Human Reproduction Update, Vol.17, No.3 pp.

418– 433, 2011

Advanced Access publication on January 24, 2011 doi:10.1093/humupd/dmq061

Environment and women’s

reproductive health
D. Caserta 1,*, A. Mantovani 2, R. Marci 1, A. Fazi 1, F. Ciardo 1,
C. La Rocca 2, F. Maranghi 2, and M. Moscarini 1
1
Institute of Gynecology, Perinatology and Child Health, Sant’Andrea Hospital, University of Rome Sapienza, Via di Grottarossa 1035, 00189
Rome, Italy 2Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy

Correspondence address. Tel: +39 06 33775696; Fax: +39 06 33776660; E-mail: donatella.caserta@uniroma1.it

Submitted on June 1, 2010; resubmitted on November 9, 2010; accepted on November 29, 2010

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table of contents
...........................................................................................................................
† Introduction
† Methods
† Results
Fertility and fecundity
Pregnancy outcomes
Trans-generational exposure and effects
† Conclusions

background: There is significant evidence that continuous and prolonged exposure to several endocrine disrupting chemicals (EDC) is
a risk factor for reduced fertility and fecundity in women. There is also evidence that ED exposure has trans-generational effects. In this
systematic review, we evaluate the evidence for an association between EDC exposure and women’s reproductive health.
methods: Studies were found by searching the PubMed database for articles published up to 2010. Associations between ED exposure
and women’s reproductive health reported in the PubMed database are summarized and classified as fertility and fecundity, pregnancy out-
comes, transgenerational exposure and effects.
results: Epidemiological studies on EDCs are not always consistent, in part due to limitations imposed by practical constraints. In order
to make progress in this field, we recommend taking advantage of biomonitoring and biobanks, including the development of appropriate
biomarkers, and taking into greater consideration modulating factors such as genetic polymorphisms and dietary habits. Further human
studies are warranted with particular focus on impaired fertility/fecundity associated with currently widespread ED (e.g. bisphenol A, phtha-
lates and polybrominated flame retardants).
conclusions: A detailed appraisal of compounds specifically related to adverse reproductive outcomes is very important for preven-
tion and risk-communication strategies. Besides research needs, the current evidence is sufficient to prompt precautionary actions to protect
women’s reproductive health.

Key words: endocrine disrupters / reproductive health / bisphenol A / phtalates / prenatal exposure

probability of conception. Clinical infertility is defined as the inability

Introduction
Fertility is commonly defined as the ability of a couple to achieve preg-
nancies that survive to birth (Tingen et al., 2004), whereas fecundity is
a woman’s biological ability to reproduce based on the monthly
to become pregnant after 12 months of unprotected intercourse
(Gnoth et al., 2005). It has been estimated that 15% of the popu-
lation in industrially developed countries is affected by infertility
(Evers, 2002). The potential for increasing the exposure to risk
factors that can affect woman’s reproductive health has grown in
industrialized and, subsequently, post-industrial society in the

& The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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Environment and women’s reproductive health
Western world. Factors related to lifestyle, such as cigarette smoking,
obesity and advanced maternal age, have an established role in mod-
ulating fecundity and fertility (Kelly-Weeder and Cox, 2006). So too
have occupational risk factors, including heavy physical work and
exposure to anaesthetic gases, anti-neoplastic drugs, heavy metals
and solvents (Kumars, 2004; Figà-Talamanca, 2006). Far less attention
has been given to exposure to chemicals present in the environment
and diet (Foster et al., 2008), despite evidence from toxicological
studies that clearly indicate that many chemicals impair female repro-
duction both directly and/or indirectly.
The real question is whether such effects occur at the chemical
exposure levels observed in the general population, i.e. to what
extent chemical hazards represent a risk factor for female infertility
(Nicolopoulou-Stamati and Pitsos, 2001).
An endocrine disruptor (ED) is an exogenous substance or mixture
that alters the function(s) of the endocrine system and consequently
causes adverse health effects in an intact organism, or its progeny,
or a (sub)population (Caserta et al., 2008). The homeostasis of sex
steroids and the thyroid are the main targets of ED chemicals
(EDC), and therefore, reproductive health, considered as a continuum
from gamete production and fertilization right through intrauterine and
post-natal development of progeny, is recognized as being especially
vulnerable to endocrine disruption (Mantovani, 2002; Guzman and
Zambrano, 2007; Ma, 2009). EDCs are a broad and diverse group
as regards the use, chemical structure and modes of action. They
include persistent pollutants able to bioaccumulate (dioxins, DDT
and cadmium), chemicals used in plant or animal food production
(azole or dicaroximide fungicides) and compounds widely used in
industry or consumer products [phthalates and bisphenol A (BPA)]
(Hotchkiss et al., 2008). Many other substances may be considered
EDCs (Caserta et al., 2008) (Table I). For instance, plant-derived hor-
monally active compounds, phytoestrogens, are subject to a number
of concerns due to high-level intake through food supplements or
‘novel’ foods. Sex hormones from urban or farm waste (e.g. estrogens
from the use of contraceptive pills and/or from anticancer drugs) can
become concentrated in industrial, agricultural and urban areas, and
may therefore be considered potential EDs for humans and/or wildlife
(Caserta et al., 2008). Overall, the general population may undergo a
daily exposure to several ED through multiple diverse exposure
pathways.
The range of female reproductive system disorders where endo-
crine disruption has been implicated is quite large, although the
weight of the evidence is variable. EDC exposure may contribute to
disorders of the ovary: aneuploidy (Crain et al., 2008), polycystic
ovary syndrome (PCOS) (Takeuchi et al., 2004), endometriosis
(Mayani et al., 1997; Cobellis et al., 2003) and altered cyclicity
(Cassidy et al., 1994; Lu et al., 2000); disorders of the uterus:
uterine fibroids (McLachlan et al., 2006); disorders of placental func-
tion and adverse pregnancy outcome: early pregnancy loss, recurrent
abortion, fetal growth restriction (Gerhard et al., 1998; Korrick et al.,
2001; Greenlee et al., 2003; Chiaffarino et al., 2006); disorders of the
breast: breast cancer, reduced duration of lactation (Olaya-Contreras
et al., 1998; Romieu et al., 2000; Crain et al., 2008) and finally to
puberal timing (Colon et al., 2000; Krstevka-Kostantinove et al.,
2001). Moreover, EDC-related reproductive disorders may result
from exposure during adulthood or as long-term consequence
of early life (Crain et al., 2008). This review article summarizes the
419
available literature on the possible relationships between EDC
exposure and adverse effects on fertility and fecundity, including preg-
nancy outcomes, as well as on trans-generational exposure associated
with pregnancy and lactation.
Methods
Studies were identified by searching the PubMed database for articles pub-
lished until 2010. MEDLINE was searched using the following keywords:
endocrine disrupters, environment, reproductive health, fecundability, fer-
tility, pregnancy, BPA, phtalates, prenatal exposure and postnatal effects.
Association between EDC exposure and women’s reproductive health
reported in the PubMed database is reviewed, and results are reported for
fertility and fecundity, pregnancy outcomes, and trans-generational
exposure and effects.
The review criteria were human, epidemiological, observational and ret-
rospective studies in which occupational or non-occupational exposure to
EDCs was compared with long-term effects on reproductive health.
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Studies published in languages other than English were considered if an
English abstract was available. As there is relatively little information on
the mechanism by which EDCs effect human reproduction, due to the
lack of experimental studies, experimental in vivo studies in animal
models were also considered in this review. We also identify gaps in the
current data and make recommendations for further research.
Results
Exposure-association study validity is dependent on the selection of
proper markers. Exposure assessment should be ideally performed
by measuring the chemicals and/or metabolite(s) in biological fluids.
Appropriate fecundability effect measures should also be considered.
The much-used time-to-pregnancy (TTP) measures delay in con-
ception at the population level, and is therefore borderline between
a biomarker and a clinical effect. However, the interpretation of find-
ings on TTP presents may confounding factors: several pathways in
both partners may be involved in a long TTP (semen quality, ovulation
and implantation), all of which are potentially subjects to EDCs. Thus,
it is advisable to support the assessment of effects on TTP with an
appraisal of available toxicological information (Mantovani et al., 2008).
Fertility and fecundity
Indications of lower female fertility and fecundity in recent decades
have been often related to lifestyle factors (Hassan and Killick,
2004). Occupational exposure to EDCs is often cited as a risk
factor for female fertility (Figà-Talamanca, 2006). Direct exposure to
EDCs through pesticide handling is a specific risk factor for poor
reproductive health in the rural environment (Fuortes et al., 1997;
Frazier, 2007). Epidemiological studies have documented an
association between agricultural occupation and the incidence of infer-
tility, congenital malformations, miscarriage, low birthweight,
small-for-gestational-age birth, preterm delivery and stillbirth.
Overall, pesticide exposure affects both male and female reproduction
(in males, there is a particular effect on sperm quality parameters),
whereas, in general, no marked effect on steroid balance has been
observed. There is, however, a relationship between the decreased
fecundability ratio and pesticide exposure (Hanke and Jurewicz,
2004). One study (de Cock et al., 1994) found that reduced fecund-
ability ratio and a longer TTP are associated with pesticide exposure.
420 Caserta et al.

