The Health Consequences of Smoking

A Report of the Surgeon General

Office of the Surgeon General (US); Office on Smoking and Health (US).
Atlanta (GA): Centers for Disease Control and Prevention (US); 2004.
ISBN-10: 0-16-051576-2

http://www.ncbi.nlm.nih.gov/books/NBK44695/

Excerpt
This new report of the Surgeon General on the health effects of smoking provides a startling picture of the damage to health
caused by tobacco use. Smoking injures almost all bodily organs, and tragically this injury often leads to incurable disease
and death. The comprehensive review process that is the foundation of this series of reports has found new causal
associations of smoking with disease, reemphasizing the need for continued monitoring of scientific evidence on the health
effects of smoking. This report also addresses changes in the cigarette and whether these changes present increased risks to
smokers.

CANCER
The topic of smoking and cancer was last addressed comprehensively in the 1990 Surgeon Generals
report on smoking cessation (U.S. Department of Health and Human Services [USDHHS] 1990) and in
the 1982 report (USDHHS 1982), which focused on cancer. The report on women and smoking
(USDHHS 2001) also considered cancer, and this chapter builds from that report for several cancers.
This chapter reviews the evidence relating smoking to a range of cancers, some previously associated
causally with smoking and some for which substantial new evidence has become available since the
1990 review in the Surgeon Generals report on smoking cessation. For some less common cancers,
little research has been conducted and these cancer sites are not included in this chapter. Lymphomas
and multiple myeloma, skin cancers, bone cancer, and testicular cancer were omitted because they have
not been linked to smoking. Pediatric malignancies are also not discussed, since this report concerns
active smoking rather than involuntary exposure to cigarette smoke in utero and after birth.
The relationship between smoking and lung cancer in men was the first to be classified as causal,
following a review by Surgeon General Luther L. Terrys committee in the landmark 1964 report
(USDHEW 1964). The many documented benefits from quitting smoking include a large decline in the
risk of lung cancer after cessation compared with the risk from continuing smoking (USDHEW
1979; USDHHS 1989, 1990). There is now equally convincing evidence that smoking causes cancer at
a number of other sites for which causal conclusions had not been previously reached.
Previous Surgeon Generals reports have concluded that smoking causes cancer in several organ sites.
The list of cancers caused by smoking has included cancers of the urinary bladder, esophagus, kidney,
larynx, lung, oral cavity, and pancreas. The past conclusions are detailed in the text that follows and are
summarized in Table 2.1. The International Agency for Research on Cancer (IARC) has also reviewed
the evidence on tobacco and cancer on two occasions, in 1986 and again in 2002 (IARC 1986, 2002).
The system used by IARC differs from that applied in the Surgeon Generals reports, but conclusions
have generally been similar.
Pp

CARDIOVASCULAR

Heart disease and strokethe main types of cardiovascular disease caused by smoking
are the first and third leading causes of death in the United States, respectively
(American Heart Association [AHA] 2002; Anderson 2002). More than 61 million people in
the United States suffer from some form of cardiovascular disease (CVD), including high
blood pressure, coronary heart disease (CHD), stroke, congestive heart failure (CHF), and
other conditions. Nearly 950,000 Americans die each year as a result of CVD, accounting
for 39.4 percent of all deaths in 2000 (AHA 2002). This chapter reviews the evidence on
the relationship between smoking and CVD. In particular, it examines the associations
between smoking and subclinical atherosclerosis, CHD and sudden death, stroke, and
abdominal aortic aneurysm (AAA).

Smoking and Increased Oxygen Demand

Cigarette smoking induces the release of catecholamines (epinephrine and norepinephrine) (Cryer et al.
1976; Hung et al. 1995), which are associated with an increased baseline heart rate and contractility and
an increase in vascular tone (Benowitz 1988). In smokers, however, cigarette smoking is associated
with a lower than expected heart rate in response to physical exercise (Srivastava et al. 2000), a
characteristic that has been associated with increased risks of mortality, arrhythmias, andMI (Lauer et
al. 1999).
Even though there is no evidence that smoking is associated with chronic hypertension, there is
compelling evidence that smoking acutely increases peripheral vascular resistance and increases blood
pressure (Cryer et al. 1976; Koch et al. 1980). These effects seem to be attributable to the
pharmacologic properties of nicotine (Benowitz and Gourlay 1997). In carefully controlled experiments
in healthy humans, cigarette smoking increased blood pressure and the sympathetic nervous system
stimulation to both the blood vessels and the heart (Narkiewicz et al. 1998). Acute and episodic
increases in blood pressure, coupled with an increased heart rate, increase the oxygen demands of the
myocardium. However, in population studies, cigarette smokers tend to have on average lower blood
pressures than do nonsmokers (USDHEW 1979; Friedman et al. 1982).
Conclusion
A substantial body of laboratory and experimental evidence now demonstrates that
cigarette smoking in general and some specific components of cigarette smoke affect a
number of basic pathophysiologic processes at the critical interface between circulating
blood components and the inner arterial wall. Smoking leads to endothelial injury and cell
dysfunction. The effects of cigarette smoking on circulation produce a substantial shift in
the hemostatic balance at the endothelium, leading to atherosclerosis and its thrombotic
complications. Furthermore, components of cigarette smoke diminish the ability of the
blood to carry oxygen and increase the physiologic demands of the myocardium. The
overall result of this constellation of toxic effects is to profoundly and adversely affect the
homeostatic balance in the cardiovascular system, thus explaining the well-documented
relationship between smoking and both subclinical and clinical manifestations of
atherosclerosis that are reviewed in the next sections.

