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Environment, lifestyle and infertility - An inter-generational issue

Article in Nature Medicine · October 2002

DOI: 10.1038/nm-fertilityS33

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 fertility supplement

review
Environment, lifestyle and infertility — an
inter-generational issue
Richard M. Sharpe*‡ and Stephen Franks†§

*MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, University of Edinburgh, Chancellor’s Building, 49 Little France Crescent, Old
Dalkieth Road, Edinburgh, EH16 4SB, UK

†Department of Reproductive Science and Medicine, Institute of Reproductive and Developmental Biology, Wolfson and Weston Research Centre for
Family Health, Imperial College of Science Technology and Medicine, Hammersmith Hospital, London, W12 0NN, UK

e-mail: ‡[email protected] or §[email protected]

The effects of adult lifestyle — primarily smoking and diet in women, and sedentary habits generally — are important
factors affecting the fertility of men and women, and can also impact the fertility of their children. This review
summarizes the effects of season, modern lifestyles and environmental chemicals on human fertility, and discusses
the implications of these effects for future generations.

O
ur bodies evolved to be ‘in tune’ with their The progressive increase in obesity in intractable infertility; in these men, sperm
environment. This connection is vital for many Western cultures therefore brings are often abnormal in shape and function9.
reproduction, as birth of the young must with it attendant fertility problems, main- The number of sperm produced per day
coincide with plentiful food, and thus a ly in women. Of more concern is that is in turn determined by the numbers of
high chance of survival1. Most mammals these ‘lifestyle’ problems in adult women Sertoli cells within the testes5,13. Variation in
are therefore ‘seasonal breeders’ and switch can have effects even when they do achieve Sertoli cell number is the main factor that
their sexual behaviour and fertility on and a pregnancy, as foetal development may be accounts for the wide variation in sperm
off, guided by the amount of daylight impaired and its future fertility may be counts between men13,14 (see Fig. 1).
(photoperiod), but influenced also by compromised. Numbers of Sertoli cells are determined
other factors, such as energy intake/bal- largely by their rates of proliferation dur-
ance (that is, availability of food)1,2. Factors determining fertility ing foetal and neonatal (1–9 months post-
Although humans are not ‘seasonal breed- — importance of foetal life natal) periods, and probably to some
ers’ — we show sexual behaviour and Infertility is considered an ‘adult problem’, extent during pre-pubertal life13,15 (Fig. 1).
reproduce all year round — our fertility is as this is when it manifests itself. However, Proliferation of Sertoli cells is controlled
influenced profoundly by our environ- many factors that impact on fertility have by a variety of hormones, including folli-
ment, including season and food intake. their origins much earlier in life, common- cle-stimulating hormone (FSH), thyroid
In recent years, the postulated threat to ly during foetal development. To under- hormones, growth hormone and possibly
fertility from exposure to environmental stand how (and when) infertility can arise, oestrogens13. Any factor that affects these
‘endocrine disruptors’ has loomed large, and what environmental factors can affect hormones, whether in foetal, neonatal or
but proven examples are elusive3–5. it, a useful starting point is the identifica- peri-pubertal life, may affect sperm counts
However, it has highlighted the vital role tion of key factors that determine whether and testicular size in adulthood (Fig. 1). At
of endogenous hormones in foetal life, a man or woman will be fertile, and when puberty, no further increase in the num-
which ensures future fertility. Exposure these are established. bers of Sertoli cells can occur and the ceil-
to the wrong hormones (for example, a In men, the key to fertility is the ejacula- ing for sperm production and testicular
female foetus exposed to male hor- tion of astronomical numbers of motile size is fixed irrevocably13.
mones) or inadequate amounts of the sperm (40–250 million per ml)9. This To be fertile, a man must have the cor-
hormone in question, and the reproduc- requires the production of 100–200 mil- rect reproductive organs internally (testes,
tive system and genitalia may not develop lion sperm every day, and each sperm takes epididymides, seminal vesicles, vas defer-
correctly, with resultant fertility prob- 10 weeks to be produced. Once sperm ens and prostate gland) and externally
lems in adulthood6,7. The hormones that counts fall below 14–40 million per ml, sig- (penis and scrotum), and the testes must
control fertility (the sex hormones) are nificant impairment of fertility may occur have descended into the scrotum6,9. Testis
also influenced by other hormones, in (Fig. 1). This includes an increased time to descent, which is a hormone-dependent
particular those determined by our diet conceive10–12 or, at very low sperm counts process, normally occurs by birth, and
and sugar intake (for example, insulin)8. (less than 5 million per ml), by more incomplete descent of one or both testes

