Biomedicine & Pharmacotherapy 155 (2022) 113730

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Molecular consequences of the exposure to toxic substances for the

endocrine system of females
Alicja Kowalczyk a, *, Marcjanna Wrzecińska b, Ewa Czerniawska-Piątkowska b,
José Pedro Araújo c, Przemysław Cwynar a
a
Department of Environmental Hygiene and Animal Welfare, Wrocław University of Environmental and Life Sciences, Chełmońskiego 38C, Wrocław, Poland
b
Department of Ruminant Science, West Pomeranian University of Technology, Klemensa Janickiego 29, 71-270 Szczecin, Poland
c
Mountain Research Centre (CIMO), Instituto Politécnico de Viana do Castelo, Rua D. Mendo Afonso, 147, Refóios do Lima, 4990-706 Ponte de Lima, Portugal

A R T I C L E I N F O A B S T R A C T

Keywords: Endocrine-disrupting chemicals (EDCs) are common in the environment and in everyday products such as cos­
Reproduction metics, plastic food packaging, and medicines. These substances are toxic in small doses (even in the order of
Endocrine-disrupting chemicals micrograms) and enter the body through the skin, digestive or respiratory system. Numerous studies confirm the
Toxic substances
negative impact of EDCs on living organisms. They disrupt endocrine functions, contributing to the development
Female fertility
Hormones
of neoplastic and neurological diseases, as well as problems with the circulatory system and reproduction. EDCs
Molecular changes affect humans and animals by modulating epigenetic processes that can lead to disturbances in gene expression
or failure and even death. They also affect steroid hormones by binding to their receptors as well as interfering
with synthesis and secretion of hormones. Prenatal exposure may be related to the impact of EDCs on offspring,

Abbreviations: 1-NP, 1-nitropyrene; 4-CP, 4-cumylphenol; ACTH, adrenocorticotropic hormone; ADI, acceptable daily intake; AMH, Anti-Mullerian Hormone;
AOP, advanced oxidation processes; AR, androgen receptor; Bax, pro-apoptotic protein; Bcl-2, anti-apoptotic protein; BBP, butyl benzyl phthalate; BPAF, bisphenol
AF; BFR, brominated flame retardants; BHC, benzene hexachloride; BPA, bisphenol A; BPC, bisphenol C; BPE, bisphenol E; BPS, biphenyl S; CCA, clear cell
adenocarcinoma; CCM, catalytic ceramic membrane; CEC, contaminants of emerging concern; COCs, cumulus-oocyte complexes; CRH, a corticotropin-releasing
hormone; CTB, cytotrophoblast cells; DBP, di-butylphthalate; DCHP, di-cyclohexylphthalate; DDD, dichlorodiphenyldichloroethane; DDT, dichlorodiphenyltri­
chloroethane; DEHP, di(2-Ethylhexyl)phthalate, diethylhexyl phthalate; DES, diethylstilbestrol; E1, estrone; E2, estradiol; E3, estriol; EE2, 17α-ethinylestradiol; EGF,
epidermal growth factor; EGFR, epidermal growth factor receptor; EM, early menopause; ERE, estrogen-responsive element; ERRγ, estrogen related receptor γ; ERα,
estrogen receptor α; ERβ, estrogen receptor β; EZH2, enhancer of zeste homolog 2; FGF, fibroblast growth factor; FO, forward osmosis; FSH, follicle-stimulating
hormone; GH, growth hormone; GHRN, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; GPER, G protein-coupled estrogen receptor 1;
HAND2, antiproliferative factor; HBB, hexabromobiphenyl; HBCD, hexabromocyclododecane; HFRs, halogenated flame retardants; Hg, mercury; HPA axis, hypo­
thalamus-pituitary gland- adrenal axis; HPG, hypothalamic-pituitary gland-gonadal; HPT, hypothalamus-pituitary gland- thyroid axis; HPTE, hydroxychlor; HSP,
heat shock protein; HSP70, heat shock proteins 70; HSP90, heat shock protein 90; IGF1, IFG2 – insulin-like growth factors 1, 2; LH, luteinizing hormone; LIF,
leukemia inhibitory factor; LOAEL, lowest observed adverse effect level; MAPK, MAP kinase; MBP, monobutyl phthalate; MBzP, mono-benzyl phthalate; MCHP,
mono-cyclohexyl phthalate; MCOMHP, mono (6-COOH-2-methylheptyl) phthalate; MECPP, mono(2-ethyl-5-carboxypentyl) phthalate; MEHHP, mono (2-ethyl-5-
hydroxyhexyl) phthalate; MeHP, mono-2-ethylhexyl phthalate; MEOHP, mono (2-ethyl-5-oxohexyl) phthalate; MEP, mono-ethyl phthalate; MiBP, mono-isobutyl
phthalate; MiNP, mono-isononyl phthalate; miRNA, microRNA; MLL1, mixed-lineage leukaemia 1; MMP, mono-methyl phthalate; MMP, phthalate metabolites mono-
methyl phthalate; MOP, mono-octyl phthalate; MXC, methoxychlor; ncRNA, non-coding RNA; NCX1, Na+/Ca2+ exchanger 1; NOEL, no-observed-effect level; NR,
nuclear receptor; o-PP, ortho-phenylphenol; OCP, organochlorine pesticides; PAC/UF, Activated Carbon with Ultrafiltration; PACs, polycyclic aromatic compounds;
PAEs, phthalates esters; PAHs, polycyclic aromatic hydrocarbons; PBBs, polybrominated biphenyls; PBDEs, polybrominated diphenyl ethers; PC, polycarbonate;
PCBs, polychlorinated biphenyls; PCDDs, polychlorinated dibenzodioxins; PCDFs, polychlorinated dibenzofurans; PCOS, polycystic ovary syndrome; PFAS, Per- and
polyfluoroalkyl substances; PFOA, perfluoroctanoic acid; PFOS, perfluorooctanesulfonic acid; PI3K, phosphoinositide 3-kinase; PMAC1, plasma membrane Ca2+-
ATPase 1; PMS, peroxymonosulfate; POF, premature ovarian failure; POI, primary ovarian insufficiency; POPs, Persistent organic pollutants; PR, progesterone re­
ceptor; PRC2, polycomb 2 repressive complex; PTM, post-translational histone modifications; ROS, reactive oxygen species; SGK1, serine-threonine protein kinase;
SOD, superoxide dismutase; T3, triiodothyronine; T4, thyroxine; TAM, tamoxifen; TBBPA, tetrabromobisphenol A; TCDD, 2,3,7,8-tetrachlorodibenzodioxin; TCS,
triclosan; TRH, thyrotropin-releasing hormone; TRPV5, TRPV6 – transient receptor potential cation channel subfamily V (TRPV) member 5 and 6; TSH, thyroid-
stimulating hormone.
