Reproductive BioMedicine Online (2013) 26, 440– 448

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YOUNG INVESTIGATOR REVIEW

Endocrine-disrupting chemicals and

male reproductive health
Jure Knez

Department of Reproductive Medicine and Gynaecologic Endocrinology, University Medical Centre Maribor, Ljubljanska
5, 2000 Maribor, Slovenia
* Corresponding author. E-mail address: knez.jure@gmail.com.

Jure Knez obtained his MD degree from University of Ljubljana Medical Faculty in 2008. He commenced his
residency of obstetrics and gynaecology in 2009 at the University Medical Centre in Maribor, where he continues
his research work in the field of infertility and andrology under the mentorship of Professor Dr Veljko
Vlaisavljević. He has been involved in several research projects on medically assisted reproduction. He is
currently a PhD student at the University of Ljubljana and his research includes the effects of endocrine-
disrupting chemicals on human semen quality and assisted reproduction outcome.

Abstract Endocrine-disrupting chemicals are substances present in the environment that can interfere with normal hormonal bal-
ance and thus exert potentially adverse health effects on the human organism. Male reproductive system development and function
may be susceptible to the effects of such environmental toxicants. Bisphenol A, phthalates and alkylphenols are important compo-
nents of multiple products and are thus ubiquitously present in the environment. It has been demonstrated under laboratory con-
ditions that they can exert detrimental effects on the male reproductive system. However, human exposure data are scarce and do
not uniformly support toxicity of these substances at environmental concentrations. Despite substantial research efforts, the final
answer to the problem of endocrine-disrupting chemicals is not yet in sight. RBMOnline
ª 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. Open access under CC BY-NC-ND license.
KEYWORDS: alkylphenols, bisphenol A, endocrine-disrupting chemicals, male reproductive health, phthalates

Introduction (Kavlock et al., 1996). Considering reproductive function,

Endocrine-disrupting chemicals are a heterogeneous group
of substances that began to attract attention two decades
ago due to possible harmful effects (Colborn et al., 1993).
According to the US Environmental Protection Agency, an
endocrine-disrupting chemical is defined as ‘an exogenous
agent that interferes with the production, release, trans-
port, metabolism, binding, action, or elimination of natural
hormones in the body responsible for the maintenance of
homeostasis and the regulation of developmental processes’
most of the effects are exerted through disturbance of oest-
rogen- or androgen-mediated processes. In many reports
written in the last two decades, increasing exposure to
these substances has even been proposed as the mechanism
for decreasing male reproductive function and lower aver-
age sperm counts, although the hypotheses about deterio-
rating male reproductive capabilities are controversial
(Andersson et al., 2008; Carlsen et al., 1992; Jouannet
et al., 2001; Safe, 2012). The use of some of the established
toxic substances, such as polychlorinated biphenyls or

1472-6483 ª 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.rbmo.2013.02.005
Endocrine disrupters and male reproductive health
polybrominated diphenyl ethers, has been restricted or
even banned in the Western world. Nonetheless, many of
these substances can still be detected in considerable con-
centrations in the environment (Rudel and Perovich, 2009).
Moreover, unresolved controversies around certain other
compounds, including bisphenol A and phthalates, have
resulted in increasing exposure to these chemicals in the
last decades.
This brief review will critically investigate the possible
effects of bisphenol A, phthalates and alkylphenols on the
male reproductive system and current research efforts.
First, the production, use and sources of exposure to dis-
cussed endocrine-disrupting chemicals will be presented.
Second, possible mechanisms of action and demonstrated
effects in laboratory conditions will be discussed. Finally,
the current evidence of possible effects of bisphenol A,
phthalates and alkylphenols on the human male reproduc-
tive system is reviewed.
Production and human exposure
Bisphenol A, phthalates and alkylphenols are important
components of many industrial processes. Although exact
quantities are difficult to estimate, it is reckoned that
around 6 million tonnes of phthalates are produced world-
wide every year (Rudel and Perovich, 2009). For bisphenol
A, estimates range 2.2–4.7 million tonnes, of which around
1.2 million tonnes are produced in the EU, and the amounts
are rising by about 6–8% yearly (Fernandez, 2010; Huang
et al., 2012). The annual production of alkylphenols has
been estimated to be 154,000 tonnes in the USA and
75,000 tonnes in the EU (Soares et al., 2008). Since these
data were published, the use of alkylphenols has been
restricted in the EU, but they are still found in considerable
concentrations in the environment (Soares et al., 2008). All
of these substances or their metabolites have been
detected in human urine, serum, amniotic fluid of pregnant
women, in breast milk and even in semen (Calafat et al.,
2005; Guenther et al., 2002; Huang et al., 2009; Main
et al., 2006).
Bisphenol A is one of the most investigated and, for many
authors, one of the most potent endocrine-disrupting chem-
icals (Maffini et al., 2006). It is extensively used in polycar-
bonate plastic and epoxy resin production. Thus, bisphenol
A can be found in plastic water bottles, food containers, a
variety of household products (e.g. compact disks, con-
sumer electronics), medical equipment (e.g. dental fillings)
and thermal paper. Human exposure is widespread, as every
large biomonitoring study has detected bisphenol A in more
than 90% of tested samples (Vandenberg et al., 2010). The
largest yet-performed study, the US National Health and
Nutrition Examination Survey detected bisphenol A in the
urine samples of 92.6% of US males (Calafat et al., 2008).
Current knowledge suggests that the oral route is most
important for bisphenol A exposure (Geens et al., 2012).
However, several authors suggest that alternative routes,
such as inhalation or transdermal absorption, may be under-
estimated sources of exposure (Stahlhut et al., 2009).
Diesters of 1,2-benzenedicarboxylic acid (phthalic acid),
commonly referred to as phthalates, are a group of sub-
stances widely used in industry and thus ubiquitously
441
present in many everyday products. High-molecular-weight
phthalates (e.g. di(2-ethylhexyl) phthalate (DEHP), diisono-
nyl phthalate and di(n-octyl) phthalate) are mainly used as
plasticizers in the manufacture of flexible vinyl, whilst
low-molecular-weight phthalates (e.g. diethyl phthalate
and dibutyl phthalate (DBP)) are used in personal care prod-
ucts. Thus, they can be found in food containers, vinyl
upholstery, adhesives, perfumes and eye shadow. However,
they are not covalently bound to plastic material and conse-
quently can be released into the environment with time and
the use of products. Like bisphenol A, their metabolites can
be widely detected in the population. Thus metabolites of
the parent compounds have been found in the vast majority
of males in the USA (Silva et al., 2004). Similarly to bisphe-
nol A, the exposure to phthalates is primarily through oral
intake, although transdermal route or inhalation may con-
tribute significantly (Rudel and Perovich, 2009).
Alkylphenol ethoxylates are a group of substances most
commonly used as surfactants in common consumer prod-
ucts, such as detergents, disinfectants, surface cleaners,
cosmetic products, spermicides and pesticides. The most
important members of this group are nonylphenol ethoxy-
late and octylphenol ethoxylate (Tubau et al., 2010). These
substances undergo metabolic breakdown in the environ-
ment and lose ethlylene oxide side chains to become alkyl-
phenols (4-n-octylphenol and 4-n-nonylphenol). Unlike most
of the exogenous chemicals, which usually become less
toxic with biodegradation, alkylphenols actually increase
their toxicity during this process. Alkylphenols are fre-
quently found in wastewaters (White et al., 1994; Ying
et al., 2002) and are also present in food (Guenther et al.,
2002). Ingestion routes have not been definitely described,
but primarily oral ingestion and secondarily inhalation and
transdermal route are most likely (Wilson et al., 2001).
Mechanisms of action on the male reproductive
system
A disturbance of the male reproductive system can take
place at different periods of a lifetime. In order to study dis-
turbances, it is important to consider first what is known of
the physiological mechanisms that ultimately lead to
healthy sperm production. The development of the male
reproductive system requires the activation of specific path-
ways by hormones, notably androgens and anti-Müllerian
hormone. Thus, although testis formation itself is not hor-
mone dependent, most other aspects of masculinization
depend on normal testicular hormone production. Further-
more, testis cell development (as opposed to testis forma-
tion) is dependent on the local action of hormones
(Sharpe, 2001). Androgens are the most important hor-
mones in the normal development of Wolffian ducts that dif-
ferentiate into epididymis, vas deferens and seminal
vesicles (Wilson, 1978). Dihydrotestosterone, which is pro-
duced locally from testosterone by 5-a-reductase, is the
most important hormone in masculinization of external gen-
italia and prostate (Fisher, 2004). Hence, a balanced hor-
monal environment is essential for a normal development
of the male genitourinary tract. Hormonal disturbances
have been linked to masculinization anomalies, but little
research has been performed to relate early hormone
442
imbalances to long-term testicular function in terms of fer-
tility (Sharpe, 2001). It seems likely that the abnormal
development of testes in fetal and neonatal life can have
long-term consequences for sperm production (Sharpe,
2001). It has also been surmised that prepubertal exposure
to endocrine-disrupting chemicals is more likely to have
negative effects on reproductive function, because the
blood–testis barrier in humans is developed just before
puberty (Latini et al., 2006).
With these points in mind, the effects of endocrine-dis-
rupting chemicals mediated through the activation or the
inhibition of androgen and oestrogen receptors are of primary
concern for male reproductive function. However, action
through the aryl hydrocarbon receptor, which is a cytosolic
transcription factor with roles in developmental processes,
xenobiotic metabolism and immunological responsiveness
may also be of importance (Bonefeld-Jørgensen et al., 2007).
Besides the direct action through nuclear or membrane
receptors, oestrogenic endocrine-disrupting chemicals can
also exert more general effects through the induction of oxi-
dative stress (Anderson et al., 2003; Aydoğan et al., 2008;
Chitra et al., 2003; Gong and Han, 2006).
Furthermore, possible negative actions on progeny via
epigenetic toxic mechanisms have recently been suggested.
Epigenetic modifications involve heritable changes in gene
expression without changes in DNA sequence. These
changes include DNA methylation alterations, histone mod-
ifications and the expression of non-coding RNA. The early
developmental period is the most susceptible to epigenetic
mechanisms because the rate of DNA synthesis is the high-
est. Studies have been performed that demonstrate possible
epigenetic actions of bisphenol A and phthalates in rodents
and even in human cell cultures (Singh and Li, 2012), obser-
vations that further expand the possible toxic mechanisms
of endocrine-disrupting chemicals, but which are yet to be
verified in human studies.
Animal studies
Bisphenol A
Bisphenol A has been considered as a prototypical non-ste-
roidal oestrogen that interferes with nuclear oestrogen
receptors in several targets in the body. The affinity of bind-
ing to the oestrogen a and b receptors however, has been
demonstrated to be weak, in some studies even up to
1000–100,000 times lower than 17-b-oestradiol (Welshons
et al., 2003). bisphenol A is reported to cause its effects
by interfering with both androgen production and function
(Akingbemi et al., 2004; Lee et al., 2003; Paris et al., 2002;
Roy et al., 2004). It has also been shown to have the ability
to impair Sertoli cell function by interfering with expression
and localization of tight junction proteins (Fiorini et al.,
2004; Li et al., 2009; Salian et al., 2009). Furthermore,
not only direct, but also indirect actions through the induc-
tion of epigenetic mechanisms, with most studies showing
evidence of DNA hypomethylation, have been described
(Doshi et al., 2011; Singh and Li, 2012).
In laboratory rodents, prenatal, perinatal and adult
exposure to bisphenol A by the oral route or subcutaneous
injections has been shown to cause developmental
J Knez
genitourinary anomalies, decreased epididymal weight,
daily sperm production or increased prostate weight even
when exposed to doses lower than 50 mg/kg/day, which is
currently accepted as the lowest observed effect dose used
to calculate the acceptable daily intake in humans (Nagel
et al., 1997; Richter et al., 2007; Salian et al., 2009; vom
Saal et al., 1998; Williams et al., 2001). When considering
doses significantly lower than 50 mg/kg/day, exposure of
pubertal rats and mice to 3 mg/kg/day of bisphenol A by
subcutaneous injections, resulted in lower concentrations
of epididymal spermatozoa and testosterone (Herath
et al., 2004) whilst in adult mice, lower concentrations of
epididymal spermatozoa were observed even when exposed
to as low as 25 lg/kg/day of bisphenol A by oral route
(Al-Hiyasat et al., 2002). When injected subcutaneously at
1 mg/day, bisphenol A resulted in lower testosterone con-
centrations along with higher LH concentrations in adult
rats (Tohei et al., 2001). Contrary to these findings, several
studies demonstrated no negative reproductive effects at
doses as low as 0.2 lg/kg/day or even as high as
5 mg/kg/day administered by the oral route (Ema et al.,
2001; Tinwell et al., 2002; Tyl et al., 2002). A recent study
by Howdeshell et al. (2008a) reported that no negative
reproductive effects on male offspring could be observed
when pregnant rats were gavaged with 2–200 lg/kg/day
of bisphenol A in contrast to ethinyl oestradiol exposure.
The same group subsequently reported that gestational
exposure to bisphenol A did not result in negative develop-
mental effects on female rat offspring (Ryan et al., 2010).
Because these results directly oppose the bisphenol A oes-
trogenic effects demonstrated in early studies, it has been
suggested that concerns about possible bisphenol A oestrog-
enicity at environmental concentrations should end
(Sharpe, 2010). Hence, it can be concluded that evidence
suggesting low-dose bisphenol A exposure has an effect on
the male reproductive system in laboratory conditions is
unconvincing.
Phthalates
Phthalates are considered to be one of the major groups of
anti-androgenic substances and thus are established repro-
ductive and developmental toxicants (Grady and Sathyan-
arayana, 2012). They can exert their anti-androgenic
action by directly inhibiting testosterone synthesis in Leydig
cells, which has been proposed to be a result of cytochrome
CYP 17 dysfunction (Foster, 2005). Some phthalates have
also been shown to disrupt the patterns of gene expression
that regulate cholesterol and lipid homeostasis or insulin
signalling, which could also result in lower testosterone syn-
thesis (Barlow et al., 2003; Liu et al., 2005). Even a weak
action via oestrogen receptors has been demonstrated for
some phthalates (Harris et al., 1997).
It has been shown that rats exposed to phthalates during
the prenatal period can develop specific developmental
reproductive anomalies that have been identified as
‘phthalate syndrome’. These include cryptorchidism,
smaller testes and penis size and alterations to the vas def-
erens and epididymis as well as a shorter anogenital dis-
tance (Foster, 2006). A dose-dependent correlation
between DBP administered during pregnancy and lactation,
reduced anogenital distance (Mylchreest et al., 1998) and
Endocrine disrupters and male reproductive health
lower testosterone concentration has been reported at
doses as low as 50 mg/kg/day (Lehmann et al., 2004). DEHP
exposure in juvenile rats has been correlated with increased
testicular apoptosis and the loss of seminiferous epithelium
when administered at 2 g/kg/day (Park et al., 2002). More-
over, prepubertal rats have been shown to be more suscep-
tible to DEHP-induced changes than adult rats. Prepubertal
rats treated with as low as 10 mg/kg/day DEHP for 14 days
have produced lower concentrations of testosterone, whilst
adult rats have not shown any differences (Akingbemi et al.,
2001). However, paradoxically, with extended, 28-day
exposure, an increase in serum testosterone concentration
associated with Leydig cell hyperplasia was observed in pre-
pubertal rats (Akingbemi et al., 2001, 2004).
Alkylphenols
Nonylphenol and octylphenol are substances with weak
oestrogen-receptor binding potency (1000–1,000,000 lower
than 17-b-oestradiol) (Preuss et al., 2010; White et al.,
1994). They can be present in the environment in a range
of isomers. It has been shown for nonylphenol that isomers
vary in their oestrogenic potency (Gabriel et al., 2008; Pre-
uss et al., 2006). However, the identification and quantifica-
tion of each isomer presents an additional difficulty when
investigating their effects (Ying et al., 2012). Additionally,
antagonistic effects upon androgenic receptors have been
demonstrated (Lee et al., 2003; Paris et al., 2002; Roy
et al., 2004).
The effects of endocrine disruption by alkylphenols have
been studied extensively in laboratory rodents. An early,
multigenerational study by Chapin et al. (1999), examined
the male and female offspring of pregnant rats treated for
4 weeks with high (200–2000 parts per million, correspond-
ing to 9–350 mg/kg/day) doses of 4-n-nonylphenol for up to
the third generation. It was concluded that 4-n-nonylphenol
has only minor effects on reproductive system parameters
in the offspring of tested rats at the highest doses applied.
A later study confirmed the observation of a possibly lower
epididymal weight in the male offspring at higher 4-n-nonyl-
phenol dose exposure (15–75 mg 4-n-nonylphenol/kg/day
for 8 days) (Hossaini et al., 2001). Neonatal exposure
(8 mg/kg/day for up to 15 days post partum) of rats by intra-
peritoneal application of 4-n-nonylphenol did not result in
developmental reproductive anomalies (Odum and Ashby,
2000), but exposure of juvenile rats to administration of
100 mg 4-n-nonylphenol/kg/day for 30 days resulted in sig-
nificant testicular damage and a reduction in spermatogen-
esis (Tan et al., 2003). It has also been shown that
4-n-octylphenol can induce a lower epididymal sperm count
in pubertal rats at the low-dose exposure of 3 mg/kg/day
for 2 weeks (Herath et al., 2004). A significantly increased
rate of Sertoli cell apoptosis was observed when cultured
in vitro with 4-n-nonylphenol for 72 h at the high concentra-
tions found in the environment (Wang et al., 2003). Also,
rats treated with high doses of 4-n-nonylphenol by gavage
(250 mg/kg/day for 50 days) subsequently exhibited both
lower epididymal weight and sperm count compared with
controls (Han et al., 2004). Various 4-n-nonylphenol isomers
have also been shown to be able to inhibit testosterone bio-
synthesis in rats (Laurenzana et al., 2002; Ying et al., 2012).
However, a few in-vitro studies suggest a biphasic effect
443
with an increase of testosterone production at low-dose
4-n-octylphenol or 4-n-nonylphenol exposure and a
decrease of testosterone production at high-dose exposure
(Murono et al., 1999; Wu et al., 2010).
The data lead to the conclusion that exposure to high
concentrations of alkylphenols probably produces various
negative effects on the male reproductive system in labora-
tory conditions. As well as for other endocrine-disrupting
chemicals, including bisphenol A and phthalates, low-dose
exposure presents with inconclusive results. Considering
that exposure to endocrine-disrupting chemical in the envi-
ronment occurs at low doses, this presents a special chal-
lenge in the design of human population studies.
Human studies
Bisphenol A
Reviewing the studies on human populations, the first data
on bisphenol A were published in 2002 by Takeuchi and
Tsutsumi (2002), who interestingly demonstrated a positive
correlation between bisphenol A exposure and total/free
testosterone values in men and women. It has also been
shown that occupationally exposed men have higher urinary
bisphenol A concentrations than controls and that bisphenol
A is related to lower FSH concentrations (Hanaoka et al.,
2002). A recent study performed on a population of 360 pre-
sumptively fertile men (partners of pregnant women) con-
cluded that bisphenol A is inversely correlated with free
androgen index concentrations, but no correlation with
semen quality was noted (Mendiola et al., 2010). In a subset
of 167 men attending an infertility clinic, Meeker et al.
(2010a) demonstrated a negative correlation between uri-
nary bisphenol A concentration and inhibin B concentration
and oestradiol/testosterone index (a marker of aromatase
activity) as well as a positive correlation between urinary
bisphenol A and both FSH and FSH/inhibin B ratio (a marker
of Sertoli cell function). An additional study by the same
group reported a non-significant trend with increasing
bisphenol A concentration related to lower sperm concen-
tration, motility and morphology and higher levels of DNA
damage (Meeker et al., 2010b). A small study that included
27 couples undergoing IVF even suggested that male bisphe-
nol A exposure might negatively influence embryo develop-
ment after fertilization of oocytes (Bloom et al., 2011).
However, currently available data do not provide enough
sound evidence to reveal detrimental environmental bisphe-
nol A exposure effects on male reproductive capability in
terms of sperm quality.
Phthalates
In humans, evidence demonstrating a negative action of
phthalates on the reproductive tract is also accumulating.
A relationship between anogenital distance and maternal
urinary concentrations of phthalate metabolites was noted
in 85 boys studied by Swan et al. (2005). This study investi-
gated the effect of prenatal environmental exposure to
phthalates on genital development in newborns. Mothers
classified in the highest quartile of exposure gave birth to
sons with shorter anogenital distances compared with
444
mothers in the lowest quartile (Swan et al., 2005). How-
ever, this result was not confirmed in a subsequent smaller
study (n = 33) by Huang et al. (2009). A study by Main et al.
(2006) found inverse relationships between several phthal-
ate monoesters in breast milk samples and the serum ratio
of LH to free testosterone of breastfed boys (n = 130), indi-
cating a possible adverse effect on Leydig cells or the pitu-
itary–gonadal axis; however, no correlation with the
incidence of cryptorchidism was observed (Main et al.,
2006).
A few studies have shown that exposure to phthalates in
adulthood could result in decreased male fertility.
Short-term (12-hour) in-vitro incubation of spermatozoa
with the highest concentrations of phthalates detected in
human semen samples through environmental exposure
(13.47 lg/ml DBP and 5.73 lg/ml DEHP) resulted in
decreased sperm motility, whilst prolonged incubation
(96 h) resulted in sperm cytotoxicity (Pant et al., 2011).
Recently performed human fetal testis explant studies pro-
vide an interesting insight into the potential phthalate dis-
turbance of human male steroidogenesis. It has been
demonstrated that DEHP and monoethylhexyl phthalate
(MEHP, a metabolite of DEHP), when cultured in vitro with
adult human testes explants, can inhibit testosterone pro-
duction (Desdoits-Lethimonier et al., 2012). Conversely,
these observations could not be confirmed in in-vivo studies
of human developing testes. Two studies investigating
in-vivo DBP exposure to human fetal testes explants
xenografted to rodent hosts have recently been performed.
Although DBP could suppress steroidogenesis in testes of
mice and rats, no effects could be demonstrated in human
xenografts for a range of applied DBP concentrations (Heger
et al., 2012; Mitchell et al., 2012). However, a negative
effect on testicular germ cell development was noted and
should be further investigated (Heger et al., 2012).
Only a few epidemiological studies directly investigated
the detection of phthalate metabolites and any correlation
with human testicular function. One of the first studies
investigated 168 men from subfertile couples and concluded
that specific phthalate metabolites, when categorized in
tertiles, are correlated to lower sperm concentration and
motility (Duty et al., 2003). Further studies on this subject
have confirmed weak associations between exposure to
phthalate metabolites and lower sperm concentration,
motility and morphology in adults (Duty et al., 2004;
Hauser, 2008; Hauser et al., 2006; Liu et al., 2012; Wirth
et al., 2008), although, some have not proved this connec-
tion (Herr et al., 2009; Jönnson et al., 2005). It has also
been shown that sperm DNA damage may be increased by
phthalate exposure (Hauser et al., 2007). Regarding
hormonal balance, a study by Meeker et al. (2009) con-
firmed an inverse correlation between an interquartile
increase in MEHP and the testosterone, oestradiol and free
androgen indices. Combined with the results from rodent
studies, it seems reasonable to conclude that phthalates,
with their anti-androgenic effects, could be related to gen-
itourinary developmental anomalies, but more evidence
from the human population is needed to validate these
results. In the adult, however, a strong relationship
between environmental exposure to phthalates and male
reproductive function is not evident due to conflicting
available evidence.
J Knez
Alkylphenols
In spite of a substantial amount of available data on the
action of alkylphenols in rodent and marine studies, human
evidence is lacking. Studies investigating infant exposure
through mothers’ breast milk have shown that exposure to
alkylphenols is considerable and can be at the level of toler-
able daily intake calculated on the basis of rodent studies
(Ademollo et al., 2008). When performing the literature
search, however, human epidemiological studies linking
alkylphenol exposure to possible health effects were not
found.
Interactions of endocrine-disrupting chemicals
The human environment does not expose us to specific
endocrine disrupters, but to a complex cocktail. This fact
poses the question: does this cocktail of substances have
different effects than exposure to single isolated sub-
stances? There are still relatively few studies investigating
this scenario. Generally, oestrogenic substances are thought
to act in concentration-additive mode, which means that
mixture effects can be predicted by each substance concen-
tration and the relative binding affinity to the oestrogenic
receptor (Howdeshell et al., 2008b; Sun et al., 2009). How-
ever, the recent demonstration that some endocrine-dis-
rupting chemicals at certain concentrations can also act in
‘ompetitive antagonism on oestrogen receptors challenges
this view (Li et al., 2012). Moreover, the complexity of
the mechanisms involved in endocrine-disrupting chemical
actions means that their health effects can be the result
of the action through multiple pathways, potentially leading
to greater-than-additive effects (Kortenkamp, 2007). Such
interactions could even allow substances that would not
produce any effects by themselves to produce significant
effects at concentrations present environmentally (Chris-
tiansen et al., 2012; Kortenkamp, 2007).
Conclusions
Exposure to endocrine-disrupting chemicals in the environ-
ment is complex. Although the restrictions on the use of evi-
dently toxic substances have been implemented in certain
countries, some endocrine-disrupting chemicals and their
derivatives can still be widely detected in the environment.
After almost 20 years of research, the question that still
occupies the scientific community is: how seriously and at
what concentrations do endocrine-disrupting chemicals
compromise human health? The period of sexual develop-
ment appears to be most susceptible to the negative effects
of environmental pollutants. At least for exposure to phtha-
lates, a higher incidence of developmental anomalies in
human populations has been observed. This finding led sub-
sequently to the restriction of their use for children’s acces-
sories in several countries. Similar limitations have been
adopted for bisphenol A, although its toxicity potential at
environmental concentrations is not definitely proven. Sev-
eral substances that show negative effects in in-vitro or ani-
mal studies have not been proven to exert detrimental
effects in humans. Often, they are present in the environ-
ment at concentrations several magnitudes lower than the
Endocrine disrupters and male reproductive health
exposure under laboratory conditions. However, substances
that may not be toxic at environmental concentrations may
act synergistically with other endocrine-disrupting chemi-
cals to potentiate their toxic potential. The final answer
to whether the toxicity of bisphenol A, phthalates and aklyl-
phenols is of serious concern is not yet in sight and remains
to be answered with further studies.
Acknowledgments
The author thanks Veljko Vlaisavljević for all the guidance
and support received in his work. The author would also like
to thank Martin Johnson for critical readings of the
manuscript.
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Declaration: The author reports no financial or commercial
conflicts of interest.
Received 15 December 2012; refereed 4 February 2013; accepted 5
February 2013.