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Figure 1 Factors affecting sperm counts in adult

Foetus men and their role in fertility. As shown in the

? Environmental graphs (right), sperm counts below 40–50 million

chemicals per ml are associated with reduced fertility
? Maternal hormones (increased time to conceive; ref. 10). The key
in pregnancy
factor that determines sperm counts, and the
? Effects of variation in sperm counts between men, is the
6 months breast/formula number of Sertoli cells in the testes13,14. Sertoli cells
Hormones in foetal life feeding
proliferate in foetal and neonatal life, and also
+ 1st year after birth
for some time before puberty. Their proliferation
is driven or influenced by several hormones13.
Thus, environmental or maternal factors that
affect these hormones may affect future sperm
counts of the male foetus/neonate. Other fac-
10 years Sertoli cell number tors can function in adulthood to alter sperm
1000
Number of Sertoli cells

Hormones in counts (notably, ejaculatory frequency) but also

prepubertal life
per testis (106)

750 season, and in rare instances, certain environ-

mental chemicals may exert effects.
500

250
monthly ovulation of a mature egg
0 (oocyte) and a reproductive tract that has
0 50 100 150 200 250 300
been prepared to accommodate the ovu-
Daily sperm production
(106 per testis) lated egg and to provide the optimum
Number of Sertoli cells
environment for fertilization, early
embryo development, implantation into
Sperm count
40 the uterus and normal foetal develop-
Lifestyle, season,
? exposure to 30
ment. These processes must be carefully
Percentage
of men

enviromental co-ordinated, and principally, this is driv-

chemicals 20
en by the cyclical changes in sex steroid
Hormones 10 production by the ovary.
0
The production of a mature oocyte that
40 80 120 160 200 250+ is capable of being fertilized is a lengthy
Sperm count
process20–22. The human ovary acquires its
(106/ml/ejaculate)
full complement of germ cells (oocytes)
Adult Daily sperm production during foetal life (Fig. 2). Most are des-
Fertility tined to die by atresia, so that at birth,
Percentage becoming

40
pregnant per cycle

germ cell number has fallen from approx-

30
Ejaculatory imately 7 million to 1–2 million, and less
20
frequency than 500 oocytes will be ovulated in adult-
10
hood. The ‘primary oocytes’ in the foetal
0 ovary are arrested in the first meiotic
0 50 100 150 200 250 prophase, and remain so until just before
Sperm count
(106/ml)
ovulation some 15–50 years later, when
Sperm count in the ejaculate resumption of meiosis (maturation) is
triggered by the midcycle ‘surge’ of
luteinizing hormone (LH), which stimu-
(cryptorchidism) is associated with lower Fertility also requires masculinization of lates ovulation. Thus, the critical stages of
sperm counts/fertility in adulthood and the brain and the neuronal ‘wiring’ that germ cell production occur in the foetus
increased risk of testicular cancer5,16,17. controls production of the reproductive and are therefore subject to influence by
Cryptorchidism affects 2–3% of boys at hormones, ensuring men show appropri- the maternal environment.
birth, whereas testicular cancer is the most ate sexual behaviour19 and a male pattern Development of the follicle to the point
common cancer of young men and almost of hormone production. Much of this is of ovulation takes several months21. Early
certainly arises from abnormal develop- also established during foetal life. follicular development is not dependent
ment of germ cells in the foetal testis18. In women, the key to fertility is the on LH/FSH (the ‘gonadotrophins’), but

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Factors acting in Factors acting in Factors affecting Factors acting

foetal life that can pregnant mother future fertility that in adulthood
affect future fertility that can affect are already determined that can
of the baby foetal development at birth–1 year of age affect fertility