* Correspondence to: Chełmońskiego 38C, 51-630 Wrocław, Poland.
E-mail addresses: alicja.kowalczyk@upwr.edu.pl (A. Kowalczyk), marcjanna.wrzecinska@zut.edu.pl (M. Wrzecińska), ewa.czerniawska-piatkowska@zut.edu.pl
(E. Czerniawska-Piątkowska), pedropi@esa.ipvc.pt (J.P. Araújo), przemyslaw.cwynar@upwr.edu.pl (P. Cwynar).

https://doi.org/10.1016/j.biopha.2022.113730
Received 2 August 2022; Received in revised form 5 September 2022; Accepted 19 September 2022
Available online 21 September 2022
0753-3322/© 2022 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
A. Kowalczyk et al.
resulting in effects of these substances on the ovaries and leading to the reduction of fertility through distur­
bances in the function of steroid receptors or problems with steroidogenesis and gametogenesis. Current liter­
ature indicates the need to continue research on the effects of EDCs on the female reproductive system. The aim
of this review was to identify the effects of endocrine-disrupting chemicals on the female reproductive system
and their genetic effects based on recent literature.
1. Background
1.1. Endocrine-disrupting chemicals (EDCs)
Endocrine-disrupting chemicals (EDCs) are a group of chemical
compounds that are considered pollutants [1,2]. These substances
include polycyclic aromatic hydrocarbons (PHAs), polychlorinated bi­
phenyls (PCBs), pesticides, flame retardants, phthalates, phenols, and
toxic metals [3–6]. Among these factors, one of the best studied and
known substance influencing the endocrine system is bisphenol A (BPA)
[7]. The exposure to mentioned substances occurs through the respira­
tory and digestive systems or dermal contact [8]. Most of them are
highly lipophilic and can accumulate in the adipose tissue [2,9,10].
Therefore, the accumulation of these substances is frequent and more­
over, they have a long half-life [11]. It should be noted that BPA has
approximately 6 h of an average half-life in human tissues, for phtha­
lates, the half-life was reported usually as several hours (up to around
30 h), for the 2,3,7,8-tetrachlorodibenzodioxin (TCDD) this time is
oscillating in a period of 5–10 years, and for polybrominated diphenyl
ethers (PBDEs) it is 2–16 years, but for PCBs, it is already a half-life of
one to 35 years [12,13]. It has been proven, that EDCs, such as plasti­
cizers, pesticides, and persistent organic pollutants (POPs), can get into
the surface water, as well as the groundwater with industrial and do­
mestic wastewaters and with agricultural drains [14]. In the surface and
groundwater, the EDCs can pose a threat to water intake points and
sources of drinking water [13]. In research conducted by Čelić et al. [15]
the content of selected endocrine-disrupting chemicals was analyzed in
90 samples taken from 30 different locations, including untreated urban
and industrial wastewater, water from the Danube, fountains, and water
networks in Serbia. It was shown, that in terms of the concertation of
urban sewage, estrogens and their sulphate metabolites were the highest
(average concentrations: estradiol (E2): 7.2 ng/L, estrone (E1): 5.9 ng/L,
estriol (E3): 4.9 ng/L, E1–3S: 4.4 ng/L, E3–3S: 6.6 ng/L), while BPA
concertation was 9.1 ng/L. Moreover, the most frequently detected EDCs
in drinking water was bisphenol A (up to 57 % of the frequency), up to
70 % in surface waters, and up to 84 % in wastewater. Detection of
estrogens in sewage was up to 30 % for E2, 84 % for E1, and 34 % for E3,
while in surface waters the detection rate reached 60 % for E1 and 27 %
for E3. No estrogens were found in the drinking water. In this research, a
risk assessment was carried out, with E1 and E2 showing the highest risk
(18 and 26, respectively), and BPA representing the risk in only one
sample (RQ 14) in an industrialized area. In the case of estrogenic ac­
tivity, the total estrogenic activity exceeded the threshold of 1 ng/L of
estradiol. The authors suggested that aquatic organisms may be exposed
to the EDCs in the case of chronic exposure [15]. It has been suggested
that EDCs contribute to the death of certain animal species by increasing
sterility, such as in alligators, and sex change in fish and crustaceans.
Exposure of frogs to organochlorine pesticides, especially herbicides and
fungicides, results in hermaphrodism, and male gonadal dysfunction is
observed in alligators. Moreover, reproductive and hormonal disorders
caused by exposure to PCBs and PBDEs have been detected in seals and
whales [16]. In studies conducted on freshwater snails, golden apple
snail Pomacea canaliculata (Lamarck) (Caenogastropoda: Ampullariidae)
investigated the effect of tamoxifen (TAM) on the snail’s hormonal
balance. TAM is used in the treatment of breast cancer and infertility,
and its concentration in surface waters is a maximum of 212 ng/L. In the
study, the snails were divided into groups according to the TAM doses –
150, 300, and 600 μg/L, respectively, and the control group without
2
Biomedicine & Pharmacotherapy 155 (2022) 113730
TAM, which were administered for 6 weeks. After exposure, male and
female reproductive organs were dissected and the effect of TAMs on
them was determined. From the second week of exposure, the snails
were shown to lay fewer eggs than those of the control group, and the
males were less active in mating behavior. The fewest eggs were laid by
snails in the group in which 600 μg/L of TAM was administered (33),
and the most by snails from the control (270). The snails from the
control group were characterized by the highest fertility, and in the
experimental groups, the fertility decreased drastically with the con­
centration of TAM. It was shown that the content of estradiol and pro­
gesterone in females dropped drastically to the lowest dose of the
preparation from the level for E2 ( ~500 pg/g to ~20 pg/g), and with
progesterone (~1100 pg/g to ~0 pg/g) [17]. Livestock is exposed to
EDCs through the consumption of water or feed, and the accumulation
of these substances impairs reproductive performance by disturbing the
hormonal balance. In ruminants, rumen poisoning is observed due to
toxic substances released from plastic [18]. Moreover, the organochlo­
rine compounds, such as DDT, can accumulate in products that reach in
fats, such as ruminant’s meat and milk [5]. Ho et al. [2] indicate that
there are almost 1500 EDCs, and this number may increase by intro­
ducing new substances to the market.