Table I Main classes of EDCs present in food and in environment with major relevance for female reproductive system.

Chemical(s) Pathways of exposures Mechanisms of action

.............................................................................................................................................................................................
POPs
Polychlorobiphenyls (PCB) Food chain (fat-rich food, e.g. milk and derivatives, fatty Alteration steroid hormone metabolism/transport,
fish, etc.), living environment ability to bind with the thyroxin transport protein, TTR,
interaction with thyroid hormone receptors,
neuroendocrine effects
Dioxins and ‘dioxin-like’ PCBs Food chain (fat-rich food, e.g. milk and derivatives, fatty Aryl hydrocarbon receptor interaction leading to altered
fish, etc.), living environment steroid hormone metabolism and neuroendocrine
effects including on thyroid
DDT and metabolites Food chain (fat-rich food, e.g. milk and derivatives, fatty Mainly estrogenic activity but also interaction with
fish, etc.), living environment and workplaces (in
developing countries)
Substances used in agricultural and farm animal production
Organochlorine insecticides (e.g. Food chain (fat-rich food, e.g. milk and derivatives, fatty Homeostasis of steroid hormones (estrogenic and/or
Lindane) fish, etc.), living environment, workplaces (mainly in anti-androgenic effects, interaction with PR)

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developing countries)
Triazoles, imidazoles Food chain (agricultural and zootechnical fungicides), Inhibition of steroid hormone biosynthesis
living environment and workplaces (agricultural areas)
Triazines Food chain (herbicides), living environment and Effects on HHG axis
workplaces (agricultural areas)
ETU (metabolite of ethylene Food chain (agricultural and zootechnical fungicides), Thyreostatic effects
bis-dithiocarbammates, e.g. Maneb), living environment and workplaces (agricultural areas)
benzimidazoles
Industrial products and daily-use products
Nonyl-phenols and octyl-phenols Detergent by-products: food chain (seafood) and Estrogen agonists—ER a
consumer products
Bisphenol A Food chain (e.g. plastics in contact with food), consumer Estrogen agonist—ER a
products (e.g. dental sealant, plastic additive, etc.)
Several phthalates (di-2-hexyl-ethyl-, Food chain (e.g. plastics in contact with food), consumer Agonists of PXR, effects on steroid hormone
di-n-butyl-, etc.) products (e.g. PVC, deodorants, adhesives, etc.) biosynthesis
Polybrominated flame retardants Food chain (fat-rich food, e.g. milk and derivatives, fatty Interaction with PXR leading to altered steroid and
fish, etc.), living environment, workplaces, consumer thyroid hormone homeostasis
products (e.g. electronic devices, etc.)
Organotins Food chain (seafood), consumer products (e.g. Aromatase inhibition
antifouling agents)
Perfluorooctane sulphonate Food chain (bioconcentration in animal tissues), Alteration HHG axis
consumer products (e.g. plastics, carpets, materials,
etc.)
Parabens Main cosmetic, toiletries and pharmaceutical Estrogen agonist—ER a and b
preservatives
UV-screen (benzophenone 2, Mixture for protection against UV radiation Estrogen agonist—ER a
4-methylbenzylidene camphor, etc.)
Cadmium Food chain (e.g. refined food as flour, rice, sugar; Estrogen agonist—ER a
seafood), cigarette smoking
Phytoestrogens
Isoflavones, lignans, etc Food chain (e.g. vegetables, soy-based food), consumer SERMs, high affinity for ER b
products (e.g. cosmetics)

POPs, persistent organic pollutants; PR, progesterone receptor; ETU, ethylenethiourea; PXR, pregnane X receptor; HHG axis, hypothalamo-hypophysis-gonadal axis; ER, estrogen
receptor; SERM, selective ER modulator.