Female infant
- Oocyte number (timing of menopause)
- Complete reproductive tract + genitalia
- Likelihood of PCOS partly determined Diet
(under-nutrition
or over-weight)

Female foetus
Reproductive system Female adult Season
develops without
hormone input
Lifestyle Occupation
(eg. smoking)
Diet Hormone changes
(obesity, refined
Pregnant Lifestyle
(caused by over-weight
sugar intake) mother (eg. smoking)
or under-nutrition)
Environmental
chemicals
(eg. those present Male foetus
in cosmetics) Development of the
reproductive system
dependent on correct Season
hormone production
Male adult
and action
Occupation

Male infant
- Complete reproductive tract + genitalia
- Testis descent into scrotum Scrotal heating
- Sperm counts in adulthood partly determined (eg. time spent seated)
- Risk of testicular cancer

Figure 2 Key environmental/lifestyle factors than can affect human fertility. system does not require hormonal input. However, factors that affect the
Note that all of the cell types and organs/structures essential to the fertility female are more likely to result in outright infertility than those affecting the
of both sexes are already in place at birth, although the number of Sertoli male. Importantly, changes to the reproductive system induced in foetal
cells (Fig. 1) is not finalized at this time. Also note that development of the life are mainly irreversible, whereas those induced in adulthood are usually
male reproductive system and genitalia is completely dependent on hor- reversible. Further details of the nature and importance of the various fac-
mone stimulation (mainly by androgens), whereas the female reproductive tors are given in the text.

the local and/or endocrine factors respon- internal and external reproductive organs impact on fertility. In addition, the effects
sible for initiation of growth of these folli- occurs without the obvious influence of on oocyte number will determine the span
cles are unclear. Later stages of follicle sex steroids (Fig. 2). of female reproductive life. Such effects
maturation are gonadotrophin-depend- In the adult female, cyclical changes in might be induced early in development, in
ent, and in the two weeks preceding ovula- the levels of sex steroids drive a series of which case they are likely to be permanent.
tion, they are precisely regulated by the co-ordinated events in the reproductive Alternatively, they may arise in adulthood,
cyclical changes in LH and FSH secretion. tract. These events include modification in which case they may be reversible (Fig. 2;
During these stages, the oocyte undergoes of the cervical mucus to facilitate sperm these effects are considered separately
cytoplasmic and nuclear maturation, transport, changes in tubal motility and below). Note that the effects on women are
which enables it to resume meiosis and to secretions (encouraging transport and inherently more likely to induce infertility
prepare for fertilization20,22. During this fertilization of the egg), and most than the effects on men, as even major
critical phase, the endocrine environment importantly, secretory changes in the decreases in sperm counts in normal men
of the follicle, which is susceptible to the endometrium that allow normal may not result in infertility (Fig. 1).
external environment, can profoundly implantation.
influence oocyte maturation. In summary, the effects of environment Environmental and lifestyle
Unlike the foetal testis, the foetal ovary and lifestyle on sperm count, oocyte devel- effects on fertility in adulthood
is thought to be hormonally quiescent7,16. opment/ovulation, fertilization and The effects of photoperiod on humans are
Therefore, normal development of the implantation are those most likely to demonstrable23, as testified by ‘seasonal

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affective disorder’. This also extends to The effect of sedentation is at its worst in hypothalamus/pituitary gland, which
effects on fertility. The incidence of twins paraplegic men35. determines the timing of puberty and
and the frequency of births both show menarche (menstruation) in girls, and ovu-
seasonal trends (especially in Northern Effects of lifestyle and diet lation and fertility in adulthood; oestradiol
Europe, where photoperiodic changes are Increased rates of smoking and consump- and progesterone also negatively ‘feed back’
most extreme and result in a peak in tion of alcohol have been identified in to the hypothalamus/pituitary to inhibit
spring births)24. This is not caused by a infertile couples11. In men, smoking can be secretion of GnRH, LH and FSH.
seasonal variation in sexual activity, as associated with minor reductions in sperm A normal calorie intake is necessary for
differences also occur in fertilization rates count/morphology, but this is inconsistent normal pubertal development, the onset
and embryo quality in women undergo- and not usually associated with altered fer- of menstruation and for ovulation.
ing in vitro fertilization (IVF)25. tility36,37; however, effects on IVF outcome During adolescence, there is a change in
Furthermore, sperm counts in men are have been reported38. There are also con- the accumulation and distribution of fat,
consistently ~30% lower during the sum- cerns that smoking induces DNA damage including an increase in abdominal adi-
mer than in the winter5,26. The latter in sperm39,40. There is no consistent rela- posity that is closely associated with a
effects could be caused by the higher sum- tionship between moderate alcohol intake reduction in sensitivity of muscle and fat
mer temperature, which can impair and sperm count in men9 or fertility in to insulin (insulin resistance), and a com-
sperm production (see below and Fig. 2) women41,42. However, in women, there is pensatory increase in insulin secretion.
and conception27. However, temperature unequivocal evidence that smoking nega- This physiological elevation in circulating
changes fail to account for all of the sea- tively impacts on virtually all aspects of insulin levels results in a reduction of cir-
sonal trends in births, especially in fertility43–47. This includes effects on follicle culating sex hormone binding globulin
Northern Europe27. Presumably, the sea- development/ovulation, oocyte pick-up (SHBG), with consequent release of ‘free’
sonal changes are a distant echo from our from the ovary and its transport down the (biologically active) oestrogens and
seasonally breeding ancestors and reflect fallopian tubes, fertilization and early androgens, thereby amplifying the effects
subtle changes in the hormone drive to embryo development. Such effects have of these hormones and facilitating sexual
the reproductive system. been demonstrated by numerous studies maturation49. Fat cells themselves produce
Probably the most widespread envi- in a variety of countries. As detailed below, metabolic signals — particularly leptin50
ronmental factor that reduces sperm when pregnancy occurs in a woman who — that can influence the secretion of
counts in adult men is interference with smokes, the future fertility of the foetus (as GnRH by the hypothalamus and thus
the ability of the scrotum to cool the well as its’ general health and well-being), stimulate secretion of gonadotrophins
testes, as sperm production requires the whether male or female, is also put at risk. (Fig. 3). In addition to its effects on the
testes to be 3–4 °C cooler than core body It is now advocated that smoking should ovary, insulin may also affect reproductive
temperature5,28,29. Interference with testic- be phased out as an integral part of human function by acting on the brain51.
ular cooling has even been shown to be infertility treatment. Underweight women (Fig. 3b), such as
an effective approach to male contracep- Bodyweight and body-mass-index have those suffering from anorexia nervosa,
tion30. Although extremes of heat (for little effect on sperm count, but can have rarely ovulate and menstruate52. Ovarian
example, through occupational expo- important effects on female fertility48. The function is ‘switched off’ through reduced
sure) may pose mild risk to individuals31, control of female reproductive hormones production of GnRH, which results in
every-day lifestyle factors probably have by the brain is highly sensitive to the effects gonadotrophin concentrations that are too
more widespread effects (Fig. 2). For of nutrition (Fig. 3). In a female of normal low to sustain ovarian function. This may
example, immersion in moderately hot weight and with a normal diet (Fig. 3a), the be regarded as a protective mechanism for
baths for more than 20 min will impair hormonal drive to the ovary for the regula- both mother and potential conceptus,
sperm production5,29. Another threat tion of follicle development and ovulation through the prevention of pregnancy (with
comes from our increasingly sedentary functions primarily through the its high energy cost) in the face of under-
habits at work and leisure (for example, gonadotrophins LH and FSH, which are nutrition. Circulating leptin concentrations
sitting in front of a computer or driving). released from the pituitary gland. The are low in underweight women53 and this
Continuous temperature monitoring has secretion of LH and FSH is regulated by the may be the factor that switches off secretion
shown scrotal temperature increases by brain hormone, gonadotrophin releasing of GnRH (Fig. 3b).
1.7–2.2 °C within 2 h of starting to drive hormone (GnRH). FSH and LH regulate Being overweight is also associated with
a car32. A relationship between average the development of follicles in the ovary, reproductive dysfunction (Fig. 3c). Obese
daily scrotal temperature and sperm which are then stimulated to produce the women are less likely to ovulate and more
counts has been detected33, and drivers sex steroids (testosterone, oestradiol likely to suffer miscarriage than lean age-
are often identified as an occupation at and progesterone). In turn, these sex matched women48,54. Although obesity per se
risk of low sperm counts/infertility9,31,34. steroids affect the uterus, breast and may impair fertility, there is an important