In current literature, the authors highlight the influence of these
compounds on hormonal signaling and health pathways, fertility, and
homeostasis of the organism [3–6,9,11]. Exposure to these chemicals
has long-term effects [5]. It has been proven, that exposure to EDCs
causes health issues such as brain, liver, and lung damage, carcinogen­
esis, and reproductive and endocrine disorders [4].
The aim of this review was to identify the effects of endocrine-
disrupting chemicals on the female reproductive system and their ge­
netic effects based on recent literature.
1.2. Classification of EDCs
Endocrine-disrupting chemicals are widespread due to their
numerous and frequent use throughout the world, so they become a
global issue [1,19]. They can be found in food, textiles, electronics,
plastics, medical devices, cosmetics, etc. [20]. These substances are
divided into two groups depending on the origin – natural EDCs and
anthropogenic EDCs. Anthropogenic endocrine-disrupting chemicals,
also known as synthetic EDCs, have sources of human activity, and on
the other hand natural EDCs can come from plants and animals, such as
animal excrement [1,5]. Table 1 (Table 1) presents sources of selected
endocrine-disrupting chemicals.
1.2.1. Persistent organic pollutants (POP)
These substances are persistent in the environment and highly toxic.
Among them, there are polychlorinated industrial chemicals, poly­
brominated biphenyls (PBBs), aldrin, heptachlor, dichlorodiphenyltri­
chloroethane (DDT), and polycyclic aromatic hydrocarbons (PAH).
These substances were banned by the Stockholm Convention in 2004
[13,26].
PCBs are aromatic compounds that have been widely used in agri­
culture and industry, including for capacitors, paints, plastics, and
pesticides. Despite the limitations in the use of PCBs, they are still pre­
sent in the environment. PCB has neurotoxic, carcinogenic, hepatotoxic,
nephrotoxic, and cytotoxic effects [13,29].
PBDEs are polyhalogenated aromatic compounds used as flame re­
tardants. They are mainly found in textiles, plastics, and electronics
A. Kowalczyk et al. Biomedicine & Pharmacotherapy 155 (2022) 113730

Table 1 [32].
Sources of selected EDCs.
EDCs Source References 1.2.2. Non-persistant EDCs
The BPA and phthalates are a group of plasticizers that are used in
Dichlorodiphenyltrichloroethane agricultural practices [5,8,21,
(DDT), (pesticides, insecticides, 22] plastic products to obtain shape and flexibility. As opposed to the POPs,
dichlorodiphenyldichloroethane fungicides) non-persistant EDCs are not lipophilic and do not bioaccumulate in the
(DDD), aldrin, dieldrin, endrin, body [29]. BPA is used to produce epoxy resins, polycarbonates, poly­
chlordane, benzene hexachloride sulfones, or as an additive to plasticizers. It is present in electronics,
(BHC), toxaphene
Bisphenol A (BPA), styrene, packaging (food-storage [23–25]
plastic packaging, and ophthalmic lenses. Phthalates are a group of
polycarbonate (PC), phthalates esters materials, plastics), multifunctional industrial chemicals used as plasticizers, e.g. for the
(PAEs), butyl benzyl phthalate (BBP), thermal receipt paper production of polyvinyl chloride, personal care products, solvents, or as
di-butylphthalate (DBP), toxic metals carriers for insecticidal preparations [33].
Brominated flame retardants (BFR) [8,13,25,
polybrominated diphenyl ethers 26]
(PBDEs), bisphenol A, 1.3. Degradation of EDCs
tetrabromobisphenol A (TBBPA)
Triclosan (TCS), chlorine, chlorine medical care (drugs, [1,16,20, The contaminants of emerging concern (CECs) are a category of
dioxide, chloramine, parabens, 17α- biocides, disinfectants, 26,27]
chemicals that have been detected in the water cycle and include in­
ethinylestradiol (EE2), prednisone, personal care products)
fluoxetine, codeine, benzophenones and pharmaceuticals and
dustrial chemicals, endocrine-disrupting chemicals, and persistent
personal care products organic pollutants [16]. The CECs are not easily removed from the water
(PPCPs), sunscreens through physical processes during the treatment of water, such as
Ortho-phenylphenol (o-PP), textile industry, PVC [13,19] filtration, adsorption, coagulation, or precipitation [5,16]. Chemical
polybrominated diphenyl ethers, plastics
methods including advanced oxidation processes (AOP), electro­
phthalates
Polycyclic aromatic hydrocarbons combustion of coal, oil, [28] chemical oxidation, ozonation, and photocatalysis may have a higher
(PAHs), toxic metals, sulfate, nitrate foods, tobacco, wood, EDCs removal efficiency than physical methods but are characterized by
fumes the formation of EDC byproducts [5]. The currently used technologies,
Per- and polyfluoroalkyl substances domestic products, fire- [26] such as chemical coagulation, precipitation, adsorption, and activated
(PFAS), perfluorooctanesulfonic acid fighting foams, surface
(PFOS), perfluorooctanoic acid coating
sludge, for water purification, reduce the concentrations of these sub­
(PFOA) stances, not their complete removal [16]. For this reason, innovative
Alkyphenols, nonylphenols, octylphenol detergents, pesticides, [26] methods to remove EDCs from wared are fooled. A promising approach
industrial surfactant may be carbon adsorption, membrane technology, or nanostructured
Persistent organic pollutants (POPs), industry process, forest [25]
photocatalysts [5]. A study by Chen et al. [34] used a nganese (III)
polychlorinated dibenzodioxins fires, volcanic eruptions
(PCDDs), polychlorinated oxide-based catalytic ceramic membrane (CCM) to activate perox­
dibenzofurans (PCDFs), ymonosulfate (PMS) to degrade various EDCs from drinking water,
polybrominated diphenyl ethers including bisphenol A, bisphenol S, bisphenol F, bisphenol B, bisphenol
(PBDEs) Z, bisphenol D, bisphenol E, bisphenol AP, 17α-ethinylestradiol. These
Polycyclic aromatic chemicals (PACs), cigarettes, internal [25]
cenzopyrene, pyrene, anthracene combustion,
membranes showed the potential to efficiently degrade EDCs in the
miscellaneous burning mg/L to ng/L concentration range. Mentioned studies have achieved
over 90 % efficiency in removing EDC from water, except bisphenol S
(efficiency of about 20 %) and bisphenol AF (about 70 %) [34]. Table 2
[26]. In the European Union, the ban on the use of PBDE was introduced shows the methods of EDC degradation technologies and their
in 2004 and 2008 [13]. effectiveness.