Of particular importance when considering the association of pesti-
cides and health is the active compounds involved; it is insufficient to
consider pesticide classes (e.g. ‘fungicides’ and ‘herbicides’), as these
include highly diverse chemical groups, only a few of which are
EDCs. An attempt to identify exposure with specific pesticide usage
patterns has been undertaken by the Ontario Farm Family Health
Study. Involvement in specific pesticide-related activities during
exposure intervals (e.g. re-entry in treated areas) was related to a
fecundability reduction in the range of 249% to 220%. Since, in
most cases, activities were performed with the male partner, the
Environment and women’s reproductive health
contribution of reduced fecundity from either male or female partner
was not measurable, and the effect on the couple (e.g. on fertilization
ability) is the outcome measure (Curtis et al., 1999).
Other studies do not confirm these findings; a study analysing a
large population from Veneto, an agricultural area of the North
Eastern Italy where reliable estimates of specific pesticide compound
usage are available, showed no relationship between the fertility rate
and pesticide use. The results provide some reassurance about the
safety of pesticide use according to the current European regulations
(Clementi et al., 2008). However, greenhouse work is peculiar as it
implies that continuous exposure to pesticides. Certain activities,
possibly associated with a specifically increased exposure to chemicals,
are consistently associated with a significant 20 –30% reduction in
fecundability, i.e. handling cultures many hours per week, spraying of
pesticides and lack of glove use (Abell et al., 2000). In a Finnish
study, such associations were observed for pyrethroids and, to a
lesser extent, organophosphorus and carbamate insecticides, although
only in workers using inadequate protection (Sallmén et al., 2003).
A more recent Dutch study observed that exposure of male green-
house workers led to a significantly prolonged TTP in couples
attempting to conceive their first pregnancy, but not in those who
already at least have one child (Bretveld et al., 2008). As for specific
groups of potential EDCs, the occupational exposure of male green-
house workers to chlorinated insecticides, triazines and benzimida-
zoles pesticides was related to both longer TTP and an increased
risk of spontaneous abortion in their spouses (Petrelli et al., 2003).
Occupational exposure to substances other than pesticides has
received relatively less attention. A retrospective study was conducted
on TTP among 250 Portuguese shoe manufacturing workers exposed
to solvents compared with 250 unexposed women working in food
storage units and warehouses. Reduced fertility was more evident
with longer duration of exposure (years) to solvents and was in the
40 –50% range in the exposure subgroups. The effect may be
related to one or combination of the solvents commonly used in
shoe manufacturing (n-hexane and hexane isomers, toluene,
methyl –ethyl-ketone, acetone, ethyl-acetate and dichloromethane)
(Sallmén et al., 2008).
Exposure to EDCs in the general population, through food or the
living environment, is most reliably measured using biomarkers such
as parent compound and/or metabolite(s) levels in serum, plasma or
urine. Organochlorines are the most investigated group of persistent
EDCs contaminating the food chain. The major representatives are
polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs)
such as DDT, polychlorinated dibenzo-p-dioxins (PCDDs) and
polychlorinated-dibenzofurans (PCDFs). For a long time, PCBs and
OCPs were used intensively, but are now banned from industrialized
countries, although PCDDs/PCDFs are still introduced in the environ-
ment as combustion by-products. All these compounds bioaccumulate
in the lipid fraction of body tissues, eggs and milk. An interaction with the
aryl hydrocarbon receptor has been described for PCDDs/PCDFs and
some PCBs (Krauthacker et al., 2009). A thorough investigation has
been carried out in the US Great Lakes area, due to long-term PCB pol-
lution and, to a lesser extent, other persistent EDCs. Fish, a primary
staple food in the area, is therefore a major dietary route of exposure
to PCBs. In the New York State Angler Cohort Study, long-term
exposure to PCBs, estimated by taking into account the consumption
of fish from the contaminated Great Lakes, was correlated to reduced
421
fecundability: women regularly consuming locally caught fish for 3–6
years had a fecundability ratio ¼ 0.75 [95% confidence interval (CI) ¼
0.59 –0.91] when compared with unexposed women. On the other
hand, male exposure apparently did not play a major role (Buck et al.,
1999). The association between serum levels of PCB and the persistent
DDT metabolite, o’p’DDE, exposure and TTP were investigated in the
USA using a biobank of 390 pregnant women. Compared with women
in the lowest exposure category (PCBs , 1.24 mg/l, DDE , 14 mg/l),
TTP increased for women in the highest exposure category in terms of
both PCBs (fecundability odds ratio for PCBs ≥ 5.00 mg/l ¼ 0.65, 95%
CI: 0.36 –1.18) and DDE (fecundability odds ratio for DDE ≥ 60 mg/
l ¼ 0.65, 95% CI: 0.32 –1.31). The dose–response trend was not
straight-forward and the effect, even though apparent, was not statisti-
cally significant. Thus, it is possible that such contaminants, in addition to
other factors such as nutrition or genetic susceptibility, could impact
fecundability (Law et al., 2005). Preconception blood samples from 83
women planning pregnancies (contributing 442 menstrual cycles)
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were analysed for 76 PCB congeners by gas chromatography with elec-
tron capture; serum lipids were quantified with enzymatic methods.
PCB congeners were grouped into three groups as estrogenic, anti-
estrogenic (dioxin-like) and highly persistent; both estrogenic and anti-
estrogenic were strongly associated with reduced fecundability (0.32;
95% CI 0.03 –3.90 and 0.01: 95% CI , 0.00 –1.99, respectively).
The persistent perfluorinated acids perfluorooctane sulphonate
(PFOS) and perfluorooctanoic acid (PFOA) are used as additives in a
number of industrial and consumer products; PFOSs and to a lesser
extent PFOAs are found extensively in wildlife and humans. Seafood
consumption is the primary route of exposure for the general popu-
lation (European Food Safety Authority, 2008). Among 1240 women
from the Danish National Birth Cohort, longer TTP was significantly
associated with higher maternal plasma levels of PFOA and PFOS;
30% reduced fecundability was detected in the three highest PFOS
quartiles compared with the lowest quartile, whereas a linear-like
trend was observed for PFOA (0.72, 0.73 and 0.60 for three highest
quartiles versus lowest quartile). The findings also suggest that
reduced fecundity may occur at PFOA and PFOS plasma levels seen
in the general population of developed countries (Fei et al., 2009).
BPA, widely used in polycarbonate plastic products and epoxy
resins, shows estrogenic activity by binding to the a- and, to a
lesser extent, b-estrogen receptors in vitro and in vivo. It also affects
other relevant endocrine activities, such as the stimulation of prolactin
release (European Food Safety Authority, 2006). PCOS is character-
ized by disordered folliculogenesis. Serum BPA concentrations were
found to be significantly higher (in the range +30 to 40%) in non-
obese and obese women with PCOS. The same report was found
in obese, normal non-PCOS women compared with non-obese
non-PCOS women. In the same study, higher serum BPA was also sig-
nificantly correlated with total and free testosterone, androstenedione
and DHEAS, indicating that BPA may enhance androgen concen-
trations in adult women (Takeuchi et al., 2004). This study indicates
that more investigation is needed on the relationships between
exposure to EDCs and the onset and/or clinical course of PCOS.
Methoxychlor is an organic chlorine compound with estrogen-
agonist action, like DDT. Early post-natal exposure inhibits folliculo-
genesis and stimulates anti-Müllerian hormone (AMH) production in
the ovaries of rats (Uzumcu et al., 2006). AMH, involved in the tran-
sition of follicles from primordial to primary stages in polycystic
422
Figure 1 Schematic presentation of EDCs distribution in the materno-feto-placental unit.
ovaries, is considered a biomarker of ovarian follicular status (Visser
et al., 2006).
Endometriosis is a complex disease and a major risk factor for poor
fecundability in women living in industrialized countries (Rogers et al.,
2009). Endometriosis is undergoing intensive investigation because it
is both a social and a health burden. Accordingly, EDCs have been
hypothesized as risk factors (Crain et al., 2008). Some experimental
studies show that tetrachlorodibenzo-p-dioxin (TCDD) and
17-b-estradiol may work in combination by promoting chemokine
secretion and the invasion of the endometrial stromal cells in vitro (Yu
et al., 2008). In fact, there is interest in the link with exposure to dioxin-
like chemicals (PCDD/Fs and dioxin-like PCBs), as the chemicals may
alter endocrine-immune cross-communication. Nevertheless, several
epidemiological studies yield inconsistent and inconclusive results: a
recent US study on 60 infertile women with endometriosis found that
PCDD/F and PCB levels did not differ with respect to controls
(Niskar et al., 2009). The inconsistency of results might indicate that
more attention is needed in terms of individual susceptibility. Cyto-
chrome P450 genotypes with the CYP1A1 462Val allele reduce the
risk of advanced endometriosis in combination with high serum levels
of dioxin-like chemicals (adjusted odds ratio 0.13, 95% CI 0.02– 0.76)
(Tsuchiya et al., 2007). Increased levels of the plasticizer
di-(2-ethylhexyl)-phthalate, a PPAR (peroxisome proliferator-activated
receptors) agonist modulating steroid biosynthesis and metabolism,
were detected in women with endometriosis (Cobellis et al., 2003).
Moreover Reddy et al. (2006) found a positive association with four
phthalates, hinting to a possible additive effect. Oxidative stress and
immune modulation may be other side effects of ED exposure, which
may be highly relevant to reproductive health. Vulnerability to such
effects is affected by diet, such as the intake of bioactive food com-
ponents with activities modulating endocrine and/or redox balance
(Baldi and Mantovani, 2008). Phytoestrogens are biologically active phe-
nolic compounds that mimic the primary mammalian estrogen
17-b-estradiol (E2) (Sirtori et al., 2005). Four main classes of
Caserta et al.