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Normal nutrition Under-nutrition Over-weight/PCOS

Gonadotrophin
releasing hormone GnRH
a (GnRH) b GnRH c

Leptin (+ other
metabolic signals) Leptin
Leptin
Pituitary
gland
Fat
cells
Fat LH
cells Insulin
LH LH
FSH Insulin FSH Insulin Pancreas
– +
Pancreas Pancreas
– + – +
Insulin
Insulin Insulin

Ovary
Ovary Ovary
'Physiological'
hyperinsulinaemia Hyperinsulinaemia
at puberty reduces reduces SHBG
Testosterone (T) SHBG and thus T levels and thus
T
Oestradiol (E2) Puberty amplifies normal E2 Delayed amplifies ovarian
Progesterone (P) Menarche production of puberty P Anovulation androgen
P
Sex steroids Ovulation sex steroids Sex steroids Amenorrhoea Sex steroids Hirsutism production

Figure 3 The hormonal mechanisms that link nutrition/diet and female fertili- In turn, the absence of these hormones results in a lack of follicular develop-
ty. a, Normal ovarian function — resulting in normal puberty and reproduc- ment, a lack of sex steroids and an absence of ovulation. c, By contrast, in
tive competence —is controlled primarily by the gonadotrophins LH overweight women and/or those with polycystic ovary syndrome (PCOS),
(luteinizing hormone) and FSH (follicle-stimulating hormone) from the pitu- an increase in the number of fat cells results in a cascade of changes,
itary gland, the secretion of which is regulated by the brain hormone, involving increased leptin and insulin levels and a preferential increase in LH,
gonadotrophin releasing hormone (GnRH). Nutrition is linked to the female but not FSH, levels. The net effect of these changes is to stimulate the partial
reproductive system through the effects of a hormone emanating from fat development of follicles that secrete supranormal levels of T, but which
cells (leptin) and by insulin from the pancreas, which alters the bioavailabili- rarely ovulate (hence low progesterone (P)). These changes are exacerbat-
ty of oestradiol (E2) and testosterone (T) by affecting production of SHBG ed by insulin-induced reduction in SHBG, which amplifies ovarian T produc-
(sex hormone-binding globulin) from the liver. Insulin can also function tion/action. In addition, there is a genetic predisposition to PCOS. It should
directly on the ovary. b, DurIng under-nutrition, when leptin secretion from be noted that impaired foetal growth (IUGR; see text) can also result in an
fat cells plummets, the reproductive system essentially shuts down because increase in the number/size of fat cells and an increase in insulin resistance
of reduced production of GnRH and consequent reduction of LH and FSH. in adulthood, although the relationship to fertility and PCOS is still unclear.

interaction of overweight/obesity with accumulate abdominal fat, as well as resist- life, maternal factors that affect the ‘foetal
polycystic ovary syndrome (PCOS). This ance to and hyper-secretion of insulin59. This environment’ may also influence the foetal
syndrome — so-called because the ovaries is reminiscent of, although more exaggerat- reproductive system. Because of its own
contain many small follicles — is one of the ed than, the physiological changes at puber- physiological processes, the foetus adapts to
commonest causes of infertility and is asso- ty (Fig. 3a). The consequences of abdominal its ‘environment’ and it may be these adap-
ciated with a failure of ovulation55. Its aeti- obesity in women with PCOS include an tations that result in adverse effects. For
ology is unclear, but genetic factors are increased chance of anovulation and infer- example, girls who were born to mothers in
important56,57. A tenable hypothesis is that tility, excess secretion of testosterone (result- developing countries and then adopted to a
polycystic ovaries and the associated hor- ing in unwanted body hair) and, in the long Western country as babies have a ~15% risk
mone abnormalities (principally, excess term, a greatly increased risk of developing of precocious puberty at the age of 7–10
secretion of testosterone by the ovary) are type-2 diabetes in later life59. years60,61. This may result from a ‘conflict’
genetically programmed during ovarian between an adaptation of the foetus to the
development in the foetus58. However, there Effects on future fertility that low nutritional plane of its mother and its
is also an interaction with key environmen- are induced in foetal/early childhood development, when food intake
tal factors, especially nutrition. PCOS is life is not limiting, although the cascade of
characterized by a cluster of metabolic As the reproductive system and its hormon- physiological changes is unclear62. Exposure
abnormalities, including a tendency to al control systems are established in foetal to environmental chemicals (for example,