Respiratory Diseases
Go to:

Introduction
Smoking has adverse health effects on the entire lungaffecting every aspect of lung structure and
functionincluding impairing lung defenses against infection and causing the sustained lung injury
that leads to chronic obstructive pulmonary disease (COPD). In fact, among the postulated causes of
COPD are acute respiratory infections, for which smokers are at an increased risk. This chapter
addresses smoking and acute and chronic respiratory diseases other than lung cancer (seeChapter 2,
Cancer), and discusses the relevant evidence of the underlying mechanisms. COPD was the focus of
the 1984 Surgeon Generals report (U.S. Department of Health and Human Services [USDHHS] 1984),
and a number of previous reports have addressed acute respiratory infections, which can range in
severity from minor to fatal. This chapter emphasizes acute respiratory illnesses and COPD, which are
leading causes of morbidity and mortality in the United States and worldwide.
Conclusions of Previous Surgeon Generals Reports

Previous Surgeon Generals reports on smoking and health have noted possible adverse effects of
cigarette smoking on acute respiratory infections. The 1979 report (U.S. Department of Health,
Education, and Welfare [USDHEW] 1979) cited data from the 19641965 Health Interview Survey,
which found a higher age-adjusted incidence of self-reported influenza in male and female smokers
when compared with non-smokers, and more upper respiratory illnesses (URIs) in female smokers than
in female nonsmokers. The 1989 report (USDHHS 1989a) identified a number of studies that reported
higher mortality ratios for smokers than for nonsmokers suffering from respiratory tuberculosis (the
range of ratios was 1.275.0 in three studies), and from influenza and pneumonia as one combined
category (the range of ratios was 1.42.6 in seven studies). The 1990 report focused on the health
benefits of smoking cessation, and it comprehensively reviewed evidence suggesting that smoking
increased the risk of acute respiratory illnesses (USDHHS 1990).
Providing a more detailed analysis of the smoking-related mortality data presented in the 1989 report,
the 1990 report identified exposure-response relationships between mortality from pneumonia and
influenza and the number of cigarettes currently smoked, and identified reductions in mortality rates of
former smokers in relation to years of not smoking (USDHHS 1990). A review of possible mechanisms
related to acute respiratory illnesses documented a variety of effects on host defenses: increases in
peripheral blood total leukocyte counts, increases in poly-morphonuclear leukocyte and monocyte
counts, decreases in monocyte intracellular killing, decreases in the CD4/CD8 ratio in heavy smokers,
decreases in concentrations of serum immunoglobulins (other than IgE), an increase in alveolar
macrophage release of superoxide anions, a decrease in microbicidal activity of the macrophages, and a
blunted immune response to an influenza vaccination. Although the 1990 report noted that smoking
cessation restored many of these impaired defenses, it also found that few epidemiologic studies
directly addressed the effects of smoking on acute respiratory morbidity. Conflicting data were
observed for nonspecific acute lower respiratory illnesses (LRIs), but findings for increased morbidity
from influenza virus infections in smokers were more consistent. The 1994 report (USDHHS 1994),
which focused on young people, added little new information.
Biologic Basis

Animal Studies

More than 25 years ago, in vitro exposure of rabbit alveolar macrophages to a water soluble fraction of
tobacco smoke was shown to impair the ability of macrophages to kill bacteria (Green and Carolin
1967). An extensive body of data has since accumulated on the effects of exposure to tobacco smoke on

immune and cellular function in animal models. However, differences in responses among species to
different experimental exposures of tobacco smoke and its products make it difficult to provide a
simple, unifying summary of the animal data. Impaired immunoglobulin responses to immunization
(Roszman and Rogers 1973) and dose-dependent decreases in responses to T cell and B cell mitogens
have been reported for both short-term in vitro (Roszman et al. 1975) and in vivo (Johnson et al. 1990)
exposures to tobacco smoke. Johnson and colleagues (1990) provide a comprehensive review of in vivo
subchronic exposures in animals (Table 4.1) and of the voluminous relevant animal toxicology
literature through 1990. In addition to the general immunologic effects summarized in Table 4.1, direct
effects of tobacco smoke exposure on lung defenses include suppressed functioning of bronchialassociated lymphoid tissue, increased numbers of alveolar macrophages that have a higher than normal
metabolic rate, and increased generation of reactive oxygen species precursors during phagocytosis, but
without changes in bactericidal capacity (rat alveolar macrophages [summarized in Johnson et al.
1990]).

5Reproductive Effects
Go to:

Introduction
Smoking harms many aspects of reproduction. An estimated 6 million women become pregnant each
year in the United States, and more than 11,000 give birth each day (Ventura et al. 2000; Martin et al.
2002). Studies have shown that women who smoke are at an increased risk for a delay in becoming
pregnant and for both primary and secondary infertility. Research has also shown that women who
smoke during pregnancy risk complications, premature birth, low birth weight (LBW) infants, stillbirth,
and infant mortality. LBW is a leading cause of infant deaths (Martin et al. 2002). Despite increased
knowledge of the adverse health effects of smoking during pregnancy, only 18 to 25 percent of women
quit smoking once they become pregnant. Data also suggest that a substantial number of pregnant
women and girls continue to smoke (estimates range from 12 to 22 percent) (U.S. Department of Health
and Human Services [USDHHS] 2001). This chapter reviews the evidence for a relationship between
smoking and adverse reproductive effects. In particular, it examines the associations between smoking
and fertility, smoking and pregnancy complications, and the health of children born to smokers.
iologic Basis
The biologic basis of smoking and reproductive effects is complicated by how exposure is defined for
reproductive effects, and is perhaps best discussed using a methodologic framework. When researchers
examine the effects of smoking on reproductive outcomes, measuring exposure to smoking and
adjusting for possible confounding are two important methodologic concerns. The critical exposure
periods during gestation are brief for some adverse reproductive outcomes that have possible causal
associations with active smoking. For example, when examining the relationship between smoking and
congenital malformations, relevant data include exposure to tobacco smoke during the early part of
pregnancy or during organogenesis. Similarly, for studying fetal growth restrictions, knowledge of
smoking habits during the third trimesterthe time when most of the growth in the fetus occursis of
critical importance. However, in many studies the average amount smoked during pregnancy has been
used as the exposure measure without collecting or reporting information sorted by the month of
pregnancy or by the trimester.
For pregnancy outcomes, several potential confounding factors should be considered along with
tobacco use, such as social class and racial and ethnic group. Among women of a lower social standing,

not only are rates of smoking higher but rates of adverse pregnancy outcomes are also higher. Whereas
lower social standing is thus a potential confounding variable, it may also be part of a common causal
pathway serving as one of the determinants of exposure to smoking. Most recent studies do take
potential confounders into account, and within the body of relevant literature, confounding has been
adequately considered in the aggregate. However, for studies of some outcomes, such as those that
examine associations of active smoking during pregnancy with child outcomes (i.e., physical,
neurologic, and cognitive development), fully accounting for all potential confounders in the
postpartum period is not feasible. The appropriateness of accounting for confounders will be discussed
in each of the three sections that follow.
Another challenging issue that should be addressed is the mechanistic role of smoking in the causal
pathway of adverse reproductive outcomes. For the role of smoking in preterm deliveries, for example,
prenatal cigarette exposure might (1) increase the risk for pregnancy complications leading to a preterm
delivery (e.g., the premature rupture of membranes), (2) decrease immune system functioning leading
to an increased susceptibility to infections, or (3) act more directly through mechanisms not yet
understood. Many studies do not capture data in a way that facilitates an adequate dissection of the
underlying pathway. For example, few studies stratify analyses by the presence of pregnancy
complications, and most such studies do not account for infections, as this purported risk factor for a
preterm delivery has emerged only recently.
This methodologic challenge is further illustrated by SIDS, smoking during pregnancy, and the role of
birth weight in the causal pathway. Because prenatal smoking results in lower birth weights
and LBW is also a risk factor for SIDS, most studies account for birth weight, and some studies even
limit the analyses to infants born weighing at least 2,500 g. It is unclear, however, that this analytic
strategy is the most appropriate if the total contribution of smoking to the risk of SIDS is of interest.
Only a few studies have examined the association between smoking and SIDS by stratifying the sample
by birth weight.
Studies reviewed for this chapter were selected from a MEDLINE literature search from the mid-1960s
to 2000, with some earlier studies identified through bibliographies. Title and abstract search terms
included smoking, and outcomes of interest such as pregnancy, fertility, pregnancy
complications, birth weight, preterm delivery, cognitive development, congenital
malformations, infant mortality, and SIDS. For some searches (e.g., pregnancy complications),
specific disorders were used as a search term (e.g., placenta previa). Smoking was also used as a
Medical Subject Headings term, and review articles were consulted as additional sources for references.
As some of the topics presented in this chapter have been extensively investigated and the evidence
found to support causality (e.g., smoking and birth weight), this chapter focuses on more recent studies
and emerging areas such as male erectile dysfunction. When possible, recent studies were reviewed as
the patterns of smoking among women of childbearing age and pregnant women have changed over the
past few decades. In addition, the topic of smoking and cervical cancer is discussed in Chapter 2.
Fertility
Epidemiologic Evidence

Smoking and Sperm Quality

Cigarette smoking among men can affect spermatogenesis and sperm quality through hormonal and
toxic influences. In a review of the literature on male reproduction and smoking, Vine (1996) noted that

the cytotoxic effects of exposures to tobacco smoke may reduce the numbers and function of sperm, or
may affect male reproductive hormone levels and lead to impairment of spermatogenesis. Although the
results of studies supporting the latter mechanism are mixed, several studies have found that levels of
testosterone, estradiol, estrone, androstenedione, and follicle-stimulating hormone are increased among
smokers compared with nonsmokers (Barrett-Connor and Khaw 1987; Simon et al. 1992; Field et al.
1994; Vine 1996), while other studies have found decreases among smokers compared with
nonsmokers or no differences between the two groups (Andersen et al. 1984; Barrett-Connor and Khaw
1987; Klaiber and Broverman 1988; Simon et al. 1992). Small sample sizes may partially explain the
conflicting findings (Vine 1996) as larger studies tend to find increased levels of male reproductive
hormones in smokers compared with nonsmokers (Simon et al. 1992; Field et al. 1994). Toxins found
in tobacco smoke, such as cadmium, nicotine, lead, and radioactive alpha-particle emitting elements
(internal emitters in particular), may be directly toxic as they circulate in the blood and reach the testes
(Mattison 1982; Ravenholt 1982; Mattison et al. 1989; Oldereid et al. 1989).
In the following discussion, the studies examined associations between sperm production and male
smoking and had larger sample sizes as well as some consideration of potential confounders. However,
many of the studies on sperm quality included men seeking treatments for infertility, and the findings
may have restricted generalizability. Also most do not adequately consider potential confounders such
as abstinence, occupational exposures (e.g., teratogens and toxins in the workplace), or health behaviors
(e.g., caffeine, alcohol, or drug use). Studies on smoking and sperm quality have examined measures
such as ejaculate volume and sperm output, density, viability, motility, and morphology (Vogel et al.
1979; Evans et al. 1981; Godfrey 1981; Andersen et al. 1984; Handelsman et al. 1984; Kulikauskas et
al. 1985; Dikshit et al. 1987; Saaranen et al. 1987;Marshburn et al. 1989; Oldereid et al. 1989; Close et
al. 1990; Holzki et al. 1991; Lewin et al. 1991; Chia et al. 1994) (Table 5.2). Handelsman and
colleagues (1984) studied 119 healthy volunteer sperm donors and examined a variety of physical,
demographic, and health behavioral factors and sperm quality. Although it is not clear how the category
of smokers was defined, when compared with nonsmokers this group had a significantly reduced total
sperm output (316 million versus 181 million sperm), motility (72 million versus 67 million sperm),
motile sperm (235 million versus 127 million sperm), and total oval sperm (251 million versus 120
million sperm). These values were unadjusted for other factors. Marshburn and colleagues
(1989) studied 445 men and reported a significantly reduced sperm volume for smokers compared with
nonsmokers but no differences in sperm density, sperm motility, or the presence of abnormalities or
dead sperm. The authors, however, warned against the confounding effect of coffee drinking in this and
other studies. Chia and colleagues (1994)studied 618 men receiving treatment for infertility and
reported means for volume, density, motility, and morphology adjusted for age, medical history,
occupational exposure to cigarette smoke, and testicular size. Current smokers had a lower sperm
density, a lower proportion with normal morphology, and a higher proportion with head defects than
nonsmokers (lifetime nonsmokers and former smokers). Most studies have not found dose-response
relationships with the amount smoked, and a number of studies found no difference in sperm quality
between smokers and non-smokers (Saaranen et al. 1987; Oldereid et al. 1989; Close et al.
1990; Holzki et al. 1991; Lewin et al. 1991). One large study found no differences between those
exposed to tobacco smoke and chewing and those not exposed to tobacco smoke and chewing (Dikshit
et al. 1987).
Conclusions

1. The evidence is inadequate to infer the presence or absence of a causal

relationship between active smoking and sperm quality.

2. The evidence is sufficient to infer a causal relationship between smoking and

reduced fertility in women.
Implications

Regarding smoking and sperm quality, future studies should also include more samples of men not
seeking treatment for infertility, larger study populations, and the information to adjust for potential
confounding factors such as occupational exposures (e.g., teratogens and toxins in the workplace) and
health behaviors (e.g., caffeine, alcohol, or drug use). Women intending to become pregnant should be
warned that their smoking reduces fertility; health care workers should be aware of the causal
association of smoking by women with reduced fertility.
Smoking and Ectopic Pregnancy

Ectopic pregnancy, a rare yet serious complication, occurs when implantation of the fertilized ovum
takes place outside of the uterus, often in the fallopian tubes. The etiology of ectopic pregnancy is not
fully known but involves the motility and patency of the fallopian tubes. Exposure to nicotine in rhesus
monkeys has been shown to decrease tubal motility. Reduced motility may result in the fertilized ovum
remaining in the tubes for a longer time which, in turn, may increase the chance of tubal implantation
and ectopic pregnancy (Mattison et al. 1989). Cigarette smoking also has been associated with pelvic
inflammatory disease, a strong risk factor for tubal pregnancy (Marchbanks et al. 1990). It is unclear
whether this association is due to confounding factors such as more sex partners among smokers
compared with nonsmokers, or to a direct biologic effect through suppressed immune function in
smokers (Holt 1987).
Smoking and Pregnancy Complications
Placenta Previa

Placenta previa occurs when the maturing placenta is close to the cervical os or completely obstructs
the os. The etiology of placenta previa is still largely unknown. Some researchers claim that placental
enlargement among smokers increases the chance that the placenta implants near or at the cervical os.
However, others have found that placentas in smokers and nonsmokers are similar in size, so
differences in placental size may be due to factors other than smoking (Zhang and Fried 1992). Zhang
and Fried (1992) also note that a detection bias may lead to the greater ascertainment of placenta previa
among smokers and will consequently inflate this association in many studies.
Placenta previa consistently has been found to be more frequent in smokers compared with
nonsmokers; ORs range from 1.3 to 4.4 with most estimates around 2.3 (Kramer et al. 1991; Williams
et al. 1991b; Zhang and Fried 1992; Handler et al. 1994; Chelmow et al. 1996) (Table 5.6). A few
studies have examined dose-response associations based on the number of cigarettes smoked per day;
one reported a significant dose-dependent relationship (Monica and Lilja 1995) while others were only
suggestive (Handler et al. 1994; Chelmow et al. 1996). Most recent studies adjusted for potential
confounders including age, parity, prior caesarean sections, and prior pregnancy terminations.

Current Impact of Smoking

Smoking Attributable Mortality and Years of Potential Life Lost

For this report, the annual SAM and YPLL calculations for 19951999 have been updated from the
most recent Centers for Disease Control and Prevention (CDC) report (CDC 2002a) by using the
additional diseases now causally attributed to smoking (stomach cancer and acute myeloid leukemia),
using new estimates for perinatal RRs, and excluding hypertension, which was previously included as a
cause of smoking-related deaths on the assumption that smoking attributable heart disease deaths were
included in this category. These estimates include adult and perinatal deaths for 19 disease categories
among adults and 4 adverse infant health outcomes (also listed in the tenth revision of the International
Classification of Diseases[ICD-10] [CDC 2002b,d]) that are caused by smoking (see Appendix 7-1).
Deaths attributable to residential fires caused by smoking (589 males and 377 females [Hall 2001]) and
deaths from secondhand smoke exposure for adults are also included (nationally, 3,000 for lung cancer
and 35,000 to 62,000 for heart disease [National Cancer Institute (NCI) 1999; CDC
2002d; International Agency for Research on Cancer (IARC) 2002]).
Relative risks for smoking-related diseases and smoking prevalence estimates for current and former
smokers 35 years of age and older and for maternal smokers were used to calculate smoking
attributable fractions (SAFs) and SAMs as in the previous CDC report (2002a). Age-adjusted RR data
were obtained from CPS-II (19821988, see Appendix 7-1), and gender-specific smoking prevalence
data for adults aged 35 years and older were obtained from NHIS (Table 7.2). Relative risk estimates of
the deaths of infants whose mothers smoked during pregnancy were obtained from McIntosh
(1984) andGavin and colleagues (2001). Maternal smoking prevalence data from most states for 1995
1999 were obtained from birth certificates (see http://www.cdc.gov/nchs/births.htm). Age- and genderspecific mortality data were obtained from National Center for Health Statistics (NCHS) reports
(Hoyert et al. 2001). YPLL for persons aged 35 years and older were calculated using remaining life
expectancy (life expectancy at any given age of death minus age at death and for infants, from
birth). SAMand YPLL include nationally reported deaths from cigarette-caused residential fires; SAM
includes lung cancer and heart disease deaths from secondhand smoke exposures (15,500 men and
22,500 women [NCI 1999]).
Total Smoking Attributable Mortality, 19651999

The total SAM estimates for 19651999 were derived from annual PAR estimates for the time since the
publication of the first Surgeon Generals report on the health consequences of smoking in 1964 (Table
7.4). The PARs for each of 19 smoking-related disease categories were calculated using smoking
prevalence and the RR estimates for mortality for current and former smokers aged 35 years and older.
The PARs for each of four adverse health outcomes were calculated using maternal smoking prevalence
and RR estimates for smoking-related infant deaths. The mortality RR estimates for adults were
obtained from both CPS-I and CPS-II data (see Appendix 7-1). CPS-I data (19591965) were used in
conjunction withNHIS smoking prevalence data from 19651971, CPS-II data (19821988) were
applied to NHIS prevalence data from 19821999, and the midpoint RRs between CPS-I and CPS-II
were used with NHIS prevalence data for 19721981, applied to each years mortality data during that
period. Current and former smoking prevalence data, by gender and for ages 35 through 44 years, 45
through 64 years, and 65 years and older, were obtained from NHIS (Table 7.2). Linear extrapolation
was used to estimate prevalence in the years that surveys were not conducted. Data on maternal
smoking status for earlier years were extrapolated using the ratio of maternal smoking prevalence to
current smoking prevalence among women aged 18 through 24 years from 19951999. These data

produced more conservative prevalence estimates than smoking rates among women of childbearing
age (18 through 44 years).

The legacy of paternal smoking

Do early paternal exposures to lifestyle factors such as smoking
increase the risk of chronic diseases in the offspring?
http://www.nature.com/ejhg/journal/v22/n12/full/ejhg2014206a.html
Adelheid Soubry1, Geert Verbeke2 and Cathrine Hoyo3,4
1.

Epidemiology Research Group, KU Leuven, Leuven, Belgium

2.

I-Biostat, KU Leuven, Leuven, Belgium

3.

Department of Biological Sciences, NC State University, Raleigh, NC, USA

4.

Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA

Correspondence: , E-mail: adelheid.soubry@hotmail.com

The results of a recent epidemiological study on the effects of paternal smoking on children's body
composition published in EJHG1 contribute to the limited research in humans on environmentally
induced risk for chronic diseases in the next generation(s) through the father. Inherited nongenetic changes may be an evolutionary response to adapt relatively quickly to environmental
variations. However, if an individual is exposed to an adverse environmental exposure, such as a
new pollutant, chemical, or pathogen, during a critical developmental stage in life, the risk of
developing an endocrine, metabolic, or mental disorder or even cancer in the offspring may
increase. Thus far, most research in this area focuses on maternal contributions, while a potential
transgenerational epigenetic effect through the father has generally been underexplored. The Avon
Longitudinal Study of Parents and Children (ALSPAC), led by Pembrey, showed that adolescent
sons of fathers who started smoking before puberty are at high risk of being obese.1Although no
underlying biological mechanism has been shown yet, this fascinating finding suggests that
cigarette smoke metabolites may induce epigenetic changes during prepubertal production of
spermatogonia in the testes. Remarkably, in order to persist until the offsprings early adulthood,
this epigenetic information needs to be carried on through all developmental processes, including
spermatogenesis, conception, and embryonic growth. An earlier historical Swedish study by the
same authors showed a similar transgenerational response to food availability. The longevity of
men was decreased if their paternal grandfathers had been exposed to an excess of food during
the slow growth period, before the prepubertal growth peak.2 These gender- and time-specific
associations suggest that the epigenome of the male germ line is malleable by environmental
factors at specific timepoints in life. An epigenetic link in humans was shown for the first time in
the Newborn Epigenetic Study (NEST); this NC-based birth cohort showed that imprint-regulatory
regions of newborns are differentially methylated in response to paternal obesity.3,4
The theory on environmentally induced epigenetic transgenerational inheritance of disease
susceptibility through the male germ line has been supported through a number of animal
experiments on male exposures to various factors such as environmental toxins (insecticides,
bisphenol-A, jet-fuel, etc.) and dietary components (alcohol, folate, genistein, high-fat or lowprotein diet). Susceptibility time windows for such environmentally induced epigenetic changes
through the paternal germ line have recently been reviewed.5 Although animal models provide a
useful tool to explore the individual effects of each environmental component through maternal or
paternal exposures at different timepoints, human responses to these particular components may
be different. Extrapolating the findings from rodents to humans is often difficult. Doseresponse
may be different and the human natural environment contains more components that may interact

with the one under study. Moreover, temporal differences in expression patterns of genes during
early development as well as in maturation of germ cells complicate translation of animal data to
humans. Hence, epidemiological studies are essential, but difficult to perform, especially if multiple
generations are needed to explore.
The study by Northstone et al1 suggests that paternal cigarette smoking causes a stable
signature in the germ line, especially if the exposure occurred before puberty. However, further
investigations are needed to confirm these findings, via other data sets, but also through refined
analyses of the ALSPAC data. ALSPAC includes repeated measurements of the same children at
different ages, from 7 to 17 years. Northstone et al performed cross-sectional analyses at each
age separately, and did not explore the information present in the longitudinal trends. This is
worrisome since considerable loss of follow-up is observed, apparently related to BMI, but
potentially also to gender or unmeasured factors, which often leads to bias. 6 The data of
Northstone et al highlight that paternal smoking before the age of 11 years is associated with
increased BMI, waist circumference, and total body fat mass of adolescent sons. Raw BMI scores
alone in children are generally difficult to interpret. However, findings on fat mass and waist
circumference were significant and encouraging, but they were mainly based on less than 20 sons
aged 13 and 15 years, and no data were collected on waist circumference at age 17. Furthermore,
a systematic comparison between different ages of paternal smoking is lacking; the reference
group included an equal number of fathers who started smoking after the age of 11 years and
non-smoking fathers, and the specificity test on adjusted data was only performed in the category
of fathers who started smoking between 11 and 13 years of age (Supplementary Table 8). Here
too, sample sizes were limited, and no results were shown for childrens BMI. The study further
presumes a potential trend in smoking behavior in young children from fathers who smoked at
young age (Supplementary Table 6). Although P-values did not reach statistical significance,
presumably because of the small samples, it is recommended to include personal smoking by
children as a potential confounder. Northstone et al adjusted for child-smoking in one of their
analyses (Supplementary Table 7) and showed that this did not change the overall conclusion for
boys. However, their data indicated that if smoking in daughters was included in their regression
analyses the earlier detected association between paternal smoking at age <11 and waist
circumference or fat mass at age 13 was attenuated (compared to Table 3). This remarkable
finding corresponds with the finding of Pasch et al7 in a longitudinal study, showing that smoking
at a young age predicts an increase in body fat percentage a few years later; however, sex
differences were not examined. The differences shown between the sons and daughters in the
data of Northstone et al remain unexplained, but sample sizes were often small. Moreover, no
formal interaction tests for differences between boys and girls were discussed.
We conclude that although the ALSPAC study indicates that timing of onset of paternal smoking,
especially at pre-puberty, is important for the next generations health, the information present in
this study has not been fully explored. Further research is needed to confirm the harmful healthrelated effects of paternal lifestyle on the next generation. Current epidemiological studies only
show the tip of the iceberg, but the field of epigenetic inheritance is evolving. It is promising for a
better understanding of the effects of several common exposures at certain stages in paternal life
and their risks of developing diseases in the offspring.
Topof page

References
1. Northstone K, Golding J, Davey Smith G, Miller LL, Pembrey M: Prepubertal start of fathers
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The American Journal of Gastroenterology

Volume 96, Issue 5, May 2001, Pages 14021408

http://www.sciencedirect.com/science/article/pii/S000292700102336X

Effect of lifestyle, smoking, and diet on development of intestinal metaplasia

in H. pylori-positive subjects

A Russoa, ,
G Maconia,
P Spinellia,
G Di Felicea,
M Ebolia,
S Andreolaa,
F Ravagnania,
D Settesoldia,
D Ferraria,
C Lombardoa,
L Bertarioa
Received 7 July 2000, Accepted 4 January 2001, Available online 8 May 2001

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doi:10.1016/S0002-9270(01)02336-X
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Abstract
OBJECTIVES:
This study aimed to evaluate the influence of environmental and sociodemographic factors and the effect of
smoking, alcohol, and dietary habits on the risk of gastric intestinal metaplasia (IM) in Helicobacter pylori
infected subjects.

METHODS:
The investigation was based on 2598 consecutive volunteer blood donors tested for the presence of antibodies
against H. pylori from March 1995 to March 1997. Endoscopy with multiple biopsies was offered to all H. pylori
positive, symptomatic subjects. The presence or absence of IM was diagnosed by gastric biopsies. A
serologically H. pyloripositive subject with gastric IM was defined as a case, whereas serologically H. pylori
positive subjects without IM were used as controls. All patients answered a detailed questionnaire collecting
sociodemographic characteristics and smoking, alcohol drinking, and dietary habits. Odds ratios (ORs) and their
95% CIs were estimated by unconditional logistic regression, including terms for age and sex, to assess the
association between the data collected and IM.
RESULTS:
Three hundred forty-four subjects with serological H. pylori infection and upper-GI symptoms underwent GI
endoscopy, during which biopsies were taken for histological diagnosis. Histology revealed metaplasia in 74
subjects (21.5%). Incomplete IM was found in 37.8% of these cases. No significant associations were found
between IM and anthropometric or sociodemographic factors. There was a significant association between age
and IM (2 for trend, 6.67; p value, 0.009). Current smokers of over 20 cigarettes per day had a 4-fold risk of IM
(OR, 4.75, 95% CI, 1.3316.99). A 2-fold increased risk was found for high butter consumers (OR, 2.17; 95% CI,
1.144.11). No significant specific associations were found between the variables studied and complete or
incomplete IM.
CONCLUSIONS:
This study found that smoking and high butter consumption may increase the risk of having gastric IM in H.
pyloripositive subjects.
Reprint requests and correspondence: L. Bertario, M.D., Instituto Nazionale Tumori, Preventive and
Predictive Unit, Via Venezian, 1, 20133 Milan, Italy

The Health Consequences of

Smoking 50 Years of Progress
A Report of the Surgeon General

2014
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Office of the Surgeon General
Rockville, MD

Suggested Citation
U.S. Department of Health and Human Services. The Health Consequences of
Smoking: 50 Years

of Progress. A Report of the Surgeon General. Atlanta, GA: U.S. Department of

Health and Human
Services, Centers for Disease Control and Prevention, National Center for
Chronic Disease Prevention
and Health Promotion, Office on Smoking and Health, 2014.

Conclusions of Previous Surgeon

Generals Reports
The Surgeon Generals report on smoking cessation
(USDHHS 1990) noted an association between smoking
and HCC that persisted after controlling for potentially
confounding lifestyle factors, including consumption of
alcohol. The report also noted that HBV infections may
modify the effects of smoking on the risk of liver cancer.
The Surgeon Generals report on women and smoking
(USDHHS 2001) concluded that smoking may be a contributing factor to the
development of liver cancer. The
Surgeon Generals report on the health consequences of
smoking (USDHHS 2004) noted a consistent association
between smoking and HCC after controlling for potentially confounding factors,
but it called for further consideration of the history of viral hepatitis and
consumption of
alcohol. Overall, the 2004 report concluded that although
the data were suggestive of an association between smoking and liver cancer,
further evidence was required to classify smoking as a cause of liver cancer.
Summary
Over the 50 years that began with the seminal 1964
report, the conclusions of the Surgeon Generals reports
on smoking and health have evolved greatly, moving from
the few causal associations set forth in the 1964 report
to the inference of causal relationships between not only
active smoking but also exposure to secondhand smoke
and a wide range of diseases and other adverse health
effects. The 2004 and 2006 reports provided comprehensive coverage of the
evidence on active smoking and
exposure to secondhand smoke, respectively, and the 2010
report addressed the mechanisms underlying the causal
relationships described in these reports. The 2012 report,
Preventing Tobacco Use Among Youth and Young Adults,
provided additional coverage of the effects of smoking
on the health of children, adolescents, and young adults,
highlighting the linkages between early life events and
subsequent risk for disease (USDHHS 2012).
Notably, this 2014 review extends the list of diseases
and other adverse health effects caused by smoking and
reaffirms the widespread consequences of smoking. In the
2004 report, it was noted that smoking affects nearly every
organ of the body; the evidence in this report provides
additional support for that finding.