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compounds are currently recognized as phytoestrogens: isoflavones,
stilbenes, coumestans and lignans (Sirtori et al., 2005; Moon et al.,
2006). These types of phytochemicals are some of the most prevalent
compounds found in fruits, vegetables, legumes and tea (Moon et al.,
2006). Several studies have shown prolonged menstrual cycle in
healthy premenopausal women with a daily intake of 45 mg of isofla-
vones from soy protein (Cassidy et al., 1994; Lu et al., 2000).
However, in a study on flaxseed ingestion, the luteal phase was reported
to be prolonged (Phipps et al., 1993).
The possibility that different phytoestrogens do exert various
actions cannot be ruled out. Data on the actual exposure to EDCs
impairing female fertility are limited. Useful information could be
derived from the presence of xenobiotics in the ovarian follicular
fluid of women undergoing assisted reproductive techniques (Jarrell
et al., 1993). In a limited sample of 21 women, Younglai et al.
(2002) found a detectable presence of chlorinated EDC and cotinine
in more than 50%, whereas cadmium was present in 38%. The fer-
tilization rate was, moreover, negatively correlated with serum and
follicular fluid p, p’-DDE. In 99 infertile women undergoing IVF,
levels of PCB and DDT and metabolites in the follicular fluid were
highly variable: both compounds showed some correlation with
IVF-embryo transfer success, but the trend was unclear (Jirsová
et al., 2010).
Pregnancy outcomes
Transplacental transfer is well recognized for most EDCs: a synthesis
of the exposure pathway of the placental –fetal unit is shown in Fig. 1.
The issue of the long-term effects of EDCs on fetal programming is a
major topic for risk assessment (Mantovani, 2006). Cigarette smoking,
entailing exposure to a mixture of chemicals including potential EDCs
(e.g. cadmium), is a recognized risk factor for impaired placental devel-
opment and fetal growth restriction (Chiaffarino et al., 2006; Aguilera
et al., 2010). A significant association between EDCs and spontaneous
abortion and preterm delivery has also been observed in several
Environment and women’s reproductive health
studies (Perin et al., 2010; Yi et al., 2010). The increased risk seems to
be associated with both active and passive smoking (George et al.,
2006). Occupational exposure to toxic compounds, such as ‘pesti-
cides’ (insecticides, herbicides and fungicides), is often cited as a risk
factor for early pregnancy loss and pre-term delivery. Greenlee
et al. (2003) found an association between adverse reproductive out-
comes in women and the practice of mixing and applying herbicides as
well as the use of fungicides. The possible role of male partner
exposure is suggested by an increased risk of miscarriage with the
reported use of several compounds, including thiocarbamates, atrazine
and phenoxy herbicides (Arbuckle et al., 1999). This hypothesis has
been supported by Italian retrospective studies that show a signifi-
cantly increased risk of conception delay and spontaneous abortion
among the spouses of high-exposure workers (greenhouse, applica-
tors). The risk increased with reported exposure to some pesticide
groups only, including potential EDCs such as chlorinated insecticides
and triazines (Petrelli et al., 2001). Consumption of fish from the Baltic
Sea has been linked to preterm delivery and reduced birthweight and,
possibly, fetal growth restriction (Rylander et al., 2000). The Baltic Sea
is another area affected by long-term pollution with PCBs and other
persistent organochlorines. In the 1980s and 1990s, a number of
studies investigated fetal outcomes in relation to the consumption of
fish from the US Great Lakes. Similar associations were reported,
and the effect was comparable in magnitude to that reported for ciga-
rette smoking, i.e. an average decrease in neonatal weight in the range
of 160 –190 g (Fein et al., 1984).
Lin et al. (2008) reported significant decreases in gestation and
birthweight associated with exposure to PCBs, generally through fish
consumption; however, some older studies did not find a significant
association (Lonky et al., 1996). At the present time, other EDCs
would deserve more attention as toxicants and are indicated for
their possible effect on placenta and fetal growth.
The biocide tributyltin is a ubiquitous contaminant; the general
population is primarily exposed through seafood consumption (Euro-
pean Food Safety Authority, 2004). Tributyltin modulates aromatase,
which catalyses placental estrogen production, although the effect may
depend on the target system. It inhibits human aromatase from gran-
ulosa cell-like tumour cell-line (Cooke, 2002), whereas in human pla-
cental choriocarcinoma cells, it enhances both aromatase and type I
17-b-hydroxysteroid dehydrogenase (Nakanishi, 2008). In pregnant
rats, exposure to tributyltin increases post-implantation loss and
decreases litter size and fetal weights (Adeeko et al., 2003). Some find-
ings indicate that organotins are also potent agonists for the nuclear
receptors RXR and PPARg, but the related human toxicological
effects have yet to be characterized (Nakanishi, 2008). Considering
that dietary exposure to tributyltin is widespread (European Food
Safety Authority, 2004), studies on the possible effects on human
reproductive outcomes may be warranted.
The widespread heavy metal cadmium was recently recognized as
an estrogenic EDC, possibly acting on the pathways mediated by
estrogen receptors rather than on the receptors themselves (Zang
et al., 2009). Cigarette smoke and seafood are the main sources of
cadmium exposure. High-level dietary cadmium intake has been
recently suggested as a risk factor for post-menopausal endometrial
cancer (Akesson et al., 2008). A Chinese study showed that cord
blood cadmium levels .0.40 mg/l were associated with a 2.24 cm
decrease in neonatal birth height, whereas no association with
423
birthweight has been found (Zhang et al., 2004). Cadmium concen-
trates in the placenta, as shown by the significant increase in both
the metal and metallothionein in the placenta of smokers (Ronco
et al., 2005). Recently, increased concentrations of cadmium, as well
as lead and arsenic, and reduced iron were observed in the placentas
of mothers delivering low birthweight babies (Llanos and Ronco,
2009).
When assessing the risk of adverse pregnancy outcomes, it is of the
utmost importance to measure exposure through appropriate bio-
markers (e.g. representative metabolites) as well as to consider ‘real-
life’ exposure to multiple EDs. Wolff et al. (2008) correlated 5 phenol
and 10 phthalate urinary metabolites in a multiethnic cohort of 404
women in New York City during their third trimester of pregnancy
and the size of infants at birth. Higher prenatal exposures to
2,5-dichlorophenol, a main metabolite of 1,4-dichlorobenzene,
although not identified as an EDC predicted lower birthweight in
boys (2210 g average birthweight difference between the third
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tertile and first tertile, 95% CI, 71–348 g). Higher maternal
benzophenone-3 concentrations had a sex-related effect, being associ-
ated with a decrease in birthweight in girls but with higher birthweight
in boys. Levels of low-molecular-weight phthalate monoesters, major
phthalate metabolites, were associated with longer gestational age and
increased head circumference.
A multivariate analysis of persistent chlorinated EDCs in 41 cord
blood samples collected in Singapore indicated that PCBs and chlor-
dane levels were inversely correlated with better indexes of fetal
growth (birthweight, length and head circumference) and health
(Apgar scores) (Tan et al., 2009). In broader terms, it is important
to consider that chemical pollutants may interact additively with
other risk factors, such as dietary habits and lifestyle.
Recurrent miscarriage is a complex disorder occurring in 1–2% of
fertile women (Brigham et al., 1999); risk factors include genetic pre-
disposition as well as immunological, endocrine and blood coagulation
disturbances (Christiansen et al., 2008). A positive association
between the body burden of persistent chlorinated EDCs (PCB,
DDT and metabolites, other chlorinated insecticides) and recurrent
miscarriage was observed in case –control studies carried out in
Germany (Gerhard et al., 1998) and the USA (Korrick et al., 2001).
In a limited pilot study, maternal exposure to estrogen-like BPA has
also been associated with recurrent miscarriages (Sugiura-Ogasawara
et al., 2005). BPA is a strong ligand of the estrogen-related receptor
gamma (ERRgamma), a nuclear receptor whose physiological ligand
has not been identified yet. ERRgamma is strongly expressed in the
human placenta (Takeda et al., 2009). More studies are thus war-
ranted on the placental effects of BPA. Nevertheless, conflicting
observations have been made with regard to the role of EDC
exposure in recurrent miscarriage. A study of Japanese patients with
a history of recurrent miscarriage did not find an association with
serum levels of industrial products such as PCBs, hexachlorobenzene
or DDE (Sugiura-Ogasawara et al., 2003). In the same vein, circulating
levels of BPA were detected in the blood of US mothers, but no
association was found with pregnancy outcomes (Padmanabhan
et al., 2008).
As far as delivery is concerned, it is known that problems may be
related to several mechanisms, from altered neuroendocrine regu-
lation to local effects on the uterus. A pilot study in Italy found a cor-
relation between higher cord blood levels of di(2)ethylexylphthalate
424
and shorter pregnancy duration (Latini et al., 2003). Longnecker et al.
(2005) found no correlation between preterm delivery and PCB
serum levels in 1034 pregnant women enrolled in the US Collabora-
tive Perinatal Project. More recently, an Australian study measured
PCB concentrations in the breast milk of 200 women as a retrospec-
tive measure of maternal body burden during pregnancy: the only
apparent effect was a direct relationship between PCB levels and
odds for prematurity, even though it was not statistically significant
(Khanjani and Sim, 2007). The results by Longnecker et al. (2005)
and Khanjami and Sim (2007) do not suggest a marked impact of
PCB exposure levels in the general population on pregnancy and deliv-
ery. However, both studies investigated total PCBs, whereas PCBs
should be analysed as subgroups characterized by different toxicologi-
cal properties.
Until now, altered neuroendocrine regulation has been among the
least investigated modes of endocrine disruption. Immune system
perturbations are involved in pre-eclampsia pathophysiology. A
Norwegian study found working in animal farming, entailing exposure
to anti-parasitic drugs and insecticides, caused a moderate but signifi-
cant increased risk for pre-eclampsia (RR 1.14, 95% CI 1.07–1.22)
(Nordby et al., 2006). Whereas the authors point out the immunomo-
dulating effects of several chemicals used in farming, EDCs should be
considered as well. Since the immune effects of EDCs are increasingly
recognized (Dietert and Zelikoff, 2008), their role in pre-eclampsia
risk is worthy of more in-depth investigation. Oxidative stress is also
involved in pre-eclampsia (Kontic-Vucinic et al., 2008). Enhanced oxi-
dative stress may be an end-point of interference with estrogen recep-
tors and other nuclear receptor pathways and, indeed, it can be
elicited by EDCs such as PCDD/Fs PCBs and phthalates. Such
effect may be at least partly counteracted by antioxidant vitamins
and trace elements (Baldi and Mantovani, 2008). Among animals, a
recently recognized group of persistent pollutants, PFOS and PFOA,
specifically induce perinatal death. Pup mortality has also been
observed as an additive effect of intrauterine and lactational exposure
(Luebker et al., 2005). Their mode of action is still unclear and poten-
tially complex; we can speculate that PFOS and PFOA may disrupt
hormone biosynthesis and/or catabolism through peroxisome
proliferator-activated receptor alpha agonism, the down-regulation
of cholesterol biosynthesis and enhanced thyroid hormone depletion
(Martin et al., 2007).
Tobacco smoking causes fetal growth restriction by a direct effect
on the placenta. It is less widely known that smoking can also
disrupt endocrine function, with effects ranging from disrupted con-
ception (Cooper and Moley, 2008) to various alterations of fetal
hormone balance that might affect pregnancy outcome or develop-
mental programming (Shields et al., 2009). Parazzini et al. (2005) ana-
lysed data collected in 1962 women who gave birth at 37 or more
weeks of gestation to healthy infants (excluding those with a low birth-
weight and twins). Women were asked about the smoking habits of
the fathers of the newborns during the periconceptional period;
thus, the smoking habits of the fathers were reported by the
women. In comparison with non-smoking parents, the odds ratio of
being male was lower than unity for the offspring of women
smoking more than 20 cigarettes/day with non-smoking fathers and
for the offspring of parents who both smoked. No clear relationship
emerged, however, between the likelihood of giving birth to a male
and the number of cigarettes smoked per day. This finding is especially
Caserta et al.
interesting as altered sex ratio has been observed in population groups
highly exposed to some EDCs: the most well-known instance is
the high prevalence of female births following high dioxin
(TCDD)-exposure in the area of Seveso (Mocarelli et al., 2000). A
recent cohort study in the USA found that the relative risk of a
male birth decreased by 33% when comparing women at the 90th
percentile of PCBs (11 main congeners tested) with women at the
10th percentile (RR ¼ 0.67; 95% CI, 0.48 –0.94; P ¼ 0.02), or by
7% for each 1 mg/l increase in PCB concentration (Hertz-Picciotto
et al., 2008). In the study on TCDD by Mocarelli et al. (2000),
there was a clear association with paternal serum level, whereas the
study on PCBs by Hertz-Picciotto et al. (2008) found an association
with maternal body burden. Altered sex ratio might be considered
an adverse effect from the standpoint of demography dynamics; epige-
netic effects, especially on male gametes (Cordier, 2008) and/or
increased, sex-related early embryonic loss, are putative underlying
mechanisms.
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Trans-generational exposure and effects
Experimental data indicate that early prenatal and/or perinatal
exposure to EDCs can lead to long-term effects on the immune (Bac-
carelli et al., 2002), respiratory (Turnowska and Marinov, 2009) and
central nervous systems (Rogan and Ragan, 2007; Sly and Flack,
2008; Larsson et al., 2009; Stefanidou et al., 2009; Crews, 2010; Mat-
tison, 2010) and on the thyroid (Koopman-Esseboom et al., 1994,
1997; Brouwer et al., 1998; Osius et al., 1999; Wang et al., 2005b),
and it can also induce cardiovascular malformations (Langlois et al.,
2009).
EDCs are not major teratogenic compounds like some drugs. There
are indications of a relationship with increased risk of hypospadias and
cryptorchidism. Whereas the evidence for estrogenic EDCs (e.g. BPA,
DDT) is rather weak. Experimental data point to the possible role of
antiandrogens (e.g. phthalates, dicarboximide pesticides and DDE),
even at environmentally relevant exposure levels. Male differentiation
is critically dependent upon androgen action. Exposure to pesticides in
the workplace and/or living environment has been suggested as a
primary risk factor for these malformations. Nevertheless, in
Europe, it appears that current regulations on pesticide use are effec-
tive concerning the prevention of developmental toxicity. A 6-year
Italian study found no ecological relationship between the use of
EDC pesticides and birth defect incidence. The study was conducted
in a broad agricultural area of north-eastern Italy, where good records
on both pesticide use (amount and type) and birth defects are avail-
able (Clementi et al., 2007). In the same vein, a case– control study
on hypospadia and cryptorchidism in an intensive agricultural area of
Sicily found only limited evidence for parental pesticide exposure,
when compared with factors such as low birthweight, maternal
alcohol consumption and parental genital disease (Carbone et al.,
2007). An increased risk (in the 2.5-fold range) was found in associ-
ation with maternal or paternal pesticide exposure, but it was not stat-
istically significant (CI being in the range 0.7– 10). Another
investigation in the same population found a significant association
with certain dietary habits. Increased risk for hypospadia was found
in cases where mothers frequently consumed fish [OR ¼ 2.33 (95%
CI 1.03– 5.31)] and fruit purchased at the market [OR ¼ 5.10 (95%
CI 1.31 –19.82)] while increased risk for cryptorchidism was found
Environment and women’s reproductive health
in mothers who consumed liver [OR ¼ 5.21 (95% CI 1.26 –21.50)]
and smoked products [OR ¼ 2.46 (95% CI 1.15 –5.29)]. Considering
the two malformations together, increased risk was associated with
maternal consumption of the liver [OR ¼ 4.38 (95% CI 1.34 –
14.26)] and with frequent consumption of wine [OR ¼ 1.98 (95%
CI 1.01– 3.86)]. The study hinted to the potential role of impaired
food safety/quality, associated with the bioaccumulation of contami-
nants (fish, liver) and/or pesticide residues (market fruit, wine) and/
or potentially toxic food components (smoked products, wine, liver)
(Giordano et al., 2008). Pollutants widely found in foods and the
living environment may elicit a more significant impact on the fetus
than pesticides. In a study carried out in Southern France, cryptorch-
idism at birth was found to be associated with higher prenatal
exposure to PCBs and DDE, as determined by colostrum concen-
trations (Brucker-Davis et al., 2008). A nested case –control study in
Spain found a significant association between the risk for cryptorchid-
ism or hypospadia and the cumulative exposure to chlorinated insec-
ticides as measured in the placenta (Fernandez et al., 2007).
Detectable estrogenic activity as well as detectable levels of some indi-
viduals compounds (o, p′ DDT, p′ p′ DDT, lindane and mirex) showed
statistically significant ORs in the 2.5 –3 range.
Pregnancy is the life stage where EDCs are passed through the gen-
erations. Pregnancy is a stage where the body burden starts building
up and is a critical phase for long-term programming of organs and
tissues. Prenatal exposure to EDCs is one of the major risk factor
for the ‘Testicular Dysgenesis Syndrome’, a programming disorder
that includes poor semen quality and increased risk of testicular
cancer (Sharpe et al., 2003). Diethylstilbestrol is a dramatic example
seen in young women who, when exposed in utero, have an increased
risk of rare clear-cell vaginal adenocarcinoma (Swan, 2000). Animal
studies indicate that dose levels of EDCs devoid of any evident
maternal or fetal toxicity may induce subtle but persistent alterations
of the female reproductive tract (Maranghi et al., 2007, 2008). PCBs
and their hydroxylated metabolites (OH-PCBs) are currently among
the most important persistent EDCs. PCBs include more than 200
congeners with somewhat different bioaccumulation potential as
well as biological properties (estrogenicity, dioxin-like and cytochrome
P-450 induction) (Negri et al., 2003). Animal studies indicate that
transplacental PCB transfer is significant for the initiation of PCB
body burden in post-natal life (Korrick et al., 2000; Sala et al.,
2001). Soechitram’s (2004) analysis of maternal and cord blood
samples from 51 women at term of gestation indicates that PCBs
and their hydroxylated metabolites OH-PCBs are detectable in
maternal and in cord plasma. There is a significant correlation
between the respective maternal and cord levels and PCBs and
OH-PCBs. The placental transfer of OH-PCBs can be explained by
their strong bond to transthyretin (TTR) and active transport across
the placenta. In contrast, PCBs are neutral lipophilic compounds
strongly attracted to lipids and therefore cross the placenta less
readily. PCB effects on thyroid hormones deserve further attention
because of the potential impact on physical and neurobehavioural
for long-term programming. Animal studies have shown a significant
reduction in thyroid hormones in the brain after exposure to
OH-PCBs. This reduction is related to the binding of OH-PCBs to
TTR, which can be explained by the strong structural resemblance
between OH-PCB and thyroxine (Ghosh et al., 2000). But animal
studies may not completely be compared with the human ones,
425
where thyroid hormones are mainly bound to thyroxine-binding glo-
bulin. The characterization of the effects resulting from OH-PCBs
binding to TTR is still insufficient, due to the small number of epide-
miological investigations on long-term thyroid effects of PCB. Never-
theless, the topic is well-worth investigation, as indicated by a
Slovak study that found marked endocrine disturbances: increased
thyroid volume, the prevalence of thyroid antibodies and impaired
fasting glucose in young adults from an area with high PCB pollution.
Exposure of parents during pregnancy was the major risk determinant
(Langer et al., 2008); maternally mediated exposure to PCBs may be
detrimental to fetal growth, particularly in boys. The gender-related
effect suggests a relationship with hormone balance, although the
effects on growth, apparently, are not persistent, any long-term
impact on metabolic programming remains (Hertz-Picciotto et al.,
2005). PCDDs, PCDFs and dioxin-like PCBs share the ability to inter-
act with the aryl hydrocarbon receptor, a cytoplasmic structure
appearing quite early in evolution history, involved in the regulation
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of a cell’s response to external stimuli, including endocrine signalling
(Gasiewicz et al., 2008). Due to widespread pollution of food chains
and the building-up of body burden from early prenatal life, dioxin-like
compounds have been subject of a number of epidemiological studies.
Impaired semen quality and neurobehavioural milestones have been
observed in humans at the high-range levels of background prenatal
exposure (Jacobson and Jacobson, 2002a; Jurewicz et al., 2009).
Altered immunological markers have been observed during a long-
term follow-up in highly TCDD-exposed adults from the Seveso
area (northern Italy) (Baccarelli et al., 2002); it would be well worth
investigating the impact of prenatal dioxins on immune function
programming.
Polybrominated-diphenyl-ethers (PBDEs) are ubiquitous environ-
mental contaminants of food chains due to their long half-life and
widespread use as flame retardants in several consumer products,
such as plastics, computers and videos. They share several chemico-
physical characteristics with PCBs, mainly their lipophilicity and
ability to bioaccumulate. In addition, these compounds, like PCBs
and PBDEs, can alter thyroid hormone metabolism (Talsness,
2008). PBDE body burden in women is potentially unfavourable to
healthy fetal programming. A recent French study showed trans-
generational human exposure to highly brominated PBDE during preg-
nancy, as well as newborn exposure through breastfeeding in the early
stages (Antignac et al., 2009). Toxicological studies on animals clearly
indicate that PBDEs are much less toxic than PCBs. PBDE exposure is
more prevalent and still occurring, whereas PCBs have slowly but stea-
dily been decreasing since they were banned 20 years ago. Finally,
PBDEs and PCBs tend to concentrate in the same foods and to
metabolize and act in the same way (Talsness, 2008); thus, an additive
effect cannot be excluded. PFOSs and PFOAs are used as additives in
industrial and consumer products. The potential for trans-generational
exposure and effects may be due to the uncharacterized long-term
impact of accumulation in the fetal liver (EFSA, 2008). The mechanism
of bioaccumulation is different from chlorinated and brominated
chemicals since it appears to be based on a marked affinity for specific
proteins (Luebker et al., 2002). BPA is employed in the manufacture of
a wide range of consumer products; BPA is an EDC that is able to bind
to estrogen receptors and other nuclear receptors (European Food
Safety Authority, 2006). The dose levels at which such effects can
be elicited is still a matter of controversy; thus, it is still debated
426
whether the current exposure levels of the general population might
be a health risk during vulnerable life stages (Kubo et al., 2001;
Markey et al., 2001; Schönfelder et al., 2002a; EFSA, 2006). Schön-
felder et al. (2002b) investigated blood samples from 37 mothers
between 32 and 41 weeks of gestation and fetal and placental
tissues and demonstrated that the human placenta does not act as a
barrier to BPA; higher concentrations of unmetabolized BPA were
observed in male fetuses, possibly related to sex differences in BPA
biotransformation. Significant trans-generational exposure has also
been reported for other widespread EDs, such as cadmium (Zhang
et al., 2004) and di(2)ethyl-exyl-phthalate (Latini et al., 2003).
One contribution to trans-generational exposure may be transfer of
lipophilic compounds to the neonate through breastfeeding (Wang
et al., 2004; Brucker-Davis et al., 2008). Breast milk may contain sig-
nificant levels of PCDD/Fs; available data indicate that levels are
lower in cord blood compared with maternal blood at birth. Wang
et al. (2004) analysed levels of PCDD/Fs and PCBs in tissues from
20 pregnant women at term. For both PCDD/Fs and PCBs, there
was a good correlation among placenta, breast milk and venous
serum levels. The pattern was different; higher PCDD/Fs levels
were found in the placenta and in venous serum compared with
breast milk, whereas for PCBs, higher levels were found in milk. In
all likelihood, PBDEs are also found in human milk, with the congeners
BDE47 and 99 being most abundant (Carrizo et al., 2007). In addition,
French data call for more attention towards highly brominated PBDE
congeners (octa- to deca-BDE) (Antignac et al., 2008). Infant exposure
in the USA through breast milk is around 300 ng/kg/day, which is
within the reference range. Doses can be calculated by dividing the
PBDE NOELs for neurobehavioural effects by standard safety
factors (Costa et al., 2008). Breastfeeding transfer should also be con-
sidered for other lipophilic EDCs. Several phthalate metabolites have
been detected in the microgram per litre range in breast’s milk. The
pattern of compounds found was different in a study from Italy com-
pared with from findings in the USA, suggesting that different com-
pound usage may lead to detectable differences in exposure (Latini
et al., 2009). Overall, besides some high-exposure situations, the pres-
ence of contaminants in breast milk is not an argument against breast-
feeding. On the other hand, the use of human milk for biomonitoring
may yield important results in order to monitor and prevent effects
from environmental pollutants (Wang et al., 2005a). Breastfeeding
can even be a protective factor against the pollutant’s effects on neu-
robehavioural programming (Jacobson and Jacobson, 2002b). Never-
theless, the presence of pollutants in breast milk is obviously
undesirable and is determined by the woman’s body burden which,
in its turn, largely depends upon dietary factors, e.g. higher seafood
consumption was significantly associated with higher content of
DDT, PCBs and b-HCH (Wong et al., 2002). Thus, food safety pol-
icies, from effective surveillance to dietary recommendations, are
important for optimizing the risk-to-benefit of breastfeeding.
Discussion
Significant evidence exists to support EDC exposure as a risk factor for
women’s fertility and fecundity, as well as for the trans-generational
transfer of undesirable, potentially toxic compounds (Table II)
(INAIL, 2008). Thus, clinical research and public health interventions
should take into account the role of chemical exposure in order to
Caserta et al.
protect and promote reproductive health. The current critical issue
is to understand what role is played by EDCs in a variety of disorders
and situations. Therefore, the issues to be addressed include the
identification of effects, the assessment of exposure and the character-
ization of factors enhancing the susceptibility to EDCs.
As for effects, almost all women’s reproductive disorders show
some evidence of correlation with EDC exposure. Lower fecundability
(Buck et al., 1999; Fei et al., 2009) and lower birthweight (Rylander
et al., 2000; Lin et al., 2008; Wolff et al., 2008; Tan et al., 2009;
Zang et al., 2009) apparently show the most solid evidence. EDCs
appear to affect reproductive success and outcomes by disturbing
hormone regulation and/or placental function, rather than by any
direct ‘toxic’ effect on target organs (Caserta et al., 2008). An inter-
esting field for further research is the role of specific EDCs that are
widespread in the environment, in multifactorial disorders of repro-
ductive health. Telling examples include: endometriosis and phthalates
(Cobellis et al., 2003; Reddy et al., 2006) or dioxin-like EDCs (Yu
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et al., 2008); PCOS and BPA (Takeuchi et al., 2004); recurrent miscar-
riage and BPA (Sugiura-Ogasawara et al., 2005) or persistent chlori-
nated EDC (Gerhard et al., 1998; Korrick et al., 2001).
Non-syndromic birth defects are also complex disorders involving
gene –environment interactions which might be difficult to extricate.
Epidemiological data suggest a correlation between maternal body
burden of estrogenic/antiandrogenic EDCs and increased risk of cryp-
torchidism/hypospadia, which appears to be worthy of further inves-
tigation (Fernandez et al., 2007; Brucker-Davis et al., 2008). Effects on
the mother –fetus and mother –newborn dyads, with trans-
generational transfer of hazards, are one cutting-edge topic for EDC
risk assessment. Evidence for the long-term impact of persistent pol-
lutants on neurobehavioural or thyroid programming is suggested by
human studies (Jacobson and Jacobson, 2002b; Langer et al., 2008).
More research on the programming effects of different EDCs is
suggested by toxicological studies showing pleiotropic alterations of
many endocrine-regulated tissues and functions, including the female
reproductive system (Maranghi et al., 2007; van Der Ven et al.,
2008). Availability of reliable internal exposure data is a major limiting
factor in the proper characterization of EDCs as risk factors for
women’s fertility and fecundity. The development of studies exploiting
biomarkers of exposure in conjunction with biomarkers of effect is
needed; this requires the support of toxicological studies elucidating
toxicokinetics as well as toxicodynamic pathways in order to
develop appropriate sets of robust, sensitive and specific biomarkers
(Mantovani et al., 2008). Moreover, the length of observation, which
may be too short to properly assess effects on programming and
sample size, may be too small to allow for the detection of risk
increases in the 20–30% range (i.e. RR 1.2–1.3) with proper statistical
significance. Indeed, such ‘small’ increases in risk can be highly signifi-
cant in public health terms, when the general population is exposed to
widespread factors; however, human prospective studies would be
complex, time-consuming and expensive. Biological banks should be
exploited in order to conduct retrospective follow-up and nested
mother– child cohort studies (Fernandez et al., 2007). Finally, studies
should be carried out in different geographical areas. The same
exposure may not show a significant association with a reproductive
outcome. Examples are the association of BPA with adverse pregnancy
outcomes in Japan but not in the USA (Sugiura-Ogasawara et al., 2005;
Padmanabhan et al., 2008), whereas POPs were significantly
Environment and women’s reproductive health 427

Table II Main classes of EDCs present in food and in environment with major relevance for reproductive and fetal adverse
effects.

Chemical(s) Pathways of exposures Reproductive Fetal effects

effects
.............................................................................................................................................................................................
POPs
Polychlorobiphenyls (PCB) Food chain (fat-rich food, e.g. milk and Reduced fecundability Mental restriction
derivatives, fatty fish, etc.), living environment
Male fertility reduction IUGR
Menstrual disorders Low weight at birth
Spontaneous
abortions
Dioxins and ‘dioxin-like’ PCBs Food chain (fat-rich food, e.g. milk and Altered sex ratio Neuroendocrine effects
derivatives, fatty fish, etc.), living environment
Reduced fecundability Thyroid dysfunction
Sperm quality

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alterations
Increased risk of
endometriosis
Substances used in agricultural and farm Food chain (fat-rich food, e.g. milk and Sperm quality Nervous system alteration
animal production Organochlorine derivatives, fatty fish, etc.), living environment, alterations
insecticides (e.g. Lindane) workplaces (mainly in developing countries)
Menstrual disorders Congenital malformations
(hypospadia, cryptorchidism)
Female and male IUGR
fertility reduction
Increased time to Mental restriction
pregnancy
Increased risk of
preterm delivery
Spontaneous
abortions
Triazoles, imidazoles Food chain (agricultural and zootechnical Sperm quality IUGR
fungicides), living environment and workplaces alterations
(agricultural areas)
Female and male Decreased of neonatal weight
fertility reduction
Increased risk of
conception delay
Spontaneous abortion
Triazines Food chain (herbicides), living environment and Increased risk of Decreased of neonatal weight
workplaces (agricultural areas) conception delay
Spontaneous abortion
Bisphenol A Food chain (e.g. plastics in contact with food), Increased PCOS Physical and neurobehavioural
consumer products (e.g. dental sealant, plastic long-term programming
additive, etc.) alterations
Toluene Rubber industry Sperm quality Cerebral tumours
alterations
Ink, points Female and male Leukaemia
fertility reduction
Army industry Spontaneous abortion Congenital malformations
Gasoline
Carbon sulphate Rubber vulcanization Sperm quality Cerebral tumours
alterations
Optics industry Female and male Leukaemia
fertility reduction

Continued
428 Caserta et al.

Table II Continued

Chemical(s) Pathways of exposures Reproductive Fetal effects

effects
.............................................................................................................................................................................................
Textile industry Amenorrhoea Congenital malformations
Insecticides Spontaneous abortion
Ethylene oxide Sterilization Menstrual disorders Embryo-toxicity
Main cosmetic, toiletries Female and male
fertility reduction
Textile industry Spontaneous
abortions
Aliphatic hydrocarbon Insecticides, fungicides Sperm quality
alterations
Food preservatives Menstrual disorders
Hormonal disorders
Cadmium Food chain (e.g. refined food as flour, rice, sugar; Sperm quality IUGR

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seafood), cigarette smoking alterations
Sexual potency
reduction
Nickel Ni-Cd battery Sperm quality IUGR
alteration
Coins Congenital malformations
Electrical stuff
Lead Pb compounds manipulation and preparation Sperm quality Mental restriction
alterations
Points, enauels Hormonal changes IUGR
Menstrual disorders Congenital malformations
Spontaneous
abortions
Mercury Pints, food preservatives Sexual potency Nervous system dysfunction
reduction
Photo labs Sperm quality
alterations
Insecticides Menstrual disorders
Pesticides Spontaneous
abortions
Fungicides
Manganese Glass, enamels Sperm quality Mental restriction
alterations
Disinfectants IUGR
Steel Congenital malformations
Estrogens Pharmaceutical industry Hormonal alterations
Biotechnological industry
Phytoestrogens Food chain (e.g. vegetables, soy-based food), Hormonal alterations
consumer products (e.g. cosmetics)
Isoflavones, lignans, etc

IUGR, intrauterine growth restriction; PCOS, polycystic ovary syndrome; POPs, persistent organic pollutants.

associated in Germany (Gerhard et al., 1998) and USA (Korrick et al.,
2001), but not in Japan (Sugiura-Ogasawara et al., 2003). This entails
the issue of vulnerability associated with genetic polymorphisms, stage
of life cycle and lifestyles. Genetic polymorphisms can modulate indi-
vidual susceptibility to a given toxic mode of action in a population
undergoing comparable levels of exposure. The most obvious role is
for cytochrome P450 gene polymorphisms influencing the extent of
xenobiotic metabolism (Tsuchiya et al., 2007). The full appraisal of
the role of genetic polymorphisms calls for an adequate understanding
of toxicity mechanisms and toxicokinetics pathways. Age at which
exposure occurs is a major factor. Several pieces of evidence from
toxicological studies show that exposure during developmental pro-
gramming is most critical for reproductive disorders in the adult organ-
ism. In most cases, late effects in the progeny occur at dose levels that
Environment and women’s reproductive health
elicit only minimal or no effects in the maternal organism. Examples
include the effects on the differentiation of mammary gland upon
gestational and/or lactational exposure to well-established EDCs,
such as dioxin-like chemicals or BPA (Fenton et al., 2002;
Muñoz-de-Toro et al., 2005), as well as altered programming elicited
by comparatively novel EDCs, such as the ER-b binder lindane
(Maranghi et al., 2007) or the neuroendocrine modulator chlorpyri-
phos (Tait et al., 2009). Finally, until now, diet and lifestyle have
been overlooked as risk co-modulators. Tobacco smoke is a recog-
nized risk factor for placental development and other adverse preg-
nancy outcomes, and it is recognized to have EDC-like activities
(Parazzini et al., 2005; George et al., 2006; Cooper and Moley,
2008; Shields et al., 2009). It is plausible that the fertility and fecundity
of smoking women would also be more vulnerable to EDC exposure.
A wealth of experimental data show that nutrients and bioactive com-
pounds interact with EDCs; for instance, vitamins with antioxidant
activities (A, E and C) appear to mitigate the effects of dioxins,
PCBs and other toxicants. Increased oxidative stress seems a
common end-point to several EDCs (Baldi and Mantovani, 2008).
An adequate intake of folic acid or dietary folates reduces the risk
of neural tube defects and other malformations (Bukowski et al.,
2009). Since preterm delivery has been related to EDC exposure by
some studies (Rylander et al., 2000; Latini et al., 2003), it might be
interesting to assess whether folate status modulates EDC effects
on female reproductive health. Food components might also modulate
kinetic pathways of xenobiotics. For instance, long-term intakes of cru-
ciferous vegetables as well as of the isoflavones chrysin and quercetin,
found in many fruits such as apples, up-regulate metabolism of many
PCB congeners. This leads to increased production as well as faster
excretion of endocrine-active, hydroxylated PCB metabolites (James
et al., 2008). Flavonoids and other phytoestrogens can themselves
have significant endocrine-modulating activities (Lu et al., 2000;
Caserta et al., 2008). Phytoestrogen intake through soy products, flax-
seeds and other vegetables products might deserve attention in order
to explain varying vulnerability to EDC exposure by populations with
different dietary habits. In conclusion, the weight of the evidence point
out the need to take into account EDC exposure in order to prevent
adverse effects on female fertility and fecundity. For proper risk assess-
ment, research needs to include a better characterization of the range
of effects. In particular, scientists are developing new models and tools
to better understand how EDCs work and high-throughput assays to
determine which chemicals cause endocrine disrupting activity. They
are examining the long-term effects of exposure to EDCs during devel-
opment and on disease later in life and are conducting experimental
studies in humans, developing appropriate biomarkers to determine
exposure and toxicity levels (NIEHS, 2010) and investigating genetic
and dietary modulating population factors. Nevertheless, the evidence
is sufficient to prompt precautionary actions to protect women’s
reproductive health.
Authors’ roles
D.C.: contributions to conception and design, revising the article cri-
tically for important intellectual content, final approval of the version
to be published; A.M.: contributions to conception and design, analysis
and interpretation of data, revising the article critically for important
intellectual content; R.M.: acquisition, analysis and interpretation of
429
data; revising the article critically for important intellectual content;
A.F.: acquisition, analysis and interpretation of data; F.C.: acquisition,
analysis and interpretation of data; C.L.R.: acquisition, analysis and
interpretation of data; F.M.: acquisition, analysis and interpretation
of data; M.M.: revising the article critically for important intellectual
content.
Acknowledgement
The paper has been written within the scope of activities of the Italian
Society for Environment and Health—ISEH (http://www.iseh.it) and
the Italian Section of WWF (World Wildlife Foundation).
Funding
The authors acknowledge the support of the project Study in model
areas on the environmental and health impact of some emerging chemical
Downloaded from http://humupd.oxfordjournals.org/ by guest on September 27, 2016
contaminants (endocrine disrupters): living environment, reproductive out-
comes and repercussions in childhood (PREVIENI) (http://www.iss.it/
prvn) funded by the Italian Ministry for Environment and Protection
of Territory and Sea.
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