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p,p′-dichlorodiphenyltrichloroethane on subsequent sperm counts in men73–75, which this occurs. Exposure of pregnant
(DDT) has also been suggested to cause though IUGR is an established risk factor mice to the polycyclic aromatic hydrocar-
precocious puberty63. Aside from maternal for cryptorchidism, hypospadias (an bons (PAHs) present in tobacco smoke
diet, smoking and exposure to other envi- abnormality of the penis), pseudoher- increases the number of oocytes undergo-
ronmental chemicals are the main factors maphroditism and testicular cancer7,16,17,76, ing apoptosis in female foetuses, resulting
with the potential to affect the future fertil- consistent with a fundamental effect on the in fewer oocytes at birth and premature
ity of the foetus. development of the reproductive system ovarian failure81. This occurred as a result
There is also great interest in the role of (Fig. 2). One study has reported an associ- of PAHs binding to the aromatic hydro-
maternal nutrition and its interaction with ation between IUGR and smaller uterus carbon receptor (Ah receptor) in the
genetic factors in determining foetal devel- and ovaries in adolescent girls77. ovary, causing the accumulation of Bax
opment and birth weight64. Low birth- Maternal smoking can also cause foetal protein in foetal germ cells, which then
weight is associated not only with greater IUGR, which, in turn, has numerous triggered cell death81,82. The same cascade
morbidity and mortality during infancy, health consequences (see above). Smoking of events can be induced in human ovari-
but also with a greater risk of developing also has adverse effects on development of an explants81, and smoking by adult
cardiovascular disease, hypertension and the reproductive system of foetuses of women may activate similar mechanisms,
type-2 diabetes in adulthood65–67. It has both sexes, independent of IUGR. Its main as it is associated with depleted oocyte
been suggested that these diseases (all of consequence in the male is to reduce reserves. Similar pathways may underlie
which are linked to insulin resistance) arise future sperm counts78. redReduced Sertoli the (postulated) changes in Sertoli cell
as a consequence of ‘programming’ of cell number is the primary mechanism by numbers induced in the foetal testis by
physiological systems during foetal life in which a permanent decrease in sperm maternal smoking, as studies in rats
response to changes in maternal environ- count (and testis size) can be induced (Fig. exposed in utero to dioxin, which also
ment. Such programming implies that per- 1), and this is the probable explanation for binds to the Ah receptor, had reduced
manent changes in gene expression occur the effect of maternal smoking. As the sperm counts in adulthood83.
during development, changes with conse- Sertoli cells orchestrate testicular develop- Past exposure to persistent environmen-
quences that last into adulthood68. In ment, effects on these cells may result in tal chemicals (for example, DDT and poly-
developed countries, environmental fac- changes in other testicular cells, such as chlorinated biphenyls (PCBs)) may have
tors (such as social class and smoking) can the Leydig cells and foetal germ cells7,17. induced effects in humans, as it undoubt-
influence birth weight, but most (although Leydig cells make the testosterone respon- edly did in some wildlife species84.
not all) epidemiological studies have con- sible for masculinization, and abnormal However, it is less clear that modern (non-
cluded that maternal undernutrition is of development of the foetal germ cells prob- persistent) pesticides pose a serious risk to
central importance68. It is possible that ably results in testicular germ cell cancer the general public. There are instances in
intra-uterine growth retardation (IUGR), in adulthood (Fig. 2). Testicular cancer is which exposure of men involved in the pro-
through its association with insulin resist- the most common cancer of young men duction or application of particular pesti-
ance in later life, contributes to the patho- and its incidence has increased progres- cides has been shown to cause infertility5,9,85,
genesis of PCOS. However, to date, no sively in Western countries in the last or where an association between pesticide
clear relationship has been established 50–60 years. Furthermore, there is evi- usage and cryptorchidism86,87 or male infer-
between birth weight and the risk of devel- dence that the incidence of ‘masculiniza- tility in farmers88 has been suggested.
oping PCOS69. Interestingly, recent studies tion’ disorders has also increased during However, other detailed studies have failed
have demonstrated insulin resistance and the same period16,17. Exposure to the active to find a significant association between
abdominal obesity in men, women and chemicals in tobacco smoke or from other pesticide exposure and male or female
mice carrying inactivating mutations in sources, such as combustion of fossil fuels infertility5,89. Similarly, there are isolated
the aromatase gene70–72. In this situation, or dietary consumption79, may have con- examples in which occupational exposure
production of oestrogen is blocked, result- tributed to these changes (see below). to non-pesticide chemicals (for example,
ing in infertility70–72. Women whose mothers smoked whilst glycol ethers) can reduce sperm counts90. It
Although epidemiological data highlight they were in utero have an earlier is uncertain how common such effects may
a link between IUGR and adult disease, lit- menopause and consequently a shorter be, as there are fundamental logistical
tle is yet known about its impact on the reproductive lifespan80. These changes are problems in undertaking semen analysis
reproductive health of the offspring. This determined by the number of oocytes in studies in many groups of workers5.
may be particularly important if the nutri- the ovaries, which is determined during Perhaps the most cautious view is that indi-
tional deprivation or other ‘insult’ occurs foetal development (Fig. 2). This suggests viduals whose occupation/lifestyle brings
during the time of gonadal development that maternal smoking results in a loss of them into everyday contact with chemicals
and germ cell multiplication. There are oocytes in the foetal ovary. Studies in mice known to be reproductively toxic should be
conflicting findings on the effects of IUGR have identified the mechanism through considered ‘at risk’, whereas there is little

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risk to the general public. produce changes in enzyme activity that or adult life, result from hormonal changes.
Maternal exposure to environmental might indicate inter-individual differences Genetic differences (for example SULT1E1
chemicals that possess either intrinsic hor- in inherent or chemically induced suscep- polymorphisms) may predispose some
monal activity or can perturb endogenous tibility to oestrogen-related disorders97. individuals to hormonal perturbation, and
hormone production/action pose a hazard Second, male rats exposed in utero to cer- this emerging area is likely to become
to reproductive health of the foetus through tain phthalate esters that were administered increasingly influential on our thinking. It
the pathways outlined above. In pregnancy, to their mothers exhibit a high frequency of has also become increasingly apparent that
exogenous exposure of humans or animals cryptorchidism, hypospadias and abnor- all hormonal (endocrine) systems have ‘rip-
to potent oestrogens (for example, diethyl- mal testes, associated with suppression of pling’ effects on other endocrine systems,
stilboestrol or ethinyl oestradiol from the testosterone levels in the foetal testis7,98–100. which is why diet and season can affect fer-
contraceptive pill) during the period of sex- These changes are remarkably similar to tility. Understanding the complex pathways
ual differentiation undoubtedly results in an the changes in human male reproductive through which these ripples work, and how
increased incidence of cryptorchidism, health mentioned above, and which can be common environmental chemicals can
penile abnormalities, poor semen quality induced by over-exposure to oestro- affect them, present intriguing challenges to
and probably testicular cancer4,16,17. These gens4,16,17. Phthalate esters have multiple and biomedicine in an age when the focus is on
effects may stem from interference with varied uses (for example, as plasticizers and genes rather than the whole body. A failure
androgen production/action or disturbance spreading agents) and are the class of envi- of science to meet this challenge and of
of the androgen–oestrogen balance91,92. ronmental chemicals to which there is individuals to amend their diet/lifestyle will
Evidence that humans are exposed to greatest (and universal) human exposure. hand the poisoned chalice of infertility to
numerous chemicals with weak oestrogenic Though the doses of phthalates required to the next generation. ❑
potency (‘environmental oestrogens’) from induce high prevalence of these disorders
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