential
element, but at high concentrations is toxic.55 However,
Co can be also acutely toxic in larger doses, cytotoxic,
and induce apoptosis and at higher concentrations causes
necrosis with inflammatory response. Co metal and salts
are also genotoxic, mainly cause oxidative DNA damage
Downloaded from het.sagepub.com by guest on December 1, 2014
5
by reactive oxygen species, perhaps combined with inhi-
bition of DNA repair.56 Chronic overexposure to Co may
result in toxic effects and exposure of pregnant and lac-
tating rats resulted in the development of oxidative stress
and the impairment of defense systems. Several studies
have been conducted with Co compounds to explore their
potential effect on fertility. Studies show that in animals
long-term exposure to Co-containing aerosols has
resulted in effects on reproductive end points. A signifi-
cant increase in the length of estrous cycle was reported
in female mice exposed to 11.4 mg of Co/m3 for 13
weeks.57 No effects on the female reproductive systems
were observed in rats similarly treated for 13 weeks.58,59
Co administration increases stress reactions in the ovar-
ian fragments by accumulation of heat shock protein
70, which increases the activity of super oxide dismutase
enzyme and catalyzes the rate of hydrogen peroxide for-
mation, overwhelming cell antioxidant defense. This
affects the normal physiological functions of ovaries.
60
Co radiation at high doses has been shown to elicit pro-
found decrements in reproductive ability in animal spe-
cies. Single doses of >100rad of 60Co radiation cause
decreased fertility in exposed female mice.60 Continuous
exposure of female mice to an average daily dose 8–16
rad/day causes a decreased number of offspring per litter
and decreased reproductive performance, with 100%
sterility occurring at 32 weeks of exposure at 8 rad/day.
Pedigo and Vernon61 reported that cobalt dichloride
(400 ppm in drinking water for 10 weeks) increases pre-
implantation losses of pregnant female rats. In utero Co
exposure has been extensively studied in animal species
and may elicit many substantial effects across many
organ systems in developing organism. Organs known
to be affected include the brain,62,63 eyes,64 hair,63 kid-
ney,64 liver,65 and so on. Devi et al.66 exposed pregnant
mice to a single dose of 0–50 rad of 60Co radiation on day
11.5 of gestation. A significant decrease in pup brain
weight and an increase in the incidence of micropthalmia
was seen at 10 rad, with decrease in head width, head
length, body length, and body weight occurring at higher
doses. Effects of Co on female reproductive system of
human includes menstrual problems, altered sexual
behavior, infertility, altered onset of puberty, altered
length of pregnancy, lactation problems, altered meno-
pause problems, and so on.
Copper
Copper in metallic form is not poisonous, but some
of its salts are poisonous such as blue vitriol and sub-
acetate. Copper is a powerful inhibitor of enzyme.
6 Human and Experimental Toxicology
Sources of copper are common in the diet, particu-
larly in vegetarian diets, and can be found in the
water due to copper plumbing.67 Many multiple vita-
mins contain relatively high doses of copper. The
hormone estrogen promotes the retention of copper
and this is why women are particularly vulnerable
to the problem of copper toxicity. Copper toxicity
may lead to poor fertility rate.68
Gold
Little is known about the maternal and fetal toxic
effects of gold-containing compounds in rodents. Kid-
ston et al.69 found that the injection of gold sodium
thiomalate into pregnant rats resulted in malformed
offspring. The administration of two gold-containing
compounds to rats, one orally and one subcuta-
neously, reported to cause maternal and embryo toxi-
city at high doses. At lower but still substantial
doses, a range of malformations resulted from expo-
sure to gold sodium thiomalate.70 Some other reports
suggested beneficial effects of gold on female repro-
ductive functions. They reported significant increase
in ovarian and uterine weight and stimulation
common recommendation for pregnant women to pre-
vent iron deficiency during pregnancy, the beneficial
effects of general iron supplementation on pregnancy
outcomes are a controversial issue.74
Until the past 10 years or so, the risk of iron
deficiency in Korean pregnant women was high with
a prevalence of approximately 20%,75 and a number
of reports are available on inverse association
between maternal iron status and pregnancy out-
comes.76,77 Recently, there has been an increasing
concern that pregnant women in Korea might be con-
suming excessive iron from supplements without
considering their dietary iron intake or iron status.
A recent survey has reported that 30–40% of Korean
women in their childbearing age consumed one or
more dietary supplements, and 47.3% of supplement
users took supplements on their own, without any
prescription.78 The amount of iron intake from sup-
plements alone was already twice the level of the
estimated average requirement (18.5 mg/day) for
pregnant women in Korea.79
The relationship between maternal hemoglobin
(Hb) concentrations and birth weight has been reported
to be of U-shaped.80 Recent studies have reported neg-
of ovarian 5-3-hydroxysteroid dehydrogenase
ative associations between high Hb concentrations
(5-3-HSD) activity and elevation of serum estra-
(>130 g/L) and pregnancy outcomes in diverse popula-
diol level were observed, following subcutaneous
tions in China,81 United States,81 Sweden,82 and
administration of gold chloride (0.2 mg/kg body
Korea.83 A possible explanation for this negative
weight/day) in immature female albino rats. More-
association is that excessive iron could lead to oxi-
over, normal cyclic changes of estrus were found
dative damage84 and decrease in the absorption of
in vaginal smears of these rats, whereas the rats of
copper and zinc,85 which are the important micronu-
other groups showed diestrus phase throughout the
trients for fetal growth.
period of experiment. Histological study of ovary
Previous studies have reported that general iron
also showed Graafian follicle with ovum in rats
supplementation have harmful effects on pregnancy
treated with 0.2 mg/kg/day of gold proving stimula-
outcomes.86 However, those studies have not taken
tion of reproductive function, which was not found in
into account the levels of iron intake from food. Even
the ovarian histological study of other groups includ-
though previous studies in the United States87 and
ing controls. Thus, the results suggest a significant
England88 have reported no relation between iron
stimulatory effect of gold chloride on female repro-
intake from both food and supplements and preg-
ductive activity in immature rats. Further, since the
nancy outcomes, fetal growth during pregnancy has
above-mentioned changes were evident at a specific
not been considered.
dose of gold chloride, the data may have some clin-
ical implications on stimulation and enhancement of
fertility in immature female rats.71 Lead
People in the general environment are exposed to Pb
Iron via food, drinking water, ambient air, dust, and soil.
Maternal iron status has been a critical factor for preg- The adverse effects of Pb on both male and female
nancy outcomes because maternal anemia as well as reproduction have been known for as much as a cen-
iron deficiency increases the risk of adverse preg- tury. Infertility, spontaneous abortions, and fetal and
nancy outcomes such as preterm delivery72 and low neonatal death have been reported after either male
birth weight.73 Although iron supplementation is a or female occupational exposure to Pb.89 In the early

Downloaded from het.sagepub.com by guest on December 1, 2014

Sengupta et al.
studies, such effects were usually associated with high
exposure levels. The evidence for effects resulting
from low to moderate exposure is less clear. In one
investigation, 831 pregnant women living near a Pb
smelter in Port Pirie, Australia, were studied prospec-
tively for Pb exposure and absorption, assessed by
blood Pb and pregnancy outcome.12 The exposed
women had a mean blood Pb concentration (PbB) of
100.6 mg/L and control women 76 mg/L. Preterm
delivery was significantly associated, in a dose-
response manner, with maternal PbB. No association
was detected for spontaneous abortion, low birth
weight (for births at term), intrauterine growth retar-
dation, premature rupture of the membranes, and con-
genital anomalies. Falcon et al.13 assessed the
relationship between placental Pb concentration and
outcomes of pregnancy. Higher placental Pb levels
were measured in premature rupture of membranes
and preterm pregnancies (gestational age 37 weeks)
compared with term pregnancies. The proportion of
abnormal pregnancy outcome associated with placen-
tal Pb concentrations above 120 ng/g was 40.6% ver-
sus 8.8% in placentas below this concentration.
Higher placental Pb levels were not generally related
to reduced size at birth. The literature on high Pb
exposure and abortion provides consistent evidence.14
In this study, spontaneous abortions were reported in
24% of women exposed to Pb, with a relative risk of
5.3, and an infant mortality more than doubled the Ita-
lian national rate at that time. In a survey carried out
by a questionnaire in more than 500 women, who had
worked at a smelter and were born between 1930 and
1959, the spontaneous abortion rates were highest
when the mother was employed during pregnancy
(13.9%) or had been employed before and was living
close to the smelter (17%). The frequency rate was
higher (19.4%) when the father worked at the smelter.
Because the smelter produced copper and Pb in addi-
tion to other metallurgical and chemical products, the
effects reported may not necessarily be attributed to
Pb alone.15 Other reports provide virtually no evi-
dence that low-to-moderate Pb exposure is associated
with an increased risk of spontaneous abortion.16 Hu
et al.17 provided interesting data on the pregnancies
of women who experienced Pb poisoning during their
childhood between 1930 and 1944. Because Pb is
stored in bone for decades, it was hypothesized that
demineralization of the skeleton might occur during
pregnancy. The proportion of pregnancies ending in
spontaneous abortion or stillbirth was approximately
30% among cases and 15% among controls. No
Downloaded from het.sagepub.com by guest on December 1, 2014
7
increased risk of spontaneous abortion was seen in
pregnancies fathered by Pb -poisoned men. Murphy
et al.18 compared the rates of spontaneous abortion
among 304 women living in the vicinity of a Pb smel-
ter with those of 335 nonexposed women. The geo-
metric mean PbB concentrations in the sample were
around 150 mg/L in exposed versus 50 mg/L in the not
exposed group. The rates of spontaneous abortions in
first pregnancies were similar, suggesting that the
reported low levels of exposure from the general envi-
ronment were not associated with increased risk of
abortion. The risk of spontaneous abortion of spouses
of male occupationally exposed to Pb seems less con-
sistent. Anttila and Sallmén19 summarized the epide-
miological studies on the possible impact of parental
occupational exposure to Pb or other metals on spon-
taneous abortion. They stated that no clear conclusion
could be reached for maternal exposure. The investi-
gation by Borja-Aburto et al.20 on pregnant women
environmentally exposed in Mexico City concluded
on the contrary that Pb exposures in the range
100–250 mg/L could have adverse effects on preg-
nancy and that some of the effects were noted close
to 100 mg/L. In a review, some researchers examined
studies conducted among populations with low-to-
moderate exposures, most of which provided little
evidence of an association with pregnancy loss or
spontaneous abortions. However, these studies were
hampered by small sample sizes, problems in defini-
tion or ascertainment of outcome, lack of controls for
confounding variables, and/or deficiencies in the
exposure assessment and evaluation of accumulated
dose. The author concluded that exposures compara-
ble to US general population levels during the 1970s
and to many populations worldwide today (i.e. far
lower than many occupational exposures) may
increase the risk for spontaneous abortion. Further
research is needed to confirm the association, to
delineate the role of maternal versus paternal expo-
sures, and to assess increases in menstrual variability
as an explanation for these findings.
In experimental animals, Pb has been shown to
reduce litter size, weight of the offspring, survival
rate, and to alter the maturation of the female repro-
ductive system or to interfere with the function in the
sexually mature animal.21 Examination of 48-h
embryos of dams exposed to Pb in their diet revealed
delays in early cell divisions, with fewer embryos
reaching the 8-cell stage. Although blastocyst forma-
tion seemed to be relatively resistant to Pb, impla-
ntation of blastocysts was impaired. Pb-exposed
8 Human and Experimental Toxicology

blastocysts were able to implant when transferred to a circulating LH and FSH and estradiol without produc-
Pb-free environment, although neither estrogen nor ing overt effects on general health and menstruation.94
progesterone levels in Pb-treated mice were signifi- The overall results of these investigations suggest that
cantly altered; the maximum binding capacity of uter- different levels of the hypothalamic–pituitary–gonad
ine cytosolic receptors for estradiol was increased in axis can be affected by exposure to Pb, mainly when
the Pb-treated animals. Coadministration of estrogens structures are undergoing rapid proliferation.
and progesterone with the Pb treatment prevented
implantation failure. The normally occurring increase Manganese
in estrogen and progesterone after implantation was
Manganese (Mn2þ) is a trace element that is essential
not observed in Pb-treated mice. These data suggest
for normal physiology and is predominantly obtained
that Pb interferes with ovarian steroid stimulation of
from food. Several lines of evidence, however, demon-
the endometrium.22,23 The onset of puberty was
strated that overexposure to manganese chloride exerts
delayed in female rats receiving Pb in drinking water
serious neurotoxicity, immunotoxicity, and develop-
from the time of weaning. Delays in vaginal opening
mental toxicity.95–97 Occupational exposure to Mn2þ
were also observed in their offspring exposed continu-
could occur often at the workplaces such as mines and
ously from conception to doses of Pb from 25–250
dried battery factories. In this respect, most studies on
ppm. No other effects on fertility or reproductive per-
the toxicological effects of Mn2þ have been focused on
formance were noted.90 Several studies have exam-
the men. Thus, reports in humans on the association
ined the importance of the exposure period. For
between Mn2þ exposure and adverse reproductive out-
example, Epstein et al.91 evaluated mice exposed at
comes in females are limited. A survey carried out in
premating, prenatal, and postnatal conditions. Com-
Australian general population found more frequent
pared with controls, prenatally and postnatally
stillbirths than expected in the group exposed to
exposed mice had slowed brain weight development,
Mn2þ.98 In rats, Mn2þ exposure reduced the number
lowered brain weight, and decreased DNA per brain,
of ovarian follicles and induced persistent corpora
but there was no effect on proteins per brain. In con-
lutea.99 Some researchers reported when Mn2þ admi-
trast, premating Pb exposure significantly increased
nistered acutely into the third ventricle, it has shown
brain weight and protein but significantly lowered
dose-dependent stimulation in LH release in prepuber-
DNA per brain. The latter effects could be due to
tal female rat, and this effect was due to a Mn2þ-
action of Pb on the developing maternal reproductive
induced stimulation of gonadotropin-releasing hor-
systems or on ovulation–fertilization. Time of expo-
mone. They have demonstrated that Mn2þ can stimu-
sure was also investigated by Ronis et al.92 when rats
late specific puberty-related hormones and suggested
were exposed to lead acetate in drinking water in
that it may facilitate the normal onset of puberty.
utero, pre-pubertally or post-pubertally. The most
According to them, Mn2þ may contribute to preco-
severe effects were observed in the ‘‘in utero’’-
cious puberty if an individual is exposed to elevated
exposed group, with delayed vaginal opening and dis-
levels of Mn2þ too early in developmental process.
rupted estrous cycling. These effects suggest Pb
They have also reported that rats exposed to Mn2þ for
actions on the hypothalamic pituitary axis and on
4 or 13 weeks showed a progressive and significant
gonadal steroid biosynthesis directly. McGivern
decrease in hypothalamic dopamine (DA), whereas
et al.93 administered lead acetate in drinking water
prolactin and pituitary transcription factor-1 messen-
to Sprague Dawley rat dams. Female offspring from
ger RNA (Pit-1 mRNA) levels increased in response
Pb-treated dams had significantly delayed vaginal
to Mn2þ exposure. These results suggest that exposure
opening, and 50% of them exhibited prolonged and
to Mn2þ decreases hypothalamic DA and promotes the
irregular periods of diestrus, accompanied by an
production of prolactin in the pituitary and that Pit-1
absence of observable corpora lutea. The release of
might be a regulator of DA and prolactin.97 In mice,
gonadotropins revealed irregular patterns of both
exposure during gestation led to fetal growth retarda-
follicle-stimulating hormone (FSH) and luteinizing
tion and anencephaly.98
hormone (LH). Alterations in pubertal progression and
hypothalamic–pituitary–ovarian–uterus functions
have been confirmed in female monkeys prenatally Mercury
or postnatally exposed to Pb. Blood levels of approxi- Limited data are available from epidemiological studies
mately 350 mg/L resulted in subclinical suppression of showing that mercury (Hg) disrupts female reproductive

Downloaded from het.sagepub.com by guest on December 1, 2014

Sengupta et al. 9

function. One recent study in girls examined the relation-
ship of organic Hg and other toxicants to timing of
menarche.99 No effects of Hg were found, although Hg
levels in the study population of girls were at or below
background levels observed in the general population.
However, earlier studies had noted menstrual cycle
changes in women who were exposed to higher levels
of Hg vapor (metallic) in the workplace.100 Decreased
fertility was noted in some dental health care workers
with increased exposure to Hg vapor and inorganic Hg
compounds.101 In contrast, a number of effects have
been described in experimental animals exposed to Hg,
including alterations in ovulation and estrous cycle. Hg
vapor (metallic) exposure resulted in prolonged estrous
cycles and alterations in progesterone and estradiol lev-
els, but primarily in animals with weight loss; morpholo-
gical changes in corpora lutea were also observed.
However, no adverse pregnancy outcomes (rate or num-
ber of implantation sites) were observed.102 Exposure of
nonhuman primates to 50 or 90 mg/kg/day methyl mer-
cury did not alter menstrual cycles or menses length
through four cycles. However, reproductive effects,
including failure to conceive and resorptions were
related to increased Hg blood levels.103 In female maca-
ques, blood levels greater than 1 ppm were associated
with decreased pregnancy rates and increased abortion
rates.104 Inorganic Hg was detected by photochemical
techniques within ovarian follicles and in the corpora
lutea of rats after chronic ingestion of mercuric chloride
(HgCl2; 1 mg/day) for 12 weeks. Estrous cycles were
prolonged in these animals.105 In golden hamsters, mer-
cury (HgCl2) was also localized to the corpora lutea after
inorganic mercury administration.106 Decreased ovula-
tion was observed at the third estrous cycle in these ani-
mals, which received 1 mg HgCl2/kg on the 4 days of the
estrous cycle. Progesterone levels in inorganic Hg-
treated animals were also different from controls.106
Watanabe and coworkers107 reported similar decreases
in ovulation in golden hamsters injected (subcuta-
neously) with 6.4 or 12.8 mg Hg/kg but found no altera-
tions in ovulation in animals treated with the same
amounts of methylmercury chloride. In a more recent
study, reproductive performance was evaluated for
mice, males and females, exposed to inorganic Hg pre-
mating, during mating and during gestation and lactation
(females only). Fertility and offspring survival were sig-
nificantly reduced, although litter size was not
affected.108 There are few mechanistic studies related
to Hg effects on female reproduction. Morphological
alterations in the actuate nucleus of the hypothalamus
were associated with changes in pituitary levels of
FSH and LH in hamsters treated with HgCl2 by
injection.109 The role of these alterations in regula-
tion of ovulation is not clear. Early development of
mouse embryos was disrupted after exposure to
methylmercury in vitro.110 Treatment of female
mice with 0.5 or 1 mg Hg/kg of methylmercury
chloride or HgCl2 on day 0 of gestation did not result
in increased abnormalities in embryos recovered on
day 3.5 of pregnancy. Exposures to higher levels of
Hg (up to 20 mg Hg/kg methylmercury and 2.5 mg
Hg/kg inorganic mercury) resulted in some abnorm-
alities. However, embryos exposed in vivo were less
sensitive to damage than those exposed in vitro.111
Nickel
The effects of nickel (Ni) exposure on female repro-
ductive function remain unclear, and available infor-
mation is sparse in both human and experimental
studies. An investigation carried out in the arctic
region of Russia showed a spontaneous abortion rate
of 15.9% in 356 women from a Ni refining plant com-
pared with 8.5% in a control group of 352 females
working in construction industry. Exposure concen-
trations were 0.08–0.196 mg Ni/m3, primarily as
nickel sulfate, and Ni concentrations in the urine ran-
ged from 3.2 to 22.6 mg/L.112 Ni exposure is reported
to affect early embryonic events in mice. Injection of
nickel chloride on the first day of pregnancy led to
decreased implantation frequency and reduced litter
size, whereas the administration on days 2–6 signifi-
cantly reduced litter sizes but did not modify implan-
tation. In vitro incubation inhibited growth of two-cell
stage embryos and development to blastocysts.113 In
more recent animal studies, no effect was demon-
strated on the length of the estrous cycle or micro-
scopic changes in the reproductive organs in mice
or rats exposed to air concentrations of nickel sulfate,
nickel oxide, or nickel subsulfide, ranging from 3 to
0.11 mg Ni/m3, respectively.114–116 Fertility was not
adversely affected in female rats exposed to nickel
chloride in drinking water.117 Other studies on histo-
logical alterations in reproductive tissues of rats
exposed to Ni or to nickel sulfate in drinking water
failed to show relevant effects.118
Platinum
After the introduction of automobile catalytic con-
verters, platinum, palladium, and rhodium have been
emitted with exhaust fumes, and increasing levels
have been found in different environmental matrices

Downloaded from het.sagepub.com by guest on December 1, 2014

10
such as road dusts, soils along heavily frequented
roads, and sediments of urban rivers. Compared with
other heavy metals, the biological availability of
platinum, palladium, and rhodium in some experi-
mental studies on road dusts ranged between that
of cadmium and Pb.119 As stated by the same
researchers, chronic effects on the biosphere cannot
be excluded because of (1) their cumulative increase
in the environment, (2) their unexpected high biolo-
gical availability and bioaccumulation, and (3) their
unknown toxicological and ecotoxicological pot-
ential. Many clinical cases of pregnant patients
affected by cancer treated by chemotherapy with
platinum complexes have been reported in the obste-
trical and gynecological scientific literature, with
births at term and normal infants. Male-mediated
effects on Sprague Dawley rats treated with a single
intraperitoneal injection of cis-platinum were stud-
ied by Kinkead et al.120 Significant preimplantation
loss was seen in the treated groups. The weights of
the fetuses were also significantly lower than those
of the control group. These results suggested that
cis-platinum has a deleterious effect on the female
reproductive system. Morphological and functional
effects on rat ovaries,121 embryotoxic effects in
rat122, embryo lethality, and teratogenic effects123
have been demonstrated after exposure to platinum
complexes.
Selenium
Many species of animals have reduced conception
rates when exposed to high concentrations of sele-
nium (Se). Both rats exposed to 3 ppm Se as selenifer-
ous wheat124 and mice exposed to 3 ppm selenate in
their drinking water125 had abnormally low rates of
conception. Decreased conception rates and increased
fetal resorption rates in cattle, sheep, and horses were
observed when they were fed natural diets containing
20–50 mg Se/kg diet.126 In contrast, in a study of
pigs sows were fed a basal diet (0.13 mg Se/kg)
supplemented with sodium selenite at 0, 2, 4, 8 or
16 mg/kg from the first estrous cycle though 9 weeks
postpartum demonstrated that conception rate, num-
ber of offspring and mortality rates of piglets were
unaffected by increase of Se concentration in the
feeds.127 These differences in clinical outcome could
simply be due to the differences in chemical form of
the Se. Embryos of avian species are very sensitive
to Se toxicosis. In one study, there was 100% mortal-
ity of embryos within 48 h postadministration of
Downloaded from het.sagepub.com by guest on December 1, 2014
Human and Experimental Toxicology
sodium selenite at 0.02 mg per embryo.128 But, on the
opposite end of the scale, eggs also have a very low
rate of hatching when hens are fed a diet of very low
Se concentrations.129 One field study demonstrated
that egg production and hatchability were decreased
when hens were fed a diet with Se at 1.55 mg Se/kg
dry matter.130 Studies with mallard eggs have shown
that selenomethionine is more embryotoxic than sele-
nite and its increased toxicity is likely due to its
increased accumulation in the eggs.131 Accumulation
of Se was approximately 10 times greater for groups
fed selenomethione in their diet than those fed sodium
selenite. When adult ducks were given Se at 10 mg
Se/kg as seleno-DL-methionine, seleno-L-methionine,
or selenized yeast, hatching of fertile eggs was sig-
nificantly lower for ducks fed seleno-DL-methionine
or seleno-L-methionine than for controls.132 Both
seleno-L-methionine and seleno-DL-methionine sig-
nificantly decreased the number of 6-day-old duck-
lings per hen and the former also decreased the
survival percentage to 6-days-old. Recent studies
on adverse effects of high dietary Se on reproduction
of birds have been reviewed by Hamilton133 and
Hoffman.134
Historically, Se toxicosis has been reported to
cause abortion in many species.135 The reports in
mammals have been difficult to prove, and there are
likely other factors that have in some cases led to mis-
diagnosis. However, teratogenesis due to selenosis is
well documented in avian species. Selenosis in poul-
try results in birth defects that include deformed or
lack of legs, toes, wings, beaks, and eyes in the
young.136 Field and research studies can differ in
interpretation of the effects of Se. Smith et al.137
reported congenital alkali disease in a 14-day-old colt
that was born to a mare that developed clinical signs
of selenosis during gestation. The clinical signs
observed in the young foal were very similar to those
normally observed in adult horses. Malformations of
lambs born to ewes that grazed on seleniferous soils
were reported by Beath et al.138 The eyes of the
lambs had cystic elevations that protruded through
the lids in addition to microphthalmia, rudimentary
development, and microcorneas. Many of the lambs
could not stand because of deformed legs with
thickening of the joints. However, different results
were observed when yearling ewes were fed high
concentrations of sodium selenite (24 mg Se/kg
of diet) or Astragalus bisulcatus (29 mg Se/kg) as
part of an alfalfa pellet for 88 days, as there was
no difference in the number of lambs born nor
Sengupta et al.
were there any defects.139 Se reportedly accumu-
lates to higher concentrations in the fetus at the
expense of the dam.140 This is thought to be a pro-
tective mechanism to allow neonates to have ade-
quate body reserves to sustain them until they
begin eating foods that would contain Se, as milk
has very little Se. Thus, the increased accumulation
of Se in the fetus may result in abortions, stillbirths
or weak/lethargic calves. In a field investigation,
Yaeger et al.141 reported that a 200-cow beef herd
in a high Se region of South Dakota fed alfalfa
with elevated Se concentrations experienced an
abortion/stillborn calf rate of 7%. Six of the seven
fetuses tested had markedly elevated hepatic Se
concentrations (11.36, 10.8, 6.15, 5.01, 3.59, and
3.33 ppm wet weight; normal range ¼ 0.3–1.2
ppm), while hepatic copper concentrations were
within the normal range. Hair sampled from the
cows contained 6.01 + 1.26 ppm dry weight (nor-
mal range ¼ 0.50–1.32 ppm). The data reported
suggested that subclinical Se toxicosis in pregnant
cows resulted in clinical Se toxicosis in the devel-
oping fetus. However, they reported that in an
experiment, in which pregnant cows were fed a diet
with high concentrations of selenite, they were
unable to successfully cause abortions and only one
cow in the high-dose group had a weak calf that
died shortly after birth and had increased hepatic
Se concentration.
Silver
Although the potential risk of silver nanoparticles
or colloidal silver to humans has recently increased
due to widespread application, their potential effects
on embryo–fetal development have not yet been
determined. Effect of silver, particularly in females’
reproductive functions, is quite contentious. Some
reports suggested silver has no known function in
the body and is not an essential mineral supplement.
Some women take colloidal silver during pregnancy
to aid the baby’s growth and health as well as the
mother’s delivery and recovery. Some articles
reported that during pregnancy, due to increased hor-
mone levels, the pH in the vagina drops to values that
are proper for the proliferation of Candida albicans,
the fungus responsible for yeast infections. Regular
antifungal substances cannot be used because of
the prohibition during pregnancy. Thus, colloidal sil-
ver has been reported to be highly efficient in the use
against candidiasis particularly if the regular diet
Downloaded from het.sagepub.com by guest on December 1, 2014
11
includes food items rich in probiotic cultures.
Although the pH level will remain modified during
the whole pregnancy period, at least the yeast infec-
tion will be under control. In addition, there are no
indications that colloidal silver has any harmful
effects on the baby or the evolution of the pregnancy.
Conversely, studies showed that colloidal silver
administered during pregnancy helps the baby’s
healthy development, it also makes delivery and
post-delivery recovery easier.142 While some other
studies reported intrauterine injection of 1% silver
nitrate on pregnancy resulted in vaginal bleeding,
beginning 1 or 2 days after treatment, that lasted for
an average of 5.3 days. In all cases, pregnancy was
terminated. Injection of normal saline had variable
sequelae, but four of six monkeys were delivered
as healthy offspring. They have also reported that after
animal recycling, two of the seven silver-treated ani-
mals subsequently became pregnant again and deliv-
ered normal healthy infants. This study demonstrates
the efficacy of intrauterine injection of 1% silver
nitrate in terminating early pregnancy.143
Vanadium
Vanadium is an important environmental and indus-
trial pollutant. It is a dilatory micronutrient and also
has been recently considered as a pharmacological
agent. Vanadium oxide (Vþ5) is a reproductive tox-
icant and exposure to it has the potential to nega-
tively influence the human reproductive system.
The severity and nature of the adverse effect is
variable and can be influenced by factors such as sex,
level of exposure, and individual sensitivity to the
chemical. Effects on the female reproductive sys-
tems can include menstrual problems, altered sexual
behavior, infertility, altered puberty onset, altered
length of pregnancy, lactation problems, altered
menopause onset, and pregnancy outcome. Adverse
effects of vanadium depend on the circulating levels
of this element. Among those effects, it is now well
established that vanadate (Vþ5) and vanadyl (Vþ4)
may be reproductive and developmental toxicants in
mammals. Decreased fertility, embryolethality, feto-
toxicity, and teratogenicity have been reported to
occur in rats, mice, and hamsters following vana-
dium exposure. The reproductive vanadium toxicity,
the maternal and embryo/fetal toxicity of this trace
element, the perinatal and postnatal effects of vana-
dium as well as the prevention by chelating agents
of vanadium-induced developmental toxicity are
12
reviewed here. The developmental effects of vana-
dium in pregnant diabetic rats are also reported.144
Environmental exposure to trivalent and pentava-
lent inorganic vanadium compounds has been
related to impaired different phases of reproduction.
Some researchers have investigated the effects of a
pentavalent inorganic vanadium compound on gen-
eral reproductive performance and fertility in both
male and female rats. Sexually mature female rats
were exposed to 200 ppm ammonium metavanadate
in drinking water for 70 days. The effects on female
fertility as well as developmental and postnatal
effects were evaluated throughout the exposure
period. The fertility was significantly reduced in the
treated group. The number of implantation sites and
the number of viable fetuses were significantly
reduced in pregnant females of both treated groups.
However, the number of resorptions, dead fetuses,
and pre- and postimplantation losses were reported
to be significantly increased. The incidence of
resorptions was significantly increased in the treated
female group compared with the untreated female
group. The behavioral responses as well as fetal
survival and viability indices were decreased in
both treated groups during the lactation period. The
incidence of these effects was more pronounced in
the treated female group. The morphological, visc-
eral, and skeletal anomalies were recorded signifi-
cantly increased in fetuses of the treated group,
with more pronounced effects.145 Vanadium also
reported to cause fibrosis in stroma, disorganized
uterine glands, and disruption of columnar epithelial
cells.146
Zinc
Zinc is a cofactor for many proteins, including tran-
scription factors and enzymes, important for a vari-
ety of cellular and developmental processes. Thus,
zinc deficiency is common in many parts of the
world and in certain populations in the United States.
Dietary zinc deficiency is known to cause develop-
mental problems throughout pregnancy. Maternal
zinc deficiency during pregnancy has been related
to adverse effects on progeny, and there are data
showing that mild to moderate zinc deficiency (as
assessed by available indicators) is quite common
in the developing world. Observational data relating
zinc deficiency to adverse fetal outcome have pro-
duced conflicting results, mainly because of the lack
of a valid indicator of zinc deficiency in pregnancy.
Downloaded from het.sagepub.com by guest on December 1, 2014
Human and Experimental Toxicology
Studies of human pregnancy and zinc supplementa-
tion, including those from developing countries,
have failed to document a consistent beneficial
effect on fetal growth, duration of gestation, and
early neonatal survival.147 Zinc can also impact the
developmental potential of oocytes. Acute zinc defi-
ciency causes meiotic defects in ovulated oocytes,
whereas dietary zinc deficiency in rats centered on
ovulation and fertilization results in lower quality
blastocyst embryos. Meiotic arrest before ovulation
and cumulus expansion are two zinc dependent
essential ovarian process. Cumulus expansion
requires activation of MAPK3/1 by EGF-LP and of
pSMAD2/3 by oocyte-secreted factors that together
stimulate the expansion-related transcripts Has2,
Ptgs2, Ptx3, and Tnfaip6 mRNA. Zinc deficiency
caused defects in oocyte maturation, cumulus expan-
sion, and gene expression in vitro.148
The teratogenic effects of severe zinc deficiency
were first observed in chicks hatched from hens fed
zinc-deficient diets. The offspring had numerous
skeletal defects and abnormalities of the brain.149
Subsequent studies soon showed that severe zinc
deficiency was also teratogenic in mammals. Hurley
and Swenerton reported that rats fed a zinc-deficient
diet throughout pregnancy had fewer offspring and
that they were growth retarded with multiple anoma-
lies.150 Every organ system displayed abnormalities
of development; malformations of the heart, lungs,
brain, and urogenital system were common. External
defects included misshaped heads and fused or miss-
ing digits of the feet. Similar defects were reported
later in zinc-deficient mice, sows, and ewes.
The underlying mechanism whereby severe zinc
deficiency causes developmental defects is not known
with certainty; however, it is likely to be the result
of the impairment of several metabolic functions.
Abnormal synthesis of nucleic acids and protein,
impaired cellular growth and morphogenesis, abnor-
mal tubulin polymerization with resultant reductions
in cellular motility and development, chromosomal
defects, excessive cell death, and excessive lipid per-
oxidation of cellular membranes may all occur in
severe zinc deficiency and contribute to teratogenic
effects.
Studies in experimental animals showed that the
only source of maternal tissue zinc available for the
developing fetus is that released from catabolized tis-
sue during anorexia. With diets totally devoid of zinc,
cyclic periods of anorexia occur throughout gestation.
However, this does not prevent multiple anomalies.
Sengupta et al.
Very little zinc is required to prevent these anomalies;
as little as 4 mg/g diet was sufficient for normal devel-
opment in rhesus monkeys. This is comparable with
2 mg/day in human diets. With marginal intakes in the
rat ranging from 2.5 to 9 mg/g diet, the onset of anor-
exia coincides with the sharp increase in placental
zinc transfer. Birth weights of monkeys with marginal
zinc intakes were higher in those animals with lower
plasma zinc concentrations and a higher degree of
anorexia. To what extent catabolism of maternal tis-
sue and subsequent zinc release offset insufficient
intakes in humans is unclear. However, taken
together, the data from animal studies support the
need for information on maternal energy and zinc
intakes along with measures of plasma zinc concen-
trations to clarify the relation between maternal zinc
status and pregnancy outcome.151
Mixed metal exposure
For humans, there are few recent studies on mixed
exposures to metals. Nordstrom and coworkers15
reported on the frequency of spontaneous abortions
and birth weights of children born near a copper
smelter in northern Sweden that emitted Pb, As
compounds, and sulfur dioxide. The comparison of
women working at the smelter with women not occu-
pationally exposed suggested increased frequencies of
abortions and depressed birth weights related to expo-
sure. Because of the low levels of exposure in the non-
occupationally exposed population and the inclusion
of smelter workers in the regional analysis, great care
must be taken in interpreting the results. Similar
results relating metal exposure to spontaneous abor-
tions have been reported by Hemminki and cowor-
kers.152 Hospital records, union memberships, and
census data were used to identify groups with poten-
tial metal exposure. In women belonging to the union
of metal workers, the rate of abortions was slightly
higher (7.82%, number of abortions; n ¼ 195) than the
national average (7.34%; n ¼ 24,107). The rate of
abortions for women belonging to union branches
with possible exposure to metals such as zinc, Co,
and As was compared for pregnancies during mem-
bership or for pregnancies before or after member-
ship. The rate of abortions for conceptions during
membership was again slightly higher than for non-
membership periods. In a community study in which
the major site of employment was a factory pro-
ducing zinc and Co, increased abortions were noted
for economically active women compared with all
Downloaded from het.sagepub.com by guest on December 1, 2014
13
women in the community and for wives of men
employed at the metallurgy factory compared with
the wives of all industrial workers. The number of
pregnancies among the female workers at the metal-
lurgical factory was too low to be evaluated. However,
data gathered from census and hospital records showed
that the rate of abortions among welders (9.5%; n ¼
28) was higher than for all industrial workers (8.2%;
n ¼ 2260).153 The effects of co-exposure to metals
on female reproductive function was demonstrated
in a study carried out by Belles et al.,154 focusing
on the developmental toxicity in mice of lead nitrate
(25 mg/kg, subcutaneously), methylmercury chlor-
ide (12.5 mg/kg, orally), and sodium arsenite (6
mg/kg, subcutaneously). Metals were administered
on gestation day 10 separately or in their binary and
ternary combinations. Maternal toxic effects were
more remarkable in the group concurrently exposed
to Pb, Hg, and As than in those given binary combi-
nations of the elements and in those given the metals
separately.145–160 With regard to developmental
toxicity, the most relevant effects, namely decreased
fetal weight and cleft palate, corresponded to the
Hg-treated groups. These data suggest that at the cur-
rent doses, the interactive effects of Pb and As on
Hg-induced developmental toxicity were not greater
than additive. In contrast, exposure of pregnant mice
to Pb and As at doses that were practically nontoxic
to dams, but administered concurrently with organic
Hg at a toxic dose, caused supra-additive interac-
tions in maternal toxicity.
Conclusion
Most published studies have reported the effects of a
single metal, although human exposure combines
toxic and essential metals that can interact. Influence
of other risk factors that can affect metal concentra-
tion and reproductive parameters in female is rarely
considered. Further research evaluating the effects
of a particular metal on reproductive health in female
should take into account the contribution of other
metals, agents, and the lifestyle. A combined analysis
could provide useful information about individual
health risk. Different scientific studies indicated that
the degree of toxic manifestation of different metals
depends on dose, duration, route of administration,
type of metal, condition of workplace, socioeconomic
status, history of disease, and other physiological fac-
tors. But extensive literature study has explored that
there is a gap of knowledge in the proper toxicity
14
survey. Current ongoing research projects will pro-
vide answers on the safety and effectiveness of expo-
sure of these metals, and further efforts should be
made to widen our knowledge in this area of research.
Conflict of interest
The authors declared no conflicts of interest.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
References
1. Sengupta P. Environmental and occupational expo-
sure of metals and their role in male reproductive
functions. Drug Chem Toxicol 2012; 36(3): 353–368.
2. Ernhart CB and Greene T. Postpartum changes in
maternal blood lead concentrations. Br J Ind Med
1992; 49(1): 11–13.
3. Sengupta P and Banerjee R. Environmental toxins:
alarming impacts of pesticides on male fertility. Hum
Exp Toxicol 2014; 33(10): 1017–1039.
4. Gerhard I, Waibel S, Daniel V, et al. Impact of heavy
metals on hormonal and immunological factors in
women with repeated miscarriages. Hum Reprod
Update 1998; 4(3): 301–309.
5. Apostoli P and Catalani S. Metal ions affecting repro-
duction and development. Met Ions Life Sci 2011; 8;
263–303.
6. Sharara FI, Seifer DB and Flaws JA. Environmental
toxicants and female reproduction. Fertil Steril
1998; 70(4): 613–622.
7. Gold EB and Tomich E. Occupational hazards to
fertility and pregnancy outcome. Occup Med
1994; 9(3): 435–469.
8. Gardella JR and Hill JA. Environmental toxins asso-
ciated with recurrent pregnancy loss. Semin Reprod
Med 2000; 8(4): 407–424.
9. Foster WG. Environmental toxicants and human fer-
tility. Minerva Ginecol 2003; 55(5): 451–457.
10. Kumar S. Occupational exposure associated with
reproductive dysfunction. J Occup Health 2004;
46(1): 1–19.
11. Dutta S, Joshi KR, Sengupta P, et al. Unilateral and
bilateral cryptorchidism and its effect on the testicular
morphology, histology, accessory sex organs and
sperm count in laboratory mice. J Hum Reprod Sci
2013; 6(2): 106–110.
12. McMichael AJ, Vimpani GV, Robertson EF, et al.
The port pirie cohort study: maternal blood lead and
Downloaded from het.sagepub.com by guest on December 1, 2014
Human and Experimental Toxicology
pregnancy outcome. Epidemiol Commun Health
1986; 40(1): 18–25.
13. Falcon M, Vifias P and Luna A. Placental lead and
outcome of pregnancy. Toxicology 2003; 185: 59–66.
14. Sengupta P. The laboratory rat: relating its age with
humans. Int J Prev Med 2013; 4(6): 624–630.
15. Nordstrom S, Beckman L and Nordenson I. Occupa-
tional and environmental risks in and around a smel-
ter in northern Sweden. Hereditas 1978; 88: 43–46.
16. Sengupta P. Potential health impacts of hard water.
Int J Prev Med 2013; 4(8): 866–875.
17. Hu H, Pepper L and Goldman R. Effect of repeated
occupational exposure to lead, cessation of exposure,
and chelation on levels of lead in bone. Am J Med
1991; 20: 723–735.
18. Murphy MJ, Graziano JH, Popovac D, et al. Past
pregnancy outcomes among women living in the
vicinity of a lead smelter in Kosovo, Yugoslavia.
Am J Public Health 1990; 80(1): 33–35.
19. Anttila A and Sallmén M. Effects of parental occupa-
tional exposure to lead and other metals on sponta-
neous abortion. J Occup Environ Med 1995; 37(8):
915–921.
20. Borja-Aburto VH, Hertz-Picciotto I, Rojas Lopez M,
et al. Blood lead levels measured prospectively and
risk of spontaneous abortion. Am J Epidemiol 1999;
150(6): 590–597.
21. WHO. Environmental health criteria 3: lead.
Geneva: WHO, 1990, p. 160.
22. Wide M. Reproductive and developmental toxicity
of metals. In: Clarkson TW, Nordberg GF and Sager
PR (eds) New York: Plenum Press, 1983, pp.
343–356.
23. Wide M and Wide L. Estradiol receptor activity in
uteri of pregnant mice given lead before implantation.
Fertil Steril 1980; 34: 503–508.
24. Tabacova S, Baird DD, Balabaeva L, et al. Placental
arsenic and cadmium in relation to lipid peroxides
and glutathione levels in maternal-infant pairs from
a copper smelter area. Placenta 1994; 8: 873–881.
25. Aschengrau A, Zierler S and Cohen A. Quality of com-
munity drinking water and the occurrence of sponta-
neous abortion. Arch Environ Health 1989; 44(5):
283–290.
26. Ihrig MM, Shalat SL and Baynes C. A hospital-based
case-control study of stillbirths and environmental
exposure to arsenic using an atmospheric dispersion
model linked to a geographical information system.
Epidemiology 1998; 9(3): 290–294.
27. Sengupta P and Sahoo S. A cross sectional study to
evaluate the fitness pattern among the young fishermen
Sengupta et al.
of coastal Orissa. Indian J Pub Health Res Dev 2013;
4(1): 171–175.
28. Schroeder HA and Mitchener M. Toxic effects of
trace elements on the reproduction of mice and rats.
Arch Environ Health 1971; 23: 102–106.
29. Holson JF, Desesso JM, Jacobson CF, et al. Appro-
priate use of animal models in the assessment of risk
during prenatal development: an illustration using
inorganic arsenic. Teratology 2000; 62(1): 51–71.
30. Prukop JA and Savage NL. Some effects of multiple,
sublethal doses of monosodium methanearsonate
(MSMA) herbicide on hematology, growth, and
reproduction of laboratory mice. Bull Environ Con-
tam Toxicol 1996; 36(3): 337–341.
31. Holson JF, Stump DG, Ulrich CE, et al. Absence of
prenatal developmental toxicity from inhaled arsenic
trioxide in rats. Toxicol Sci 1999; 51(1): 87–97.
32. Bakirdere S, Örenay S and Korkmaz M. Effect of
boron on human health. Open Min Process J 2010;
3: 54–59.
33. EVM (Expert Group on Vitamins and Minerals). Part
3: trace elements—chromium. In safe upper levels for
vitamins and minerals: Report of the expert group on
vitamins and minerals. London: Food Standards
Agency (FSA), 2003, pp. 172–179.
34. Naghii MR and Samman S. The effect of boron sup-
plementation on its urinary secretion and selected car-
diovascular risk factors in healthy male subjects. Biol
Trace Elem Res 1995; 56: 273–286.
35. Dumitrescu G, Drinceanu D, Ştef L, et al. Study of
the effect of boron supplementation in the feed of
broiler chickens on the histological structure of the
tibia. Anim Sci Biotech 2012; 45: 149–156.
36. Whorton MD, Haas JL, Trent L, et al. Reproductive
effects of sodium borates on male employees: birth
rate assessment. Occup Environ Med 1994; 51:
761–767.
37. Sipowicz M, Kostrzewska A, Laudanski T, et al.
Effects of cadmium on myometrial activity of the
nonpregnant human. Interactions with calcium and
oxytocin. Acta Obstet Gynecol Scand 1995; 74(2):
93–96.
38. Paksy K, Rajczy K, Forgacs Z, et al. Effect of cad-
mium on morphology and steroidogenesis of cultured
human ovarian granulosa cells. J Appl Toxicol 1997;
17(5): 321–327.
39. Saksena SK. Cadmium: its effects on ovulation, egg
transport and pregnancy in the rabbit. Contraception
1997; 26: 181–192.
40. Schmid BP, Hall JL, Goulding E, et al. In vitro expo-
sure of male and female mice gametes to cadmium
Downloaded from het.sagepub.com by guest on December 1, 2014
15
chloride during the fertilization process, and its
effects on pregnancy outcome. Toxicol Appl Pharma-
col 1983; 69: 326–332.
41. Baranski B. Effect of cadmium on prenatal develop-
ment and on tissue cadmium, copper, and zinc con-
centrations in rats. Environ Res 1987; 42(1): 54–62.
42. Piasek M and Laskey JW. Effects of in vitro cadmium
exposure on ovarian steroidogenesis in rats. J Appl
Toxicol 1999; 19(3): 211–217.
43. Henson MC and Chedrese PJ. Endocrine disruption
by cadmium, a common environmental toxicant with
paradoxical effects on reproduction. Exp Biol Med
(Maywood) 2004; 229(5): 383–392.
44. Johnson MD, Kenney N, Stoica A, et al. Cadmium
mimics the in vivo effects of estrogen in the uterus and
mammary gland. Nat Med 2003; 9(8): 1081–1084.
45. Shmitova LA. Content of hexavalent chromium in the
biological substrates of pregnant women and puer-
perae engaged in the manufacture of chromium com-
pounds. Gig Tr Prof Zabol 1980; 2: 33–35.
46. Bonde JP. Semen quality and sex hormones among
mild steel and stainless steel welders: a cross sec-
tional study. Int J Androl 1993; 16(Suppl 1): 1–29.
47. Hjollund NH, Bonde JP, Jensen TK, et al.
Male-mediated spontaneous abortion among spouses
of stainless steel welders. Scand J Work Environ
Health 2000; 26: 187–192.
48. Al-Hamood MH, Elbetieha A and Bataineh H. Sexual
maturation and fertility of male and female mice
exposed prenatally and postnatally to trivalent and
hexavalent chromium compounds. Reprod Fertil Dev
1998; 10(2): 179–183.
49. Iijima S, Matsumoto N and Lu CC. Transfer of chro-
mic chloride to embryonic mice and changes in the
embryonic mouse neuroepithelium. Toxicology
1983; 26: 257–265.
50. Murthy RC, Junaid M and Saxena DK. Ovarian dys-
function in mice following chromium (VI) exposure.
Toxicol Lett 1996; 89(2): 147–154.
51. Kanojia RK, Junaid M and Murthy RC. Embryo and
fetotoxicity of hexavalent chromium: a long-term
study. Toxicol Lett 1998; 95(3): 165–172.
52. Elbetieha A and Al-Hamood MH. Long-term expo-
sure of male and female mice to trivalent and hexava-
lent chromium compounds: effect on fertility.
Toxicology 1997; 116(1–3): 39–47.
53. Junaid M, Murthy RC and Saxena DK. Embryo and
fetotoxicity of chromium in pregestationally exposed
mice. Toxicol Lett 1996; 84(3): 143–148.
54. Ashmead HD. Comparative intestinal absorption and
subsequent metabolism of metal amino acid chelates
16
and inorganic salts. In: Ashmead HD (ed) The roles of
amino acid chelates in animal nutrition. Park Ridge:
Noyes Publishers, 1993, pp. 47–75.
55. Kubrak OI, Husak VV, Rovenko BM, et al.
Cobalt-induced oxidative stress in brain, liver and
kidney of goldfish Carassius auratus. Chemosphere
2011; 85: 983–989.
56. Simonsen LO, Harbak H and Bennekou P. Cobalt
metabolism and toxicology—a brief update. Sci Total
Environ 2012; 432: 210–215.
57. Bucher JR, Elwell MR, Thompson MB, et al. Inhala-
tion toxicity studies of cobalt sulphate in F344/N rats
and B6C3F1 mice. Fund Appl Toxicol 1990; 15:
357–372.
58. Bucher JR, Hailey JR, Roycroft JR, et al. Inhalation
toxicity and carcinogenicity studies of cobalt sul-
phate. Toxicol Sci 1999; 49: 56–67.
59. NTP. Toxicity studies of cobalt sulphate heptahydrate
(CAS No. 10026-24 -1) in F344/N rats and B6C3F1 mice
(inhalation studies). Research Triangle Park: United
States Department of Health and Human Services,
National Institutes of Health, National Toxicology
Program (NIH Publication No. 91-3124), 1991.
60. Philippe JV. Fertility and irradiation: a preconcep-
tional investigation in teratology. Am J Obstet Gyne-
col 1975; 123(7): 714–718.
61. Pedigo NG and Vernon MW. Embryonic losses after
10-week administration of cobalt to male mice.
Reprod Toxicol 1993; 7: 111–116.
62. Brizzee KR, Ordy JM and Kaak B. Prenatal cobalt-60
irradiation effects on early postnatal development of
the squirrel monkey offspring. DOE Symp Ser 1978;
47: 204–227.
63. Bruni JE, Persaud TVN, Froese G, et al. Effect of in
utero exposure to low dose ioinizing on development
in the rat. Histol Histopathol 1994; 9: 27–33.
64. Hirobe T. Effects of g-irradiation on the yield of
mid-ventral white spots in mice in different genetic
backgrounds and at different times during develop-
ment. Mutat Res 1994; 322: 213–220.
65. Benjamin SA, Lee AC, Angleton GM, et al. Mortality
in beagles irradiated during prenatal and postnatal
development. I. Contribution of non-neoplastic dis-
eases. Radiat Res 1998; 150: 316–329.
66. Devi UP, Hossain M and Bisht KS. Effect of gamma
radiation on the foetal haemopoietic system in the
mouse. Int J Radiat Biol 1998; 74(5): 639–646.
67. Sinkovic A, Strdin A and Svensek F. Severe acute
copper sulphate poisoning: a case report, severe acute
copper sulphate poisoning: a case report. Arh Hig
Rada Toksikol 2008; 59(1): 31–35.
Downloaded from het.sagepub.com by guest on December 1, 2014
Human and Experimental Toxicology
68. Franchitto N, Gandia-Mailly P, Georges B, et al.
Acute copper sulphate poisoning: a case report and
literature review. Resuscitation 2008; 78(1): 92–96.
69. Kidston MEF, Beck J and Llyod B. The teratogenic
effect of myocrysin injection in rats. J Anat 1971;
108: 590–591.
70. Szabo KT, Guerriero FJ and Kang YJ. The effects
of gold-containing compounds on pregnant rats and
their fetuses. Vet Path 1978; 5: 89–96.
71. Chattopadhyay A, Sarkar M and Biswas NM. Effect
of gold on stimulation of reproductive function in
immature female albino rats. Indian J Exp Biol
2006; 44: 971–975.
72. Scholl T, Hediger M, Fischer R, et al. Anemia vs iron
deficiency: increased risk of preterm delivery in a
prospective study. Am J Clin Nutr 1992; 12: 985–988.
73. Allen LH. Anemia and iron deficiency: effects on
pregnancy outcome. Am J Clin Nutr 2000; 12:
1280S–1284S.
74. Preziosi P, Prual A, Galan P, et al. Effect of iron sup-
plementation on the iron status of pregnant women:
consequences for newborns. Am J Clin Nutr 1997;
12: 1178–1182.
75. Kim EK and Lee KH. Iron status in pregnant women
and their newborn infants. Korean J Nutr 1999; 12:
793–801.
76. Lee JI, Kang SA, Kim SK, et al. A cross sectional
study of maternal iron status of Korean women during
pregnancy. Nutr Res 2002; 12: 1377–1388.
77. Kim TH, Lee HH, Chung SH, et al. Risk factors of
preterm delivery and survival rate of preterm infants
in Bucheon. Korean J Obstet Gynecol 2010; 12:
29–34.
78. Korean Ministry of Health and Welfare. The Korean
national health nutrition examination survey 2008.
Seoul: Korean Ministry of Health and Welfare, 2009.
79. Jang HM and Ahn HS. Serum iron concentration of
maternal and umbilical cord blood during pregnancy.
Korean J Comm Nutr 2005; 12: 860–868.
80. Yip R. Significance of an abnormally low or high
hemoglobin concentration during pregnancy: special
consideration of iron nutrition. Am J Clin Nutr
2000; 12: 272S–279S.
81. Scanlon KS, Yip R, Schieve LA, et al. High and low
hemoglobin levels during pregnancy: differential
risks for preterm birth and small for gestational age.
Obstet Gynecol 2000; 12: 741–748.
82. Stephansson O, Dickman PW, Johansson A, et al.
Maternal hemoglobin concentration during preg-
nancy and risk of stillbirth. JAMA 2000; 12:
2611–2617.
Sengupta et al.
83. Bai HS, Lee GJ, Lee MS, et al. Iron status indices of
maternal, umbilical cord, placenta and birth weight.
Korean J Comm Nutr 2002; 12: 686–695.
84. Puntarulo S. Iron, oxidative stress and human health.
Mol Aspects Med 2005; 12: 299–312.
85. Sandström B. Micronutrient interactions: effects on
absorption and bioavailability. Br J Nutr 2001; 12:
181–185.
86. Ziaei S, Norrozi M, Faghihzadeh S, et al. A rando-
mised placebo-controlled trial to determine the effect
of iron supplementation on pregnancy outcome in
pregnant women with haemoglobin 13.2 g/dl.
BJOG 2007; 12: 684–688.
87. Bawadi HA, Al-Kuran O, Al-Bastoni LA, et al.
Gestational nutrition improves outcomes of vaginal
deliveries in Jordan: an epidemiologic screening.
Nutr Res 2010; 12: 110–117.
88. Mathews F, Yudkin P and Neil A. Influence of mater-
nal nutrition on outcome of pregnancy: prospective
cohort study. BMJ 1999; 12: 339–343.
89. Dutta S, Joshi KR, Sengupta P, et al. Unilateral and
bilateral cryptorchidism and its effect on the testicular
morphology, histology, accessory sex organs and
sperm count in laboratory mice. J Hum Repro Sci
2013; 6(2): 106–110.
90. Kimmel CA, Grant LD, Sloan CS, et al. Chronic
low-level lead toxicity in the rat. Toxicol Appl Phar-
macol 1980; 56: 28–41.
91. Epstein HT, Newton JT and Fenton K. Lead
effects on offspring depend on when mouse moth-
ers were exposed to lead. Biol Neonatol 1999; 75:
272–278.
92. Ronis MJJ, Badger TM, Shema SJ, et al. Reproduc-
tive toxicity and growth effects in rats exposed to lead
at different periods during development. Toxicol Appl
Pharmacol 1996; 136: 361–371.
93. McGivern RF, Sokol RZ and Berman NG. Prenatal
lead exposure in the rat during the third week of
gestation: long-term behavioral, physiological, and
anatomical effects associated with reproduction. Tox-
icol Appl Pharmacol 1991; 110(2): 206–215.
94. Foster WG and Younglai EV. An immunohistochem-
ical study of the bulb and accessory study of the
GnRH neuron in hypothalamus. Am J Anat 1991;
191(3): 293–300.
95. Tsuchiya H, Shima S, Kurita H, et al. Effects of
maternal exposure to six heavy metals on fetal devel-
opment. Bull Environ Contamin Toxicol 1987; 38:
580–587.
96. Laudanski T, Sipowicz M, Modzelewski P, et al.
Influence of high lead and cadmium soil content on
Downloaded from het.sagepub.com by guest on December 1, 2014
17
human reproductive outcome. Int J Gynaecol Obstet
1991; 36(4): 309–315.
97. Pine M, Lee B, Dearth R, et al. Manganese acts cen-
trally to stimulate luteinizing hormone secretion: a
potential influence on female pubertal development.
Toxicol Sci 2005; 85: 880–885.
98. Sanchez DJ, Domingo JL, Llobet JM, et al. Maternal
and developmental toxicity of manganese in the
mouse. Toxicol Lett 1993; 69: 45–52.
99. Denham M, Schell LM, Deane G, et al. Relationship
of lead, mercury, Mirex, DDE, HCB, and PCBs to age
at menarche among akwesasne mohawk girls. Pedia-
trics 2005; 115(2): 127–134.
100. Sikorski R, Jiszkiewicz T, Pasckowski T, et al.
Women in dental surgeries: reproductive hazards in
occupational exposure to metallic mercury. Int Arch
Occup Environ Health 1987; 59: 551–557.
101. Rowland AS, Baird DD, Weinberg CR, et al. The
effect of occupational exposure to mercury vapour
on the fertility of female dental assistants. Occup
Environ Med 1994; 51(1): 28–34.
102. Davis BJ, Price HC, O’Connor RW, et al. Mercury
vapor and female reproductive toxicity. Toxicol Sci
2001; 59: 291–296.
103. Burbacher TM, Shen DD, Liberato N, et al. Compar-
ison of blood and brain mercury levels in infant
monkeys exposed to methylmercury or vaccines
containing thimerosal. Environ Health Perspect
2005; 113: 1015–1021.
104. Mottet NK, Shaw CM and Burbacher TM. Health
risks from increases in methylmercury exposure.
Environ Health Perspect 1985; 63: 133–140.
105. Stadnicka A. Localization of mercury in the rat ovary
after oral administration of mercuric chloride. Acta
Histochem 1980; 67: 227–233.
106. Lamperti AA and Printz RH. Localization, accumula-
tion, and toxic effects of mercuric chloride on the
reproductive axis of the female hamster. Biol Reprod
1974; 11: 180–186.
107. Watanabe C, Inaoka T, Matsui T, et al. Effects of
arsenic on younger generations. J Environ Sci Health
A Tox Hazard Subst Environ Eng 2003; 38(1):
129–139.
108. Khan A, Atkinson Graham TC, Thompson S, et al.
Effects of inorganic mercury on reproductive perfor-
mance of mice. Food Chem Toxicol 2004; 42:
571–577.
109. Lamperti AA and Niewenhuis R. The effects of
mercury on the structure and function of the
hypothalamo-pituitary axis in the hamster. Cell Tis-
sue Res 1976; 170: 315–324.
18
110. Matsumoto N and Spinale A. Sensitivity of early
mouse embryos to methylmercury toxicity. Toxicol
Appl Pharmacol 1982; 64: 108–117.
111. Kajiwara Y and Inouye M. Effects of methylmercury
and mercuric chloride on preimplantation mouse
embryos in vivo. Teratology 1986; 33(2): 231–237.
112. Chashschin VP, Artunina GP and Norseth T. Conge-
nital defects, abortion and other health effects in
nickel refinery workers. Sci Tot Environ 1994; 148:
287–291.
113. Storeng R and Jonsen J. Nickel toxicity in early
embryogenesis in mice. Toxicology 1991; 20: 45–51.
114. NTP. NTP Technical Report on the Toxicology and
Carcinogenesis Studies of Nickel Oxide. (CAS No.
1313-99-1) in F344 Rats and B6C3F1 Mice (Inhala-
tion Studies). Natl Toxicol Program Tech Rep Ser
1996; 451: 1–381.
115. NTP. NTP Technical Report on the Toxicology and
Carcinogenesis Studies of Nickel Subsulphide. (CAS
No. 12035-72-2) in F344 Rats and B6C3F1 Mice
(Inhalation Studies). Natl Toxicol Program Tech Rep
Ser 1996; 453: 1–365.
116. NTP. NTP Technical Report on the Toxicology and
Carcinogenesis Studies of Nickel Sulphate Hexahy-
drate. (CAS No. 10101-97-0) ) in F344 Rats and
B6C3F1 Mice (Inhalation Studies). Natl Toxicol Pro-
gram Tech Rep Ser 1996; 454: 1–380.
117. Käkelä R, Kakita A and Hyvarinen H. Effects of nickel
chloride on reproduction of the rat and possible antag-
onistic role of selenium. Comp Biochem Physiol C
Pharmacol Toxicol Endocrinol 1999; 123(1): 27–37.
118. Obone E, Chakrabarti SK, Bai C, et al. Toxicity and
bioaccumulation of nickel sulfate in Sprague-Dawley
rats following 13 weeks of subchronic exposure. J
Toxicol Environ Health A 1999; 57(6): 379–401.
119. Zimmermann S and Sures B. Significance of plati-
num group metals emitted from automobile exhaust
gas converters for the biosphere. Environ Sci Pollut
Res Int 2004; 11: 194–199.
120. Kinkead T, Flores C, Carboni AA, et al. Short term
effects of cis-platinum on male reproduction, fertility
and pregnancy outcome. J Urol 1992; 147: 201–206.
121. Borovskaya TG, Golberg VE, Fomina TI, et al. Mor-
phological and functional state of rat ovaries in early
and late periods after administration of platinum
cytostatics. Bull Exp Biol Med 2004; 137: 331–335.
122. Chug MK, Kim JC and Roh JK. Embryotoxic effects
of SKI 2053R, a new potential anticancer agent, in
rats. Reprod Toxicol 1998; 12: 375–381.
123. Ognio E, Lapide M, Ottone M, et al. Embryo-lethal
and teratogenic effect of the new platinum compound
Downloaded from het.sagepub.com by guest on December 1, 2014
Human and Experimental Toxicology
DPR in pregnant mice. Arch Toxicol 2003; 77:
584–590.
124. Munsell HE, Devaney GM and Kennedy MH. Toxi-
city of food containing selenium as shown by its effect
on the rat, USDA Tech Bull No 534. Washington:
USDA, 1936, p. 25.
125. Schroeder HA and Mitchener M. Selenium and tellur-
ium in mice: effects on growth, survival and tumors.
Arch Environ Health 1972; 24: 66.
126. Harr JR and Muth OH. Selenium poisoning in domes-
tic animals and its relationship to man. Clin Toxicol
1972; 5: 175–186.
127. Poulsen HD, Danielsen V, Nielsen TK, et al. Exces-
sive dietary selenium to primiparous sows and their
offspring. I. Influence on reproduction and growth.
Acta Vet Scand 1989; 30: 371–378.
128. Szeleszczuk P, Karpinska E, Bielecki W, et al. Eva-
luation of lithium and selenium toxicity for chicken
embryos and one day old chicks. Medycyna-Wetery-
naryjna 2004; 60: 492–495.
129. Ort JF and Latshaw JD. The toxic level of sodium
selenite in the diet of laying chickens. J Nutr 1978;
108: 1114–1120.
130. Kinder LL, Angel CR and Anthony NB. Apparent
selenium toxicity in emus (Dromaius novaehollan-
diae). Avian Dis 1995; 39: 652–657.
131. Heinz GH, Hoffman DJ, Krynitsky AJ, et al. Repro-
duction of mallards fed selenium. Environ Toxicol
Chem 1987; 6: 423–433.
132. Heinz GH and Hoffman DJ. Comparison of the
effects of seleno-L-methionine, seleno-DL-methioine,
and selenized yeast on reproduction of mallards.
Environ Pollut 1996; 91: 169–175.
133. Hamilton SJ. Review of selenium toxicity in the aqua-
tic food chain. Sci Total Environ 2004; 326: 1–31.
134. Hoffman DJ. Role of selenium toxicity and oxidative
stress in aquatic birds. Aquat Toxicol 2002; 57: 11–26.
135. Raisbeck MF. Selenosis. Vet Clin North Am Food
Anim Pract 2000; 16: 465–480.
136. Latshaw JD, Morishita TY, Sarver CR, et al. Sele-
nium toxicity in breeding ring-necked pheasants
(Phasianus colchicus). Avian Dis 2004; 48: 935–939.
137. Smith MI, Franke KW and Westfall BB. The sele-
nium problem in relation to public health. A prelimi-
nary survey to determine the possibility of selenium
intoxication in the rural population living on seleni-
ferous soil. US Public Health Rept 1936; 51:
1496–1505.
138. Beath OA, Eppson HF, Gilbert CS, et al. Poisonous
plants and livestock poisoning. Wyo Agr Exp Sta Bull
1939; 231: 1–104.
Sengupta et al.
139. Panter KE, James LF and Mayland HF. Reproductive
response of ewes fed alfalfa pellets containing sodium
selenite or Astragalus bisulcatus as a selenium
source. Vet Hum Toxicol 1995; 37: 30–32.
140. Puls R. Mineral Levels in Animal Health. 2nd ed.
Diagnostic data. British Columbia: Sherpa Interna-
tional, 1994.
141. Yaeger MJ, Neiger RD, Holler L, et al. The effect of
subclinical selenium toxicosis on pregnant beef cat-
tle. J Vet Diagn Invest 1998; 10: 268–273.
142. Yu WJ, Son JM, Lee J, et al. Effects of silver nanopar-
ticles on pregnant dams and embryo-fetal development
in rats. Nanotoxicology 2014; 8(Suppl 1): 85–91.
143. Dubin NH, Parmley TH, Cox RT, et al. Effect of sil-
ver nitrate on pregnancy termination in cynomolgus
monkeys. Fertil Steril 198; 36(1): 106–109.
144. Domingo JL. Vanadium: a review of the reproductive
and developmental toxicity. Reprod Toxicol 1996;
10(3): 175–182.
145. Morgan AM and El-Tawil OS. Effects of ammonium
metavanadate on fertility and reproductive perfor-
mance of adult male and female rats. Pharmacol Res
2003; 47(1): 75–85.
146. Shrivastava S, Jadon A, Shukla S, et al. Chelation
therapy and vanadium: effect on reproductive organs
in rats. Indian J Exp Biol 2007; 45(6): 515–523.
147. Shah D and Sachdev HP. Zinc deficiency in preg-
nancy and fetal outcome. Nutr Rev 2006; 64: 15–30.
148. Lisle RS, Anthony K, Randall MA, et al.
Oocyte-cumulus cell interactions regulate free intra-
cellular zinc in mouse oocytes. Reproduction 2013;
145: 381–390.
149. Keinholz EW, Turk DE, Sunde ML, et al. Effects of zinc
deficiency in the diets of hens. J Nutr 1961; 75: 211–221.
150. Hurley LS and Swenerton H. Congenital malforma-
tions resulting from zinc deficiency in rats. Proc Soc
Exp Biol Med 1966; 123: 692–697.
Downloaded from het.sagepub.com by guest on December 1, 2014
19
151. Brenton DP, Jackson MJ and Young A. Two preg-
nancies in a patient with acrodermatitis entero-
pathica treated with zinc sulphate. Lancet 1981; 2:
500–502.
152. Hemminki K, Niemi ML, Kostinen K, et al. Sponta-
neous abortions among women employed in the metal
industry in Finland. Int Arch Occup Environ Health
1980; 47: 53–60.
153. Hemminki K, Niemi ML, Kyyronen P, et al. Sponta-
neous abortion as risk indicator in metal exposure. In:
Clarkson TW, Nordberg GF and Sager PR (eds)
Reproductive and developmental toxicity of metals.
New York: Plenum Press, 1983, pp. 369–379.
154. Belles M, Albina ML, Sanchez DJ, et al. Interactions
in developmental toxicology: effects of concurrent
exposure to lead, organic mercury, and arsenic in
pregnant mice. Arch Environ Contam Toxicol 2002;
4: 293–298.
155. Krajewska-Kulak E and Sengupta P. Thyroid function
in male infertility. Front Endocrinol 2013; 4: 1–2.
156. Sengupta P. Current trends of male reproductive
health disorders and the changing semen quality. Int
J Prev Med 2014; 5(1): 1–5.
157. Bhattarai T, Chaudhuri P, Bhattacharya K, et al. Effect
of progesterone supplementation on post-coital uni-
laterally ovariectomized superovulated mice in rela-
tion to implantation and pregnancy. Asian J Pharm
Clin Res 2014; 7(1): 29–31.
158. Sengupta P. Recent trends in male reproductive
health problems. Asian J Pharm Clin Res 2014;
7(2): 1–5.
159. Chaudhuri P, Bhattacharya K and Sengupta P. Misty
role of amygdala in female reproductive behavior. Int
J Pharm Pharm Sci 2014; 6(2): 563–564.
160. Sengupta P. The bliss yoga inculcates during the dif-
ferent stages of pregnancy. Int J Pharm Pharm Sci
2014; 6(10): 86–87.