The organochlorine compounds (OCs) have been produced for
various purposes and belong to the group of persistent organic pollut­ 2. Mechanism of EDCs action
ants. They accumulate in organisms. These agents have been widely
used in agriculture as organochlorine pesticides (OCP), insecticides, or The endocrine system consists of glands that secrete hormones and
rodenticides. Among them, dichlorodiphenyltrichloroethane (DDT), regulate hormonal balance [28,40]. The hypothalamus, pituitary, pineal
mirex, dielrin, chlorate, heptachlor, endrin, aldrin, lindane, and endo­ gland, thyroid gland, parathyroid glands, pancreas, and gonads are part
sulfan are distinguished [26]. They were banned by Stockholm of the endocrine system [13,28,40]. Hormones act in genomic and
Convention in 2001. However, the organochlorine compounds are still non-genomic signaling [28]. Steroid hormones are lipophilic, and they
present in the environment (mainly in soil and water) [30]. act through genomic activity [41]. In the genomic mechanism, steroid
The brominated flame retardants (BFRs) include polybrominated hormones are bound to the nuclear receptors (NR), which are located in
diphenyl esters, brominated flame retardants (BFR), hex­ the cytoplasm, and the receptor itself undergoes conformational changes
abromobiphenyl (HBB), and hexabromocyclododecane (HBCD). PBDEs and translocation to the nucleus, where it participates in the regulation
are polyhalogenated aromatic compounds used as flame retardants [26]. of transcription In turn, in a non-genomic mechanism, gene expression is
They are mainly found in textiles, plastics, and electronics. In the Eu­ modulated by intracellular signaling pathways, and mainly hydrophilic
ropean Union, the ban on the use of PBDE was introduced in 2004 and hormones (e.g. catecholamine) bind to cell surface receptors [28].
2008 [13]. BFRs are used in a variety of products such as furniture, Nuclear receptors are a group of proteins that are transcription fac­
textiles, carpets, electronics molding, automotive components, building tors regulated by ligands, mainly estrogen and progesterone [13,42]. By
materials, insulators, etc. to improve their fire resistance. Moreover, sequencing the human genome, 48 nuclear receptors were revealed.
these substances are common in the environment and show the ability to Among the NRs, estrogen (ER), progesterone (PR), and androgen re­
accumulate [31]. ceptors (AR) are distinguished [41]. There are estrogen receptor α
Dioxins and furans are divided into groups that include poly­ (ERα), estrogen receptor β (ERβ), and the membrane receptor coupled
chlorinated dibenzo-ρ-dioxins (PCDDs), polychlorinated dibenzofurans with the G protein (GPER, previously termed as a G protein-coupled
(PCDFs), and dioxin-like polychlorinated biphenyls (dl-PCB). TCDD is receptor 30, GPR30), which participates in the regulation of
the most potent dioxin of PCDD. The main sources of dioxins are vol­ non-genomic mechanisms [6,10,13,43,44]. The ERα and ERβ are re­
canic eruptions, waste incineration, including tobacco, and industry ceptors for the natural estrogen 17β-estradiol, that are involved in the

3
A. Kowalczyk et al.
Table 2
EDCs degradation methods and their effectiveness.
Method Type of EDCs
Adsorption Activated carbon BPA
Activated Carbon with Ultrafiltration 17α-ethynylestradiol
(PAC/ UF)
Nano catalyst ZnO nanoparticles BPA
TiO2 nanosized Phenol
Advanced UV BPA
oxidative Ozonation cyclodien pesticides, dichlorodiphenyltrichloroethanes (DDTs), phthalates, poly-
processes aromatic hydrocarbons (PAHs) polychlorinated biphenyls (PCBs)
di-cyclohexylphthalate (DCHP)
naphthalene, phenanthrene, di-n-butylphthalate (DBP)
Membrane Forward osmosis (FO) Triclosan
Catalytic ceramic membrane (CCM) to bisphenol A, bisphenol F, bisphenol B, bisphenol Z, bisphenol D, bisphenol E,
activate peroxymonosulfate (PMS) bishenol AP, 17α-ethinylestradiol
bisphenol S
bisphenol AF
growth and maintenance of a variety of tissues such as the mammary
gland, uterus, and bone [45]. The main targets of EDCs are the ERα and
ERβ, the androgen receptor, which is present in the nucleus (ER) or
cytoplasm (AR). Binding to EDCs results in conformational changes that
result in the dissociation of the chaperone proteins and the formation of
binding to specific response elements (ERs) in DNA, which has an effect
on the modulation of gene transcription [45]. Recently, the
estrogen-related receptor γ (ERRγ) has been reported as a target of EDCs.
The ERRγ is part of the ERR family of receptors, on which ERRα and
ERRβ are also distinguished [45,46]. The estrogen-related receptor γ is
an orphan nuclear receptor that plays an important role in the meta­
bolism of mitochondria (mainly lipids, and pyruvate), and acts as a
constitutive activator of transcription. BPA was found to bind strongly to
ERRγ. The action of BPA on this receptor is to incorporate BPA into the
ligand-binding pocket by ERRγ, and the structure of bisphenol A with
two phenol-hydroxyl groups is the basis for the formation of hydrogen
bonds with the receptor. 17 different BPA derivatives have been found to
be able to bind to the estrogen-related receptor γ [47]. The ERRγ activity
can be modulated by phenols, phytoestrogens, and pesticides. The
bisphenol E (BPE) acts on the transcriptional activity of ERRγ, while the
diethylstilbestrol (DES) is an inverse agonist of ERRγ, that reduces the
action of the estrogen-related receptor γ. In the research on the stable
cell line (HG5LN), the EC50 (half maximal effective concertation) was
established for over 30 environmental substances, which were ligands to
ERRγ. It was determined, that BPA is a fairy weak agonist of estrogen
receptors (EC50 approximately 0.5 µM), however, another biphenol –
bisphenol C (BPC), hydroxychlor (HPTE) show EC50 values at the level
of 30 nM and 50 nM [46]. The steroid hormone receptors are associated
with the heat shock proteins (HSP) – mainly HSP70 and HSP90, which
regulate their functions. Activation of GPER occurs by binding to the
estrogen receptor, which forms the complex, dimerizes, and then the
chaperones are disconnected. Stimulation of adenylate cyclase occurs,
and the release of membrane-bound epidermal growth factor (EGF)
occurs. The complex then translocates to the nucleus and binds to a
specific estrogen-responsive element (ERE) that is located in the pro­
moter region of the target gene. In the cell nucleus, the estrogen-ER
complex is involved in the transcription of target genes [13,48,49].
Deletions in GPER cause insulin resistance and hypertension. GPER1
agonists have been shown to activate insulin release from the pancreas
and vasodilation. Moreover, GPER agonists prevent inflammation. EDCs
have been shown to bind to GPER via an affinity for estrogens, which
adversely affects physiology. By activating GPER, phthalates contribute
to the development of breast and cervical cancer [48,50].
Non-monotonic dose-response curves (NMDRCs) have been devel­
oped in research into the treatment of cells, animal, and human models
with EDCs. It is a plot of the biological response as a function of a specific
EDC, the slope of which changes at some point in the dose-response
curve. Such dose-response curves can be U-shaped or inverted U-
4
Biomedicine & Pharmacotherapy 155 (2022) 113730
Effectiveness References
100 % [5]
80 % [35]
97 % [36]
78 % [37]
48 % [38]
> 80 % [39]
~80 %
~40 %
79 % [35]
> 90 % [34]
~20 %
~70 %
shaped with a local minimum or maximum, respectively, or even
biphasic with two minima or maxima [51]. A feature of EDCs is the
ability to create NMDRCs [52]. Non-monotonic dose-response curves
were noted for EDCs such as pesticides, polychlorinated biphenyls, di­
oxins, bisphenol A, and phthalates [53]. NMDRCs have been demon­
strated for various EDCs in a variety of biological systems, including cell
culture, whole organ culture, laboratory animals, and human pop­
ulations [52,54]. The mechanism of NMDRC production, which is well
known, is cytotoxicity, whereby increasing doses of substances induce a
toxic effect. There is also evidence that high doses of substances are able
to inhibit cell proliferation, which has the opposite effect on cytotox­
icity. Another mechanism of NMDRC is the influence of hormone con­
centration on the number of receptors. If the number of receptors that
arise does not coincide with the number of degrading receptors, a
decrease in the response associated with an increase in hormone con­
centrations is observed [52]. One of the EDCs capable of producing
NMDRC is bisphenol A [55]. It is a widely researched compound with
high toxicological priority. In the article, Vandenberg et al. [52]
collected 109 in vitro BPA studies published during 2007–2013. Studies
with single doses and those that did not provide information on the
shape of the dose-response curve and did not show an effect of BPA were
excluded from the analyzes. Of the analyzed experiments, NMDRC was
obtained in 23.6 % (59) of the studies and at least one endpoint in over
30 % of the analyzes [52].
Endocrine-disrupting chemicals act on the endocrine system in
different ways. They can inhibit hormones binding to receptors or pre­
vent hormone signaling [56]. These substances can also block or activate
natural hormone synthesis and degradation of natural hormones [16].
These compounds have been shown to adversely affect the endocrine
system even at low doses (for example: in Danio rerio, the toxicity of BPA
for the development of fish is at the level of 50 μM [57]) by acting on
various receptors, including steroid sex hormone receptors, such as es­
trogen receptors, androgen receptors, and thyroid hormone receptors
[56,58]. Table 3 shows the acceptable daily intake (ADI), no observed
effect levels (NOEL), and the lowest observed adverse effect level
(LOAEL) of selected EDCs in terms of their influence on reproduction.
As an endocrine-disrupting chemical, bisphenol A, may act mainly
through estrogen receptors [58,66,67]. BPA is an estrogen antagonist
and exhibits non-nuclear activation of the signal mediated by the ERα.
BPA is also antagonistic to estradiol and causes ERβ signal limitation
with its nuclear receptor [6,68]. BPA has been shown to induce estro­
genic activity and interfere with the endocrine system [6,42]. In addi­
tion, it induces DNA damage and cell damage, e.g., lymphocytes.
Normal estrogen signaling is necessary for the maintenance of immune
function. Moreover, lymphocytes have steroidogenic abilities and ex­
press ERα and ERβ. Therefore, it is believed that BPA may have a
negative effect on the immune functions and affect the activity of lym­
phocytes [69]. BPA reduces the activity of superoxide dismutase (SOD),
A. Kowalczyk et al.
Table 3
ADI, NOEL, LOEAL of selected EDCs.
EDCs Doses
Acceptable Daily Intake (ADI) No Observed Effect Level (NOEL)
E2 0.05 mg/kg bw/day 10 mg/kg bw/day
methyl- and ethylparaben 10 mg/kg bw/day 1000 mg/kg bw/day
Parabens 0.3 mg/kg bw/day 1000 mg/kg bw/day
BBP 0.5 mg/kg bw/day 50 mg/kg bw per day
BPA 4–5 μg/kg bw/d 5 mg/kg bw/day
DBP 50 µg/kg bw/day 50 mg/kg bw/day
DEHP 0.05 mg/kg bw/day 5 mg/kg bw/day
resulting in an increase in reactive oxygen species (ROS) in cells, which
can contribute to DNA damage [6,42].
2.1. Other key characteristics of endocrine-disrupting chemicals
La Merrill et al. [70]point to other key features of endocrine dis­
rupting chemicals. EDCs are capable of interacting with or directly
activating hormone receptors, which may have negative health conse­
quences. These substances are capable of antagonizing hormone re­
ceptors, which is associated with inhibiting or blocking the action of
endogenous hormones, acting as their antagonists. EDCs can modulate
the expression of the hormone receptor (s) by degrading them or
reducing their expression. These substances can alter the signal trans­
duction in hormone-responsive cells, modifying the progressive intra­
cellular changes, which may then weaken or intensify the effects of
hormones. In addition, hormones can act by modifying epigenetic pro­
cesses, and EDCs can disrupt the effects of hormones and their ability to
induce epigenetic changes [54,70]. Endocrine-disrupting chemicals can
also modulate hormone synthesis by, for example, limiting the uptake of
compounds necessary for the hormone synthesis process. These sub­
stances can alter the transport of hormones across cell membranes
through selective and passive transport processes or alter the distribu­
tion of hormones or circulating hormone levels by altering the
bioavailability of the hormones. Another feature of EDCs is changing the
rate of inactivation, degradation, or removal of hormones, which mod­
ulates their concentration, as well as changes their metabolism in the
body. A final characteristic of EDCs to be reported is the ability to alter
the total number or position of cells in hormone-producing or
hormone-responsive tissues by interfering with or promoting cell dif­
ferentiation, proliferation, or apoptosis [54,70]. The key characteristics
of endocrine-disrupting chemicals are shown in the Fig. 1 (Fig. 1).
3. Endocrine aspects of EDCs
It has been proven that EDCs can disrupt the action of steroid hor­
mones, such as estrogens, and androgens, and can lead to disorders in
the reproduction [28]. The hypothalamus and the anterior pituitary
gland play a crucial role in regulating the secretion of luteinizing hor­
mone (LH) and follicle-stimulating hormone (FSH), which are involved
in modulating the function of the ovaries, uterus, and the secretion of
reproductive hormones in females [29]. Puberty is an important factor
for achieving a normal reproductive performance [71]. According to
Franssen et al. [9] late puberty in females, metabolic disorders, as well
as impaired fertility, may result from prenatal and postnatal exposure to
EDCs. The process of puberty is influenced by the action of the
hypothalamus-pituitary gland-gonadal (HPG) axis, and disturbances
within this axis translate into the puberty [9,71]. Moreover,
endocrine-disrupting chemicals prolong puberty [72,73].
EDCs are able to induce diseases and fertility disorders due to their
genotoxic activity, as well as by modulating epigenetic processes in
which steroid hormones, such as sex hormones, are involved [48]. This
leads to changes in DNA, which may directly lead to death or mutation
[42]. These changes may be passed on to the next generations [42,74].
5
Biomedicine & Pharmacotherapy 155 (2022) 113730
Lowest Observed Adverse Effect Level (LOAEL) Species References
adult human [59]
adult human [60]
100 mg/kg bw/day for rats infants [60,61]
250 mg/kg bw/day rats [62,63]
120 mg/kg bw/day mice [64]
2 mg/kg bw/day rats [62]
3 mg/kg bw/day rats [65]
Epigenetic changes caused by exposure to EDCs have a direct impact on
the emergence of diseases and dysfunctions [75]. Epigenetic mecha­
nisms include DNA methylation, post-translational histone modifica­
tions (PTM), chromatin modification, and non-coding RNAs (ncRNA)
that regulate gene expression and are involved in homeostasis and cell
development [76]. In the case of DNA methylation within the promoter
region, transcription is lost. It has been shown that these changes may
affect subsequent generations [74]. During DNA methylation, modifi­
cation of the cytosine residue in CpG dinucleotides occurs, resulting in
difficulties in gene transcription and consequently in its silencing [48,
58,77]. Disturbances in methylation can lead to retarded growth and
development of organism [48]. In turn, modifications of chromatin
through changes of histone proteins in the DNA structure may disturb
the reading of the transcription regulation. Long non-coding RNA shows
the ability to interact and modify chromatin, which causes its further
modification [58]. Another example of an epigenetic mechanism is
imprinting, which is the methylation of genes or histones of an allele
inherited from a parent [7,75].
Accurate hormone signaling is a key factor that influences the
development of the body and its reproductive capacity [78]. There is a
growing body of research pointing to the effects of EDCs on reproductive
pathologies [79]. Disorders caused by EDCs are associated with poly­
cyclic ovarian syndromes, uterine fibrosis, endometriosis, miscarriages,
breast, and prostate cancer [2,5,10,58]. Exposure to EDCs through skin
contact, inhalation, and gastrointestinal tract increases the risk of breast
cancer [80]. The mammary gland is susceptible to substances that
disrupt the endocrine system. Bisphenol A is reported to be a key sub­
stance that interferes with the development of the mammary gland and
induces the neoplastic process [81]. In rats, the effects of BPA on the
mammary gland were analyzed [82]. A group of 10 rats was adminis­
tered a dose of 5 mg/kg BPA for 8 weeks, and then the mammary glands
were dissected, the control was group of 10 animals without treatment
and 10 rats, were administered 1 ml of corn oil for 8 weeks. BPA was
shown to induce structural changes in the mammary gland of rats - the
number and size of ducts and acini increased, and epithelial nuclei
showed darker color and different shape compared to control. Moreover,
it was shown that the content of collagen fibers increased within the
connective tissue stroma, and infiltration of inflammatory cells was
observed. This study showed that the substance could induce the
development of breast cancer mainly by modulating the cell prolifera­
tion process [82]. The effects of BPA and 4-cumylphenol (4-CP) on the
viability of the MCF-7 human breast cancer cell line in vitro were
investigated. The results of the cell viability assay showed that both test
substances in the range from 10-9 to 10-5 M stimulated cell proliferation
in a non-monotonic dose-response manner. At the same time, the cell
cycle progressed from the G0/G1 phase to the S and G2/M phase, and
the expression levels of ERα mRNA and the anti-apoptotic protein
(Bcl-2) increased. At high doses (10-4 M), the substances showed an
antiproliferative effect in MCF-7 cells by inducing cell apoptosis and
blocking the cell cycle in the G0/G1 phase, the levels of Bcl-2 mRNA
expression decreased, while mRNA of pro-apoptotic protein (Bax)
increased [83]. Peremiquel-Trillas et al. [84] conducted a population
study involving 1513 cases of breast cancer patients who were
A. Kowalczyk et al.
Fig. 1. Key characteristics of EDCs (
Source: [54,70]).
professionally exposed to alkylphenol compounds. It was found that
27.2 % (412 cases) had occupational exposure to alkylphenol com­
pounds, and people with occupational exposure to these compounds
showed a greater risk of breast cancer than patients not exposed to these
compounds. People professionally exposed to these compounds showed
6
Biomedicine & Pharmacotherapy 155 (2022) 113730
a slightly increased risk of breast cancer (OR = 1.23; 95 % CI =
1.01–1.48) compared to the non-exposed person. The highest associa­
tion was found in subjects with frequent exposure and high exposure
intensity (OR = 1.25; 95 % CI = 1.01–1.55). The results suggest that
there is an association between the risk of breast cancer and alkylphenol
A. Kowalczyk et al.
compounds [84]. Moreover, it has been shown that women in Greenland
who had high levels of PFOS and PFOA, and PFAS in their blood serum
were associated with an increased risk of breast cancer. PFOS is asso­
ciated with tumors with the presence of estrogen receptors [80]. In
another study, the presence of phthalates in the urine of women was
correlated with the risk of breast cancer, and out of 140
phthalate-responsive genes, 105 genes were obtained that mutated in
the tissues of the breast tumor. Phthalates induce mutations in genes
involved in the biosynthesis of steroid hormones. Among the phthalates
tested, DBP (Odds Ratio = 1.5, 95 % Confidence Interval; 1.06–2.11,
p = 0.002) and DEHP (Odds ratio = 2.97, 95 % Confidence Interval;
1.18–7.47, p = 0.005) showed the highest affinity for breast cancer
[85]. The reproductive system is particularly sensitive to hormonal ab­
normalities during development, as it reacts to disturbances in gene
expression that lead to changes in tissues and structure within this sys­
tem [58]. EDCs cause disturbances in the oestrus cycle length and cause
germ cell nest breakdown [86]. In females, EDCs have been detected in
follicular fluid, amniotic fluid, milk, and blood serum [79,87]. It has
been proven, that bisphenol A retards the action of ovaries, uterus,
steroidogenesis, or event disrupts follicular formation [73]. Further­
more, the negative influence of BPA is indicated on the level of estro­
gens, the quality of oocytes, the formation of blastocysts, and
implantation failure is indicated [73,88]. In addition, there is also a
direct negative effect of BPA on uterine morphology, endometrial
health, and the number and growth of ovarian follicles [88].
Van Duursen et al. [89] report in their article that in the case of fe­
male reproduction there is still a lack of reports and studies showing the
effects of exposure to EDCs.
3.1. Hypothalamus
The hypothalamus is involved in the process of feeding, and main­
taining body weight, fluid balance, blood pressure, and body tempera­
ture [90]. The main role in the mammalian endocrine system is played
by the hypothalamic and pituitary glands [68]. These crucial centers of
the endocrine system are involved in maintaining homeostasis, and
modulating the body’s functions responsible for metabolism, repro­
duction, growth, lactation, or water balance. Moreover, the
hypothalamic-pituitary gland-thyroid (HPT) axis, the
hypothalamic-pituitary gland-gonadal (HPG) axis, and the
hypothalamic-pituitary gland-adrenal (HPA) axis are distinguished [28,
68,90,91].
In the HPT axis, the hypothalamus is responsible for the secretion of
the thyrotropin-releasing hormone (TRH), which signals the release of
the thyroid-stimulating hormone (TSH) from the pituitary gland. [91].
In turn, TSH participates in the regulation of thyroid metabolism and the
stimulation of the thyroxine (T4) and triiodothyronine (T3) hormones
influencing metabolism [68]. The HPA axis is involved in the secretion
of corticotropin-releasing hormone (CRH), which activates the adreno­
corticotropic hormone (ACTH) from the pituitary gland, which acts on
adrenal glands to stimulate cortisol production. The adrenal glands also
secrete catecholamines, epinephrine, and norepinephrine, to maintain
homeostasis and protect against stress [90]. ACTH is also involved in the
secretion of aldosterone, influencing the water balance [68]. In turn, on
the hypothalamus-pituitary gland-gonadal axis, the arcuate nucleus of
the hypothalamus secretes growth hormone-releasing hormone (GHRN)
peptides and gonadotropin-releasing hormone (GnRH) that stimulate
the secretion of growth hormone (GH) and gonadotropins. GH stimu­
lates body growth, and LH and FSH stimulate gametogenesis as well as
the synthesis of sex hormones [68]. LH stimulates progesterone and FSH
stimulates follicular growth by binding to G protein-coupled receptors
on granular cells and stimulating aromatase expression. Aromatase is an
enzyme produced by granular cells [28,92]. The HPG axis is involved in
steroidogenesis and folliculogenesis. Exposure to BPA can lead to dys­
functions on this axis and can lead to disorders in the fertility [93].
Reports are confirming the influence of EDCs on the functioning of
7
Biomedicine & Pharmacotherapy 155 (2022) 113730
the hypothalamus and pituitary gland [28,68,90]. Among
endocrine-disrupting chemicals, polychlorinated biphenyls (PCBs) are
considered to be the compounds that have the greatest impact on the
development of the brain as well as its functions [94].
Endocrine-disrupting chemicals can act by genomic or non-genomic
modifications of the pathways of nuclear receptors, non-steroidal re­
ceptors, and ion channels, and may be associated with abnormal growth,
inflammation, and epigenetic control [58,68]. Graceli et al. [68]
distinguished bisphenol A, phthalates, polychlorinated biphenyls, pol­
ybrominated diphenyl ethers, polybrominated biphenyls, dichlor­
odiphenyltrichloroethane, and atrazine as the EDCs with the greatest
influence on the functioning of the hypothalamus and pituitary gland.
These toxic substances have been proven to inhibit steroidogenesis and
interfere with the activity of TSH and FSH receptors [68]. Moreover,
BPA has been shown to influence the release of kisspeptin neuropeptides
from the hypothalamus and the secretion of GnRH, leading to a change
in the endocrine function of the hypothalamus [95]. As was noticed by
Pinilla et al. [82], the GnRH neurons are considered a major hierarchical
element of this system, and GnRH operates as the final output signal for
the hypothalamic regulation of the downstream elements of the HPG
axis. Adequate pulsatile secretion of GnRH is mandatory for proper
attainment and maintenance of reproductive function [82].
3.2. Ovary
The life of the female reproductive lifespan is determined by the
amount of the primordial follicle pool, which is established in the pre­
natal life [78]. EDCs negatively affect the processes that take place in the
ovary, such as primary follicles, follicle formation, follicle growth, and
activity, or steroidogenic activity. In this way, endocrine-disrupting
chemicals contribute to the onset of temporary or permanent infer­
tility in females [58,73]. EDCs contribute to the induction of ovarian cell
apoptosis [86]. In the research conducted by Shi et al. [73], the effect of
BPA, BPE, and BPS on follicular development was examined. The ex­
amination was carried out on pregnant mice, which were divided into
groups – the control group, and tested groups based on doses of EDCs –
0.5, 20, or 50 μg/kg/day doses of either BPA, or BPE, or BPS. The ani­
mals were treated with the appropriate doses on the day 11 of gestation.
During the research, the influence of prenatal exposure to BPA, BPE, and
BPS on the ovaries was analyzed. Prenatal exposure to BPA and BPE (0.5
and 50 μg/kg/day) and BPS (0.5, 20 μg/kg/day) resulted in significantly
more remain in germ cells nest compared to the control group. More­
over, BPA (0.5 μg/kg/day) and all doses of BPE and BPS exposure
significantly (P < ).01) reduced primary follicles almost doubled from
11 % for the control group to about 5 % for the test groups. In all study
groups administered bisphenols, a smaller number of primary follicles
was obtained, and in the case of secondary follicles, only BPA in any
doses induced a significantly (P < 0.01) lower number of follicles from
2.5 % in the control group to about 0.8 for 0.5 µg BPA /kg/day and 50 µg
BPA/kg/day and about 0.5 % for 20 μg/kg/day BPA [73]. The influence
of pesticides on the low weight of the ovaries of impaired ovaries and
pesticides on the rate of follicular arthritis have been described [96].
EDCs, and in particular phthalates, have been shown to reduce the pri­
mary antral follicles [78].
Aging of the ovaries is a natural process that leads to a decrease in the
quality and quantity of oocytes in the follicles. This process reduces
reproductive and endocrine capacity [97]. Ovarian aging can be influ­
enced by genetic, autoimmune, and also environmental factors, such as
endocrine-disrupting chemicals [98,99]. Exposure to EDCs has been
shown to affect ovarian dysfunction and aging, leading to infertility or
premature ovarian failure (POF). The mechanisms of action of EDCs may
be the induction of epigenetic changes, hormonal disorders, or inter­
action with hormone receptors [99].
Exposure to EDCs can also lead to early menopause (EM), polycystic
ovary syndrome (PCOS), and primary ovarian insufficiency (POI), or
even can reduce fertility and disrupt oogenesis [78,96]. The research
A. Kowalczyk et al.
carried out on a group of 30 women diagnosed with primary ovarian
insufficiency was tested for the analysis of serum phthalates [100]. The
mean concentration of monobutyl phthalate (MBP) in the serum was
statistically significantly higher in the POI group than in the control
group (8.45 ± 4.2 vs. 5.0 ± 3.47 ng/ml, p < 0.001). Other concentra­
tions of phthalate metabolites in serum, such as mono-ethyl phthalate
(MEP), mono- (2ethylhexyl) phthalate (MeHP), mono-benzyl phthalate
(MBzP), mono-methyl phthalate (MMP), mono-buthyl phthalate (MBP)
and BPA concentrations were higher in patients with POI, but the au­
thors found no significant differences. Among the examined EDCs, the
most important was MBP, the authors of which indicate the main factor
in the development of POI [100]. In the research conducted by Hu et al.
[87] in women with polycystic ovarian syndrome, higher levels of BPA
were found in the follicular fluid and blood serum of patients compared
to the control group of healthy women. In addition, neonatal exposure of
rats to BPA is reported to influence the development of PCOS in the adult
life of animals and disturbances in the ovarian and vaginal morphology
such as cyst formation [87,93]. Prenatal exposure to BPA and TCS is
associated with a decrease in follicle stimulating hormone concentration
and disturbed estrogen protein expression in ovarian granule cells,
which leads to a reduction in female fertility [86,93].
The di (2-Ethylhexyl) phthalate (DEHP; diethylhexyl phthalate) is an
endocrine disruptor that affects the functioning of the ovaries. In a study
by Brehm et al. [101] in pregnant mice treated with DEHP:
20 µg/kg/day, 200 µg/kg/day, 500 mg/kg/day and 750 mg/kg/day,
the effect of DEHP on 3 generations (F1, F2, F3) was analyzed. Exposure
to DEHP has been shown to have long-term health effects on posterity
(F2 and F3). Additionally, DEHP accelerates folliculogenesis and re­
duces the number of follicles, leading to premature reproductive aging
[101,102]. In turn, exposure to DEHP and phthalates induces cyst for­
mation in the ovaries. The dose of 200 µg/kg/day decreased the body
weight of the F3 mice. Prenatal exposure to DEHP resulted in a decrease
in ovarian weight in the studied generations, and a higher uterine
weight was recorded in the F1 generation, which may have been due to
an increase in estradiol levels [101].
Methoxychlor (MXC) is an organochlorine pesticide that disrupts
hormonal balance [102]. MXC causes decreased ovarian mass, ovulation
disorders, ovarian follicle atresia, as well as granule cell apoptosis, and
increased production of hydrogen peroxide, leading to DNA damage
[103]. The studies were carried out on 96 mice approximately 4 weeks
of age [103]. The animals were divided into 12 groups (N = 8) and
administered orally for 30 days to the MXC study groups and sesame oil
to the control groups. Four study groups were supplemented with MXC
32 mg/kg/day, and four were treated with 64 mg/kg/day. After 30 days
of exposure to MXC, the animals were euthanized, and then the ovaries
were analyzed, and the two study groups with the test doses and MXC
were supplemented for 60 days. Both doses of MXC significantly
increased the number of primary and pre-antral follicles compared to the
controls, and the dose of 64 mg/kg/day (10.4 ± 3.6) almost doubled the
number of atretic follicles compared to the controls (4.9 ± 3.5). More­
over, there were no changes in serum anti-Müllerian hormone (AMH)
levels in the study groups after exposure to MCX. In contrast, after 60
days of dosing with 64 mg/kg/day of MXC, treatment with MXC
significantly increased AMH levels (~ 1300 pg/ml) compared to the
control (~ 900 pg/ml AMH). Serum anti-Müllerian hormone is recog­
nized as a marker of the quantitative aspect of the ovarian reserve [103].
In prenatal exposure studies in mice, it has been shown that MXC con­
tributes to irregular oestrus cycles, lowering progesterone levels, as well
as stillbirths, and induction of oxidative stress causing damage to genetic
material, leading to abnormalities in oocyte structure of oocytes [104].
3.3. Uterus
The key hormones for maintaining the health of the uterus and the
reproductive cycle are estrogen and progesterone. In the case of disor­
ders between these two hormones, there is a loss of pregnancy, uterine
8
Biomedicine & Pharmacotherapy 155 (2022) 113730
pathology or even endometrial cancer [10,105]. These hormones are
also required to stimulate endometrial proliferation. Moreover, dieth­
ylstilbestrol and 17α-ethinylestradiol (EE2) act like estrogen via estro­
gen receptors and are associated with the induction of epigenetic
changes in the uterus [44,58]. In the presence of estrogen, uterine cells
produce fibroblast growth factor (FGF), which activates endometrial
FGF receptor signaling and results in endometrial cells. In turn, in the
presence of progesterone, the expression of the antiproliferative factor
(HAND2) occurs which inhibits FGF expression [105]. The uncontrolled
proliferation of the uterine lining leads to the risk of endometrial cancer
[106]. Moreover, exposure to EDCs may be associated with the risk of
developing endometrial cancer (EC) [106]. Leung et al. [107] in a study
in rats showed that exposure to 25 and 250 μg/kg BW/d) BPA affected
the oestrus cycle as the well as uterine physiology, including the growth
of endometrial cancer. Polycyclic aromatic compounds (PACs) such as
benzopyrene and halogenated flame retardants (HFRs) have also been
shown to contribute to uterine carcinogenesis [106].
The uterus is very sensitive to the effects of estrogen, therefore es­
trogenic compounds such as BPA may have an adverse effect on the
functioning of the uterus as well as on pregnancy [105]. Studies con­
ducted in mice have shown that bