Endocrine-disrupting chemicals and male reproductive health 69
Strokovni članek
1 Faculty of Industrial 
Engineering Novo mesto, 
Novo mesto, Slovenia
2 Institute for Sanitary 
Engineering, Faculty 
of Civil and Geodetic 
Engineering, University 
of ljubljana, ljubljana, 
Slovenia
Korespondenca/
Correspondence:
Damjan Balabanič,  
e: damjan.balabanic@
gmail.com
Ključne besede:
kemični povzročitelji 
endokrinih motenj; 
endogeni hormoni; okolje; 
reproduktivno zdravje pri 
moških
Key words:
endocrine-disrupting 
chemicals; endogenous 
hormones; environment; 
human male reproductive 
health
Prispelo: 20. 11. 2016 
Sprejeto: 18. 12. 2017
Endocrine-disrupting chemicals and male 
reproductive health: a review
Kemični povzročitelji endokrinih motenj in reproduktivno 
zdravje pri moških: pregled literature
Damjan Balabanič,1 Aleksandra Krivograd Klemenčič2
Abstract
Balanced functioning of the endocrine system is essential for preservation of human species by 
providing normal growth and development, reproduction, and normal functioning of all other 
organ systems. In the last decades, emerging area of interest is the impact of environmental 
exposures to human health. Important environmental pollutants are endocrine-disrupting che-
micals (EDCs), which can have adverse effects on the living organism due to their interference 
with the endocrine system. The group of known EDCs embraces ubiquitous synthetic substan-
ces used as industrial lubricants and solvents, with their by-products, incomplete combustion 
remains, pharmaceuticals and personal care products, pesticides and plasticizers. Natural com-
pounds such as genistein, a phytoestrogen, and heavy metals can also have endocrine effects. 
Endocrine disruption is a serious public health problem. EDCs among other health problems ge-
nerate reproductive disorders in males, such as decreases in sperm count and quality, increases 
in testicular germ cell numbers, prostate and breast cancers, cryptorchidism and hypospadias, 
impaired fertility, and infertility. This paper critically reviews the current knowledge of the impa-
ct of EDCs on reproductive disorders in human males.
Izvleček
Uravnoteženo delovanje hormonskega sistema zagotavlja rast in razvoj, razmnoževanje in nor-
malno delovanje vseh drugih organskih sistemov v telesu. Zato je ključnega pomena za ohrani-
tev človeške vrste. V zadnjih desetletjih narašča število raziskav, povezanih z izpostavljenostjo 
ljudi različnim kemičnim snovem iz okolja in njihovim vplivom na zdravje. Kemični povzročitelji 
endokrinih motenj (KPEM) sodijo med pomembna okoljska onesnažila z negativnim učinkom na 
organizem zaradi poseganja v endokrini sistem. V skupino znanih KPEM sodijo povsod prisotne 
sintezne snovi, ki se uporabljajo kot industrijska maziva in topila ter njihovi stranski produkti, os-
tanki nepopolnega zgorevanja, zdravilne učinkovine, izdelki za osebno nego, pesticidi, mehčala 
in drugo. Naravne spojine, kot so genistein, fitoestrogenske snovi in težke kovine lahko prav tako 
moteče delujejo na endokrini sistem ljudi in živali. Motnje endokrinega sistema so resen pro-
blem javnega zdravja. KPEM med drugim povzročajo reproduktivne motnje pri moških, kot so 
zmanjšano število speremskih celic in njihovo nižjo kakovost, rak prostate in dojk, kriptorhizem 
in hipospadijo, zmanjšano plodnost in neplodnost. V prispevku je predstavljen kritičen pregled 
trenutnega znanja o vplivih KPHM na reproduktivne motnje pri moških.
Citirajte kot/Cite as: Balabanič D, krivograd klemenčič a. endocrine-disrupting chemicals and male 
reproductive health: a review. Zdrav vestn. 2018;87(1–2):69–80.
DOI: 10.6016/Zdravvestn.2456
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reproDukcija človeka
1. Introduction
In the last decades, numerous stu-
dies have reported that certain chemi-
cals called endocrine-disrupting che-
micals (EDCs) may cause disruption 
of the endocrine system and can affect 
reproduction and development of 
exposed humans and wildlife (1-5). An 
“Endocrine-disrupting chemical” (EDC) 
has been broadly defined as “an exoge-
nous substance or a mixture that alters 
function(s) of the endocrine system 
and consequently causes adverse health 
effects in an intact organism, or its pro-
geny, or (sub)populations” (6). EDCs can 
disrupt the normal actions of endogeno-
us hormones by altering normal hormo-
ne levels, inhibiting or stimulating the 
production of hormones, or changing 
the way hormones travel through the 
body, thus affecting the functions that 
these hormones control (4).
The group of known EDCs is extre-
mely heterogeneous and includes diffe-
rent groups of chemicals such as steroids 
(ethinyl estradiol, 17β-estradiol, estrone, 
mestranol and diethylstilbenstrol), al-
kylphenols (nonylphenol, nonylphenol 
ethoxylate, octylphenol and octylphe-
nol ethoxylate), polyaromatic com-
pounds (polychlorinated biphenyls 
(PCBs), polycyclic aromatic hydrocar-
bons (PAHs) and brominated flame re-
tardants), organic oxygen compounds 
(bisphenol A (BPA) and phthalates), 
pesticides (atrazine, chlordane, deme-
ton-S-methyl, dichlorvos, dieldrin, di-
methoate, endosulfan, hexachlorobenze-
ne, lindane, linuron, pentachlorophenol, 
permethrin, simazine and trifluralin) and 
others (tributyltin, dioxins and furans) 
as well as certain heavy metals (arsenic, 
cadmium, lead and mercury) (4,7,8). The 
logKow (octanol/water partition coeffi-
cient) values for some EDCs indicate a 
high degree of lipophilicity (9) and thus 
bioaccumulation. Human exposure to 
EDCs may result from the ingestion of 
contaminated food and water, inhala-
tion of air and absorption of the EDCs 
through the skin. However, in most ca-
ses, human exposure to EDCs is through 
the ingestion of contaminated food. The 
EDCs that are most commonly present 
in contaminated food are bisphenol A 
(BPA), nonylphenol, phthalates, and he-
avy metals. BPA is used as a source ma-
terial for the production of epoxy resins, 
polyacrylates and polyesters, but mainly 
for the production of epoxy resins and 
polycarbonate plastics (10). Epoxy resins 
are used as food contact surface lacqu-
er coatings for cans, protective coatings 
and finishes, adhesives and as coatings 
for polyvinyl chloride (PVC) pipes (10). 
Polycarbonate plastics are used in the 
manufacture of household appliances, 
food packaging and plastic bottles beca-
use they have high impact strength, har-
dness, toughness, transparency, and re-
sistance to temperatures, many acids and 
oils (10). In food packaging, nonylphenol 
originates from oxidation of the antioxi-
dant additive trisnonylphenyl phosphi-
te (11). Levels of nonylphenol in different 
packaging materials were recently asses-
sed and were found to range from below 
0.03 µg/g in a polyethylene terephtha-
late (PET) water bottle to 287 µg/g in 
PVC cling film (12). Nonylphenol was 
also detected in different types of reta-
il-purchased foods: up to 78 ng/L were 
found in PET-bottled mineral water (13), 
up to 40 µg/kg in beverage cartons of 
ultra-high temperatures (UHT) whole 
milk and up to 32.3 µg/kg in high density 
polyethylene (HDPE)-bottled milk (in 
bottle sterilization) (14). Dimethyl pht-
halate, Diethyl phthalate, Diisobutyl pht-
Endocrine-disrupting chemicals and male reproductive health 71
Strokovni članek
halate, Di-n-butyl phthalate, Benzylbutyl 
phthalate, Di(2-ethylhexyl) phthala-
te, Dicyclohexyl phthalate, Di-n-octyl 
phthalate, Diisononyl phthalate and 
Diisodecyl phthalate were detect in di-
fferent fruits and vegetables, sport drin-
ks, artificial juice drinks, meat and meat 
products, fish and fish products, milk 
and nutracevtical products (15,16). Lead 
(Pb) in food originates mainly from at-
mospheric deposition and adherence of 
Pb-rich soil particles to fruits and vege-
tables (17). Exposure to excess Arsenic 
(As), principally from contaminated 
drinking water, is considered one of the 
top environmental health threats worl-
dwide (18). Most of this exposure is from 
natural geological sources of As that 
contaminate groundwater (18). It has 
been established that fish and seafood 
can accumulate organic As from their 
environment (19,20). The concentrations 
of As in fruits and vegetables depends 
on the soil content, water contaminati-
on, air pollution and the usage of fertili-
zers (19). The general human population 
is exposed to mercury (Hg) (usually in 
an inorganic form and at very low con-
centrations) primarily through the diet 
with contaminated fish, dental amalgam 
and water consumption (4,21). The level 
of Hg in foods is inconsistent and refle-
cts the level of pollution of the local en-
vironment (22).
2. Impact of endocrine-
disrupting chemicals on 
male reproduction health
Epidemiological data has revealed an 
increase in male reproductive function 
disorders over the past 50 years, sugge-
sting a correlative relationship with the 
increasing amounts of EDCs in the en-
vironment (4,8). In the context of male 
reproductive health, EDCs have been 
linked to disrupted reproductive functi-
on (such as reduced semen quality and 
infertility), altered fetal development 
(such as urogenital tract abnormalities, 
including hypospadias and cryptorchi-
dism) and testicular germ-cell, prostate 
and breast cancers (4,5,23). As previou-
sly mentioned, the potential lag between 
exposure to EDCs and the manifestation 
of a clinical reproductive disorder is of 
critical concern. In humans, this period 
may be years or decades post exposure 
because sexual maturity and fertility 
cannot be assessed until the exposed in-
dividual has attained a certain age (24). 
In 1993, Sharpe and Skakkebaek (25) sug-
gested fetal exposure to environmental 
oestrogens such as synthetic oestrogens, 
phytoestrogens, oestrogens in milk and 
oestrogenic chemicals (e.g. chlorinated 
hydrocarbon (TCDD)) to be the com-
mon aetiological factor for the observed 
rise in the incidence of testicular can-
cer, cryptorchidism and the downward 
trend in sperm quality (25). Skakkebaek 
et al. (26) have suggested that the inci-
dences of cryptorchidism, hypospadias 
and poor semen quality are risk factors 
for one another and that they are all 
predictive of testicular germ-cell cancer 
development. Cryptorchidism, hypos-
padias, poor semen quality, and testicu-
lar germ-cell cancers are defined as the 
testicular dysgenesis syndrome (TDS). 
They propose that the aetiology of TDS 
lies in the diminished androgen action 
in fetal developmental periods and has 
a negative impact on the proper functio-
ning of Sertoli cells (the cells supporting 
germ cells) and Lydig cells (where andro-
gen synthesis occurs). This hypothesis 
proposes a strong association between 
environmental exposures (e.g., to phtha-
lates, polychlorinated biphenyls (PCBs), 
dioxins and non-resistant pesticides) and 
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development of TDS (27). Identifying en-
vironmental causes of TDS in humans is 
difficult because developing fetal tissues 
are inaccessible for examination. Thus, 
the majority of mechanistic evidence 
linking EDCs to TDS comes from ani-
mal experiments. It is possible to experi-
mentally induce all the elements of TDS, 
except for germ-cell cancer, by exposing 
pregnant rats to di-2-ethylhexyl phtha-
late, di-n-butyl phthalate and butyl ben-
zyl phthalate and other chemicals that 
block androgen action (28). This model 
is referred to as the “phthalate syndrome” 
model, and it comprises cryptorchidism, 
hypospadias, poor semen quality, and 
malformations of other sex organs (29). 
Certain pesticides (dichlorodiphenyltri-
chloroethane (DDT), alachlor, atrazine, 
diazinon) are able to block the androgen 
receptor, or interfere with the conversi-
on of testosterone into dihydrotestoste-
rone, thus producing effects similar to 
phthalate syndrome. Androgen action is 
also essential for proliferation and de-
velopment of Sertoli cells, which are ne-
cessary for sperm production. Altogether, 
EDC-mediated disruption of androgen 
action during fetal development results 
in reduced fertility later in life (30). A 
study of dioxin exposure conducted by 
Mocarelli et al. (31), suggests that timing 
of exposure has a significant impact on 
semen quality. This study was based on 
men who were exposed to high levels 
of 2,3,7,8-tetrachlorodibenzo-p-dioxin 
(TCCD) as a result of a chemical plant 
explosion in 1976 in Italy. Men who were 
exposed prepubertally (1–9 years of age) 
demonstrated poor semen quality as 
adults (27). Interestingly, men who were 
exposed between 10–17 and 18–27 years of 
age showed slightly positive or no diffe-
rences in semen quality, respectively (27).
2.1. Cryptorchidism 
and hypospadias
Several studies have shown that sons 
of mothers treated with diethylstilbe-
strol (DES) during pregnancy are at 
increased risk of cryptorchidism and 
hypospadias (5,32). Exposure of fathers 
to dioxins in the Seveso accident in 
1976 resulted in an increased incidence 
of hypospadias among their sons (3). In 
exposure studies, the risk for cryptor-
chidism was higher in sons of women, 
working with pesticides (33), while si-
gnificantly higher concentrations of 
hexachlorbenzene and heptachlorepoxi-
de were found in adipose tissues of boys 
with cryptorchidism, compared to those 
of a control group (34). The aetiology of 
this entity is unknown and thus prenatal 
exposure to exogenous oestrogens is ad-
vised (34). Moreover, these findings do 
not prove a direct causality between the 
accumulation of hexachlorbenzene and 
heptachlorepoxide and undescended te-
stes since they reflect the total accumu-
lation until the time of sampling, and a 
conclusion regarding exposure during a 
specific period of development cannot 
be made. Comparison of registry-ba-
sed information on cryptorchidism and 
hypospadias may have pitfalls because 
of underreporting, differences in regi-
stration systems, and inclusion crite-
ria (35). Therefore, prospectively desig-
ned cohort studies have been performed 
in Denmark and Finland to assess the 
incidence of these disorders during the 
years 1997 and 2001. The results of these 
studies showed that the rate of congeni-
tal cryptorchidism at birth was signifi-
cantly higher in Denmark as compared 
to Finland (9.0 % in Denmark and 2.4 % 
in Finland) (36).
Endocrine-disrupting chemicals and male reproductive health 73
Strokovni članek
2.2. Decreasing sperm 
counts and quality
Based on a meta-analysis of 61 studi-
es, it has been suggested that the human 
sperm count and quality have decreased 
in the past 50 years (37). It was suggested 
that some common prenatal influen-
ces could be responsible for the decline 
in sperm density. Several studies have 
shown that sons of mothers treated with 
DES during pregnancy are at increased 
risk of decreased sperm count (5,32). A 
recent study found an inverse correla-
tion between the concentration of PCB 
metabolites in blood and seminal plasma 
and sperm motility as well as concentra-
tion (38). Guo et al. (39) concluded that 
heavy exposure to PCBs resulted in ne-
gative effects on sperm morphology and 
motility, but not on sperm concentration.
2.3. Cancer
EDCs are based on animal models, 
human clinical observations, and epi-
demiological studies suspected of cau-
sing various types of human cancer in 
males, including testicular, prostate and 
breast cancers (24,40-42). Over the last 
50 years, the incidence of prostate can-
cer in some countries (e.g. U.S., Britain 
and Denmark) has doubled, while that 
of testicular cancer has tripled (e.g. U.S. 
and Britain) or even quadrupled (e.g. 
Denmark) since 1943 (43,44). EDCs 
may be accountable for the observed 
trends (4); since both humans and wil-
dlife are chronically exposed to copio-
us potentially hazardous chemicals that 
are continuously released into the envi-
ronment (45). Most evidence depicting 
cancer risk associated with exposure to 
EDCs is limited to cellular and animal 
models (46).
2.3.1. Testicular cancer
During recent decades, there has been 
a significant increase in the incidence of 
testicular cancer, albeit with clear ra-
cial and geographical differences (the 
highest incidence is among white men 
in northern Europe) (47) suggesting that 
both genetic and environmental factors 
are important in the development of te-
sticular cancer. The main risk factor for 
testicular cancer is cryptorchidism, fol-
lowed by hypospadias (48,49). Testicular 
cancer is most common among young 
men between the ages of 15–34 years (50). 
The origins of testicular cancer are elu-
sive; however, many investigators are 
exploring the possibility that fetal and 
early-life EDCs exposures can disrupt 
the critical hormonal balance during 
development, and in turn contribute to 
the formation of testicular cancer later 
in life (41,51). It was found that men who 
have some form of gonadal dysgenesis 
are more likely to develop testicular can-
cer in conjunction with other male re-
productive abnormalities such as hypos-
padias and cryptorchidism (26,52). The 
mechanisms behind the development 
of testicular cancer are still unknown, 
but both environmental and lifestyle fa-
ctors have been associated with its deve-
lopment. Although the strength of the 
association is unclear, some EDCs have 
been identified that may play a role in te-
sticular carcinogenesis, including certa-
in types of persistent organic pollutants 
(i.e. organochlorine pesticides) (40), 
and synthetic hormones, namely oe-
strogens, gestagens and androgenic ana-
bolics used for meat production (52). 
Animal studies are helpful in assessing 
the effects of exogenous oestrogens or 
anti-androgenic chemicals after in utero 
or early-life exposures. Some examples 
of highly studied oestrogenic compou-
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nds include DES, ethinyl estradiol, and 
BPA, while anti-androgenic compounds 
include flutamide and vinclozolin (26). 
Results from animal studies have shown 
that in utero exposures to selected EDCs 
(Table 1) can lead to the development of 
hypospadias, cryptorchidism and redu-
ction in sperm volume in the majority of 
the animals exposed, and in some seve-
re cases the formation of Leydig cell tu-
mours (26). These initial studies provide 
some insight on the effects of early life 
exposures, but the animal models have 
significant limitations in terms of their 
relevance to human testicular germ-cell 
tumour also due to much higher doses 
used in experiments compared to do-
ses of human exposure. Phthalates (e.g. 
mono-n-butyl phthalate), which have 
a wide application in commercial and 
industrial plastics, have been shown to 
alter male reproductive development by 
acting as anti-androgens within the fe-
tal testis of rats, as described above (26). 
Phthalates induce multinucleated germ 
cells (MNGs) following a gestational 
exposure (53). MNGs have multiple nu-
clei that are contained within one cyto-
plasm and are postulated to be formed 
from the abnormal differentiation of 
germ cells. Although MNGs and carci-
noma in situ cells share a putative origin 
as developmentally dysgenetic germ-line 
cells, MNGs do not appear to lead to te-
sticular cancer in rodent models (53-55).
2.3.2. Prostate cancer
Prostate cancer remains an impor-
tant public health concern in Western 
countries and an emerging malignan-
cy in developing nations (e.g. U.S., 
New Zealand, Sweden, Norway, Austria 
Table 1: Reproduction problems in males and connected endocrine-disrupting chemicals. 
Male reproduction 
problems
Endocrine-disrupting chemicals References
Reduced semen 
quality and infertility
phthalates (di-butyl, di-(2-ethylhexyl) and butyl benzyl 
phthalates); tcDD; pcBs and their metabolites; DeS; ethinyl 
estradiol; Bpa; pesticides (flutamide, vinclozolin, DDe, DDt)
25, 26, 29, 31, 
38, 39
Hypospadias phthalates (di-butyl, di-(2-ethylhexyl) and butyl benzyl 
phthalates); DeS; dioxins; ethinyl estradiol; Bpa; pesticides 
(flutamide, vinclozolin, DDe, DDt)
3, 5, 26, 29, 
32
Cryptorchidism phthalates (di-butyl, di-(2-ethylhexyl) and butyl benzyl phthalates); 
DeS; ethinyl estradiol; Bpa; pesticides (hexachlorbenzene, 
heptachlorepoxide, flutamide; vinclozolin, DDe, DDt)
5, 25, 26, 29, 
32, 33, 34
testicular cancer DeS; ethinyl estradiol; Bpa; pesticides (hexachlorbenzene, 
heptachlorepoxide, flutamide; vinclozolin, DDe, DDt)
25, 26, 40, 52
prostate cancer DeS; pcB; Bpa; uv filters; heavy metals (cadmium, arsenic); 
pesticides (beta-hexachlorohexane, gamma-hexachlorohexane, 
p,p-DDe, vinclozolin)
4, 42, 60, 61, 
62, 63
breast cancer phthalates (diethyl and butyl benzyl phthalate); tcDD; insecticide 
(heptachlor); pesticides (hexachlorobenzene, organochlorine 
pesticides, organophosphorus pesticides, malathion, parathion); 
pcBs; Bpa; cosmetics (benzyl salicylate, benzyl benzoate and 
butylphenyl methylpropional); cadmium
69, 70, 71, 72, 
73, 74, 75, 76, 
77, 78
Bpa – bisphenol a, DeS – diethylstilbestrol, DDe – 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene, 
DDt – 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane, tcDD – 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Endocrine-disrupting chemicals and male reproductive health 75
Strokovni članek
(Tyrol), Canada, Switzerland, Australia, 
Iceland) (56). In the United States pros-
tate cancer has the highest incidence 
among cancers and is second leading 
cause of cancer death among men (57-
59). Despite the common occurrence of 
prostate tumours, its aetiology rema-
ins largely unknown. Prins (60), who 
contributed importantly to the study of 
prostate carcinogenesis, found out that 
there is substantial evidence from ani-
mal models about the influence of speci-
fic EDCs (Table 1) to prostate cancer de-
velopment or progression. In large part, 
these effects appear to be linked to inter-
ference with oestrogen signalling, either 
through interacting with ERs or by influ-
encing steroid metabolism and altering 
oestrogen levels within the body. Studies 
in animal models show augmentation 
of prostate carcinogenesis with several 
environmental EDCs including DES, 
PCBs, cadmium, UV filters, BPA, and ar-
senic (4,60-62). Importantly, sensitivity 
of the prostate to these EDCs appears to 
be heightened during the critical develo-
pmental windows including in utero and 
neonatal time points as well as during 
puberty. Thus infants and children may 
be considered a highly susceptible popu-
lation for EDCs exposures and increased 
risk of prostate cancers with aging (60). 
BPA, a plastic component that can be 
considered a model agent for endocrine 
disruption, was shown to induce changes 
in differentiation patterns, cell prolifera-
tion at a BPA dose of ~ 10-7 M or 23 ppb, 
and size of the prostate in male offspring 
after feeding pregnant mice 2 or 20 μg/
kg/day BPA, changes that are probably 
associated with an increase in cancer 
risk (61). Exposure to DES, especially 
prenatal and early in life, has been asso-
ciated with prostate abnormalities, inclu-
ding prostatic squamous neoplasia (60). 
UV filters, compounds of sunscreens, 
have been reported to alter prostate 
gland development and oestrogen target 
gene expression in rats (63). Especially 
4-methylbenzylidene and 3-benzylide-
ne camphor are ER-beta ligands (62-64). 
Cadmium is a known ER ligand (65). In 
vitro work has shown proliferative acti-
on of cadmium in human prostate cells, 
and in rats prostatic tumours have been 
induced by oral cadmium exposure or 
by injection (60,66,67). According to 
Benbrahim-Tallaa and Waalkes (68), 
arsenic can induce malignant transfor-
mation of human prostate epithelial cel-
ls and also appears to impact prostate 
cancer cell progression by precipitating 
events leading to androgen independen-
ce in vitro. Vinclozolin, a fungicide, has 
known anti-androgenic properties. On 
the one hand, prostate gland growth in 
rats was reduced by vinclozolin, but on 
the other hand, prenatal exposure le-
ads to aging-associated prostatitis in 
the next four generations of offspring. 
Kumar et al. (42) studied 70 newly di-
agnosed prostate cancer patients and 
61 age-matched healthy male controls. 
They found significantly higher levels of 
beta-hexachlorohexane (5.64 ± 3.06 ng/
mL vs. 4.27 ± 2.74 ng/mL), gamma-
-hexachlorohexane (7.37 ± 6.97 ng/mL 
vs. 5.33 ± 4.22 ng/mL), and p,p-DDE 
(4.16 ± 2.67 ng/mL vs. 3.02 ± 2.33 ng/
mL) in blood of prostate cancer patients 
compared to controls (42).
2.3.3. Male breast cancer
Male breast cancer is a rare disease, 
showing an increasing incidence trend 
rising along with that of female bre-
ast cancer. The 2009 Endocrine Society 
scientific statement entails considerable 
evidence indicating that EDCs contri-
bute to the risk of male breast cancer 
occurrence (24). From the clinical and 
biological point of view, male and female 
breast cancer differ mainly in the frequ-
ency of their histological type and in the 
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expression of hormone receptors and of 
epidermal growth factor receptor 2. The 
major risk factor related to male breast 
cancer is a positive family history for 
breast cancer, which indicates a relevant 
genetic component (5).
Biological effects favouring ma-
lignant transformation were observed 
on human breast cells for pesticide hexa-
chlorobenzene (69), organochlorine 
pesticides (70), organophosphorus pe-
sticides, malathion and parathion (71), 
PCBs (72), BPA (73), butyl benzyl pht-
halate (74), cosmetics benzyl salicyla-
te, benzyl benzoate and butylphenyl 
methylpropional (75) and also cad-
mium (76,77).
Experiments on animals showed that 
in utero exposure to 2,3,7,8-tetrachlo-
rodibenzo-p-dioxin (TCDD) induce 
alterations in breast development and 
increase susceptibility for mamma-
ry cancer development (78). Mice 
and rats exposed perinatally to BPA 
showed preneoplastic lesions (intradu-
ctal hyperplasias) in mammary tissue 
and such rats developed carcinoma in 
situ (79,80). Rats exposed perinatally or 
through lactation to BPA showed an in-
creased susceptibility to neoplastic de-
velopment (81,82). According to Markey 
et al. (83) perinatal exposure of mice to 
environmentally relevant levels of BPA 
(25 and 250 µg/kg body weight) indu-
ce in the mammary gland an increase 
in the number of terminal end buds, 
the structures in which mammary can-
cer originates in both rodents and hu-
mans (84). The experiment performed 
by Markey et al. (83) showed that by 
6 months of age, the mammary glands 
of exposed mice demonstrated a dra-
matic expansion of the ductal network 
with a significant increase in terminal 
ducts and alveolar structures relative to 
the control.
2.4. Poor semen quality
Although several studies have shown 
that EDCs may operate through hor-
monal pathways to affect spermatoge-
nesis (85), the decline in semen quali-
ty in men is still a controversial issue. 
The debate began when a Carlsen et 
al. (37) review highlighted a decrease 
in sperm counts, of up to 50 % during 
the period 1940–1990 (mean sperm co-
unt from 113 millions/mL in 1940 to 
66 millions/mL in 1990) and continued 
with several meta-analyses reporting 
a decline in semen quality around the 
world (4,23,31,49,86,87).
It is known that the environmental 
EDCs might affect the development of 
the male reproductive system during 
fetal or childhood life (25). However, se-
veral studies on occupational exposure 
to EDCs showed that spermatogenesis 
can also be corrupted by exposure of the 
adult man to various EDCs (88,89).
3. Conclusion
The preservation of adequate repro-
ductive capacity is crucial for the human 
species maintenance, while also being 
one of the most important determinants 
of “good health” for the individual. In 
the last decades, numerous studies have 
reported an increasing incidence of hu-
man reproductive diseases and a con-
sequent decline in reproductive functi-
on (90). Because of the short time frame, 
it is not likely that this could be expla-
ined by genetic changes. More likely 
explanation for the observed trends is 
exposure of humans to copious potenti-
ally hazardous chemicals called endocri-
ne-disrupting chemicals (EDCs), which 
can interact with the endocrine system 
and are continuously released into the 
environment. Exposure of humans to 
Endocrine-disrupting chemicals and male reproductive health 77
Strokovni članek
environmental EDCs, which are poten-
tially posing a serious health hazard, is 
among the most pressing environmental 
issues facing modern toxicology in re-
cent years. Despite the biological plausi-
bility of the effects of EDCs on animals 
demonstrated in numerous laboratory 
studies, it is not clear yet to what extent 
human health is adversely impacted by 
EDCs’ exposure. There are similarities 
between results obtained from animal 
studies and adverse effects seen in hu-
mans, but there is no direct evidence for 
possible effects of EDCs on human fer-
tility. Nevertheless, the obvious regional 
differences in male abnormalities (such 
as testicular cancer and reduced sperm 
counts) suggest the influence of envi-
ronmental factors, as opposed to genetic 
predisposition. Linking environmental 
factors with health factors is of paramo-
unt importance for the identification of 
the causes of the growing number of re-
productive diseases in humans possibly 
caused by exposure to various envi-
ronmental factors. Identification of re-
lationships between exposure to specific 
EDCs in the environment and detrimen-
tal fertility measures in humans could 
lead to preventive strategies and polici-
es aimed at limiting the production of 
these chemicals, as well as at favouring 
removal of these substances from the en-
vironment. 
References
1. colborn t, vom Saal FS, Soto aM. Developmental effects of endocrine-disrupting chemicals in wildlife and 
humans. environmental Health perspectives. 1993;101(5):378–84.
2. Safe SH. endocrine Disruptors and Human Health–is there a problem? an update. environmental Health 
perspectives. 2000;108(6):487–93.
3. Baskin lS, Himes k, colborn t. Hypospadias and endocrine Disruption: is there a connection? envi-
ronmental Health perspectives. 2001;109(11):1175–83.
4. Balabanič D, rupnik M, krivograd klemenčič a. negative impacts of endocrine-disrupting compounds on 
human reproductive health. reprod Fertil Dev. 2011;23(3):403–416.
5. coster S, larebeke n. endocrine-Disrupting chemicals: associated Disorders and Mechanisms of action. j. 
environ. public Health. 2012;2012:713696.
6. (eDStac)uSepa eDSatac. endocrine disrupter screening and testing advisory committee final report. ava-
ilable from: http://www.epa.gov/scipoly/oscpendo/history/finalrpt.htm.
7. al-Saleh i, coskun S, Mashhour a, Shinwari n, el-Doush i, Billedo G, et al. exposure to heavy metals (lead, 
cadmium and mercury) and its effect on the outcome of in-vitro fertilization treatment. international jour-
nal of Hygiene and environmental Health. 2008;211(5–6):560–79.
8. villeneuve S, cyr D, lynge e, orsi l, Sabroe S, Merletti F, et al. occupation and occupational exposure to 
endocrine disrupting chemicals in male breast cancer: a case-control study in europe. occupational and 
environmental Medicine. 2010;67(12):837–44.
9. Birkett jW. Scope of the problem. in: Birkett jW, lester jn, eds. endocrine Disrupters Wastewater and Slud-
ge treatment processes. london: lewis publishers; 2003.
10. Fasano e, Bono-Blay F, cirillo t, Montuori p, lacorte S. Migration of phthalates, alkylphenols, bisphenol a 
and di(2-ethylhexyl)adipate from food packaging. Food control. 2012;27(1):132–8.
11. Mcneal tp, Biles je, Begley tH, craun jc, Hopper Ml, Sack ca. Determination of Suspected endocrine 
Disruptors in Foods and Food packaging. acS Symposium Series: american chemical Society; 1999. p. 
33–52.
12. Fernandes ar, rose M, charlton c. 4-nonylphenol (np) in food-contact materials: analytical methodology 
and occurrence. Food additives & contaminants: part a. 2008;25(3):364–72.
13. toyo’oka t, oshige Y. Determination of alkylphenols in Mineral Water contained in pet Bottles by liquid 
chromatography with coulometric Detection. analytical Sciences. 2000;16(10):1071–6.
14. casajuana n, lacorte S. new Methodology for the Determination of phthalate esters, Bisphenol a, Bisphe-
nol a Diglycidyl ether, and nonylphenol in commercial Whole Milk Samples. journal of agricultural and 
Food chemistry. 2004;52(12):3702–7.
15. Fierens t, Servaes k, van Holderbeke M, Geerts l, De Henauw S, Sioen i, et al. analysis of phthalates in 
food products and packaging materials sold on the Belgian market. Food and chemical toxicology. 
2012;50(7):2575–83.
16. Self rl, Wu W-H. rapid qualitative analysis of phthalates added to food and nutraceutical products by 
direct analysis in real time/orbitrap mass spectrometry. Food control. 2012;25(1):13–6.
78 Zdrav vestn | januar – februar 2018 | letnik 87
reproDukcija človeka
17. nasreddine l, parent-Massin D. Food contamination by metals and pesticides in the european union. 
Should we worry? toxicology letters. 2002;127(1–3):29–41.
18. Mukherjee a, Sengupta Mk, Hossain Ma, ahamed S, Das B, nayak B, et al. arsenic contamination in gro-
undwater: a global perspective with emphasis on the asian scenario. journal of health, population, and 
nutrition. 2006;24(2):142–63.
19. alam MGM, Snow et, tanaka a. arsenic and heavy metal contamination of vegetables grown in Samta villa-
ge, Bangladesh. Science of the total environment. 2003;308(1–3):83–96.
20. Sirot v, Guérin t, volatier jl, leblanc jc. Dietary exposure and biomarkers of arsenic in consumers of fish 
and shellfish from France. Science of the total environment. 2009;407(6):1875–85.
21. clarkson tW. the three Modern Faces of Mercury. environmental Health perspectives. 2002;110(s1):11–23.
22. nasreddine l, parent-Massin D. Food contamination by metals and pesticides in the european union. 
Should we worry? toxicology letters. 2002;127(1–3):29–41.
23. campion S, catlin n, Heger n, McDonnell ev, pacheco Se, Saffarini c, et al. Male reprotoxicity and endocri-
ne Disruption. experientia Supplementum: Springer Basel; 2012. p. 315–60.
24. Diamanti-kandarakis e, Bourguignon j-p, Giudice lc, Hauser r, prins GS, Soto aM, et al. endocrine-
-Disrupting chemicals: an endocrine Society Scientific Statement. endocrine reviews. 2009;30(4):293–342.
25. Sharpe rM, Skakkebaek ne. are oestrogens involved in falling sperm counts and disorders of the male 
reproductive tract? the lancet. 1993;341(8857):1392–6.
26. Skakkebæk ne, rajpert-De Meyts e, Main kM. testicular dysgenesis syndrome: an increasingly common 
developmental disorder with environmental aspects: opinion. Human reproduction. 2001;16(5):972–8.
27. Schug tt, janesick a, Blumberg B, Heindel jj. endocrine disrupting chemicals and disease susceptibility. 
the journal of Steroid Biochemistry and Molecular Biology. 2011;127(3–5):204–15.
28. Foster pMD. Mode of action: impaired Fetal leydig cell Function—effects on Male reproductive Develo-
pment produced by certain phthalate esters. critical reviews in toxicology. 2005;35(8–9):713–9.
29. Foster pMD. Disruption of reproductive development in male rat offspring following in utero exposure to 
phthalate esters. international journal of andrology. 2006;29(1):140–7.
30. Sharpe rM. environmental/lifestyle effects on spermatogenesis. philosophical transactions of the royal 
Society B: Biological Sciences. 2010;365(1546):1697–712.
31. Mocarelli p, Gerthoux pM, patterson DG, Milani S, limonta G, Bertona M, et al. Dioxin exposure, from infancy 
through puberty, produces endocrine Disruption and affects Human Semen Quality. environmental Health 
perspectives. 2007;116(1):70–7.
32. Summary of DeS effects Stillman r: in utero exposure to diethylstilbestrol: adverse effects on the reprodu-
ctive tract and reproductive performance in male and female offspring. am j obstet Gynecol 142:905, 1982. 
journal of nurse-Midwifery. 1982;27(6):39.
33. Weidner iS, Møller H, jensen tk, Skakkebaek ne. cryptorchidism and hypospadias in sons of gardeners 
and farmers. environmental Health perspectives. 1998;106(12):793–6.
34. Hosie S, loff S, Witt k, niessen k, Waag k. is there a correlation Between organochlorine compounds and 
undescended testes? european journal of pediatric Surgery. 2000;10(05):304–9.
35. toppari j, kaleva M, virtanen He. trends in the incidence of cryptorchidism and hypospadias, and metho-
dological limitations of registry-based data. apMiS. 2001;109(S103):S37-S42.
36. Boisen ka, kaleva M, Main kM, virtanen He, Haavisto aM, Schmidt iM, et al. Difference in prevalence of 
congenital cryptorchidism in infants between two nordic countries. the lancet. 2004;363(9417):1264–9.
37. carlsen e, Giwercman a, keiding n, Skakkebaek ne. evidence for decreasing quality of semen during past 
50 years. BMj. 1992;305(6854):609–13.
38. Dallinga jW, Moonen ej, Dumoulin jc, evers jl, Geraedts jp, kleinjans jc. Decreased human semen qua-
lity and organochlorine compounds in blood. Human reproduction (oxford, england). 2002;17(8):1973–9.
39. Guo Yl, Hsu p-c, Hsu c-c, lambert GH. Semen quality after prenatal exposure to polychlorinated biphenyls 
and dibenzofurans. the lancet. 2000;356(9237):1240–1.
40. Skakkebaek ne, rajpert-De Meyts e, jorgensen n, Main kM, leffers H, andersson aM, et al. testicular 
cancer trends as 'whistle blowers' of testicular developmental problems in populations. int j androl. 
2007;30(4):198–204; discussion -5.
41. lacerda HM, akre o, Merletti F, richiardi l. time trends in the incidence of testicular cancer in childhood 
and Young adulthood. cancer epidemiology Biomarkers & prevention. 2009;18(7):2042–5.
42. kumar v, Yadav cS, Singh S, Goel S, ahmed rS, Gupta S, et al. cYp 1a1 polymorphism and organochlorine 
pesticides levels in the etiology of prostate cancer. chemosphere. 2010;81(4):464–8.
43. Hileman B. environmental estrogens linked to reproductive abnormalities, cancer. chemical & enginee-
ring news. 1994;72(5):19–23.
44. Yu M-H, tsunoda H, tsunoda M. environmental toxicology: biological and health effects of pollutants: crc 
press; 2011. p. 281–295.
45. Marques-pinto a, carvalho D. Human infertility: are endocrine disruptors to blame? endocrine connecti-
ons. 2013;2(3):r15-r29.
46. jeng Ha. exposure to endocrine Disrupting chemicals and Male reproductive Health. Frontiers in public 
Health. 2014;2.
47. Dearnaley D. regular review: Managing testicular cancer. BMj. 2001;322(7302):1583–8.
48. Sharpe rM. the 'oestrogen hypothesis'- where do we stand now?1. international journal of andrology. 
2003;26(1):2–15.
Endocrine-disrupting chemicals and male reproductive health 79
Strokovni članek
49. aitken rj, Skakkebaek ne, roman SD. Male reproductive health and the environment. the Medical journal 
of australia. 2006;185(8):414–5.
50. curado M-p, edwards B, Shin Hr, Storm H, Ferlay j, Heanue M, et al. cancer incidence in five continents, 
volume iX: iarc press, international agency for research on cancer; 2007.
51. virtanen He, rajpert-De Meyts e, Main kM, Skakkebaek ne, toppari j. testicular dysgenesis syndrome and 
the development and occurrence of male reproductive disorders. toxicology and applied pharmacology. 
2005;207(2 Suppl):501–5.
52. rajpert-De Meyts e. Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and 
environmental aspects. Human reproduction update. 2006;12(3):303–23.
53. Mylchreest e, Sar M, Wallace DG, Foster pM. Fetal testosterone insufficiency and abnormal proliferation of 
leydig cells and gonocytes in rats exposed to di(n-butyl) phthalate. reproductive toxicology (elmsford, nY). 
2002;16(1):19–28.
54. Ferrara D, Hallmark n, Scott H, Brown r, Mckinnell c, Mahood ik, et al. acute and long-term effects of in 
utero exposure of rats to di(n-butyl) phthalate on testicular germ cell development and proliferation. endo-
crinology. 2006;147(11):5352–62.
55. olesen ia, Sonne SB, Hoei-Hansen ce, rajpert-De Meyts e, Skakkebaek ne. environment, testicular 
dysgenesis and carcinoma in situ testis. Best practice & research clinical endocrinology & metabolism. 
2007;21(3):462–78.
56. Haas Gp, Delongchamps n, Brawley oW, Wang cY, de la roza G. the worldwide epidemiology of prostate 
cancer: perspectives from autopsy studies. the canadian journal of urology. 2008;15(1):3866–71.
57. Hsing aW, tsao l, Devesa SS. international trends and patterns of prostate cancer incidence and mortality. 
international journal of cancer. 2000;85(1):60–7.
58. Greenlee rt, Hill-Harmon MB, Murray t, thun M. cancer statistics, 2001. ca: a cancer journal for clinicians. 
2001;51(1):15–36.
59. cDc. centers for Disease control and prevention. united States cancer Statistics, 2012. top ten can-
cers[20.10.2015]. availabe from. https://nccd.cdc.gov/uscs/toptencancers.aspx.
60. prins GS, tang W-Y, Belmonte j, Ho S-M. perinatal exposure to oestradiol and Bisphenol a alters the prosta-
te epigenome and increases Susceptibility to carcinogenesis. Basic & clinical pharmacology & toxicology. 
2008;102(2):134–8.
61. Maffini Mv, rubin BS, Sonnenschein c, Soto aM. endocrine disruptors and reproductive health: the case of 
bisphenol-a. Molecular and cellular endocrinology. 2006;254–255:179–86.
62. Schlumpf M, Durrer S, Faass o, ehnes c, Fuetsch M, Gaille c, et al. Developmental toxicity of uv filters and 
environmental exposure: a review. international journal of andrology. 2008;31(2):144–51.
63. Hofkamp l, Bradley S, tresguerres j, lichtensteiger W, Schlumpf M, timms B. region-Specific Growth 
effects in the Developing rat prostate Following Fetal exposure to estrogenic ultraviolet Filters. envi-
ronmental Health perspectives. 2008;116(7):867–72.
64. Schlumpf M, Schmid p, Durrer S, conscience M, Maerkel k, Henseler M, et al. endocrine activity and develo-
pmental toxicity of cosmetic uv filters—an update. toxicology. 2004;205(1–2):113–22.
65. Fechner p, Damdimopoulou p, Gauglitz G. Biosensors paving the Way to understanding the interaction 
between cadmium and the estrogen receptor alpha. ploS one. 2011;6(8):e23048.
66. Waalkes Mp. cadmium carcinogenesis in review. journal of inorganic Biochemistry. 2000;79(1–4):241–4.
67. Benbrahim-tallaa l, Waterland ra, Dill al, Webber MM, Waalkes Mp. tumor Suppressor Gene inactivation 
during cadmium-induced Malignant transformation of Human prostate cells correlates with overexpressi-
on ofde novoDna Methyltransferase. environmental Health perspectives. 2007.
68. Benbrahim-tallaa l, Waalkes Mp. inorganic arsenic and Human prostate cancer. environmental Health per-
spectives. 2007;116(2):158–64.
69. García Ma, peña D, Álvarez l, cocca c, pontillo c, Bergoc r, et al. Hexachlorobenzene induces cell prolifera-
tion and iGF-i signaling pathway in an estrogen receptor α-dependent manner in McF-7 breast cancer cell 
line. toxicology letters. 2010;192(2):195–205.
70. valerón pF, pestano jj, luzardo op, Zumbado Ml, almeida M, Boada lD. Differential effects exerted on hu-
man mammary epithelial cells by environmentally relevant organochlorine pesticides either individually or 
in combination. chemico-Biological interactions. 2009;180(3):485–91
71. calaf G, roy D. cancer genes induced by malathion and parathion in the presence of estrogen in breast 
cells. international journal of Molecular Medicine. 2008.
72. ptak a, ludewig G, rak a, nadolna W, Bochenek M, Gregoraszczuk el. induction of cytochrome p450 1a1 in 
McF-7 human breast cancer cells by 4-chlorobiphenyl (pcB3) and the effects of its hydroxylated metaboli-
tes on cellular apoptosis. environment international. 2010;36(8):935–41.
73. Weng Y-i, Hsu p-Y, liyanarachchi S, liu j, Deatherage De, Huang Y-W, et al. epigenetic influences of low-
-dose bisphenol a in primary human breast epithelial cells. toxicology and applied pharmacology. 
2010;248(2):111–21.
74. Fernandez Sv, russo j. estrogen and Xenoestrogens in Breast cancer. toxicologic pathology. 2009;38(1):110–
22.
75. charles ak, Darbre pD. oestrogenic activity of benzyl salicylate, benzyl benzoate and butylphenylmethylpro-
pional (lilial) in McF7 human breast cancer cellsin vitro. journal of applied toxicology. 2009;29(5):422–34.
76. Siewit cl, Gengler B, vegas e, puckett r, louie Mc. cadmium promotes Breast cancer cell proliferation by 
potentiating the interaction between erα and c-jun. Molecular endocrinology. 2010;24(5):981–92.
80 Zdrav vestn | januar – februar 2018 | letnik 87
reproDukcija človeka
77. Yu X, Filardo ej, Shaikh Za. the membrane estrogen receptor Gpr30 mediates cadmium-induced prolifera-
tion of breast cancer cells. toxicology and applied pharmacology. 2010;245(1):83–90.
78. jenkins S, rowell c, Wang j, lamartiniere c. prenatal tcDD exposure predisposes for mammary cancer in 
rats. reproductive toxicology. 2007;23(3):391–6.
79. Murray t, Maffini M, ucci a, Sonnenschein c, Soto a. induction of mammary gland ductal hyperplasias and 
carcinoma in situ following fetal bisphenol a exposure. reproductive toxicology. 2007;23(3):383–90.
80. vandenberg ln, Maffini Mv, Schaeberle cM, ucci aa, Sonnenschein c, rubin BS, et al. perinatal exposure to 
the xenoestrogen bisphenol-a induces mammary intraductal hyperplasias in adult cD-1 mice. reproducti-
ve toxicology. 2008;26(3–4):210–9.
81. Durando M, kass l, piva j, Sonnenschein c, Soto aM, luque eH, et al. prenatal Bisphenol a exposure in-
duces preneoplastic lesions in the Mammary Gland in Wistar rats. environmental Health perspectives. 
2006;115(1):80–6.
82. jenkins S, raghuraman n, eltoum i, carpenter M, russo j, lamartiniere ca. oral exposure to Bisphenol a 
increases Dimethylbenzanthracene-induced Mammary cancer in rats. environmental Health perspectives. 
2009;117(6):910–5.
83. Markey cM, luque eH, Munoz de toro M, Sonnenschein c, Soto aM. in utero exposure to Bisphenol a al-
ters the Development and tissue organization of the Mouse Mammary Gland1. Biology of reproduction. 
2001;65(4):1215–23.
84. russo j, russo iH. Dna labeling index and structure of the rat mammary gland as determinants of its 
susceptibility to carcinogenesis. journal of the national cancer institute. 1978;61(6):1451–9.
85. toppari j, Skakkebæk ne. endocrine disruption in male human reproduction. environmental endocrine 
Disruptors: an evolutionary perspective. 2000. p. 269–290.
86. Swan SH. Semen quality in fertile uS men in relation to geographical area and pesticide exposure. interna-
tional journal of andrology. 2006;29(1):62–8.
87. Serrano M, Gonzalvo Mc, Sanchez-pozo Mc, clavero a, Fernandez MF, lopez-regalado Ml, et al. adherence 
to reporting guidelines in observational studies concerning exposure to persistent organic pollutants and 
effects on semen parameters. Human reproduction. 2014;29(6):1122–33.
88. De celis r, Feria-velasco a, González-unzaga M, torres-calleja j, pedrón-nuevo n. Semen quality of wor-
kers occupationally exposed to hydrocarbons. Fertility and Sterility. 2000;73(2):221–8.
89. Danadevi k, rozati r, reddy pp, Grover p. Semen quality of indian welders occupationally exposed to nickel 
and chromium. reproductive toxicology. 2003;17(4):451–6.
90. Woodruff tj, Zota ar, Schwartz jM. environmental chemicals in pregnant Women in the united States: 
nHaneS 2003–2004. environmental Health perspectives. 2011;119(6):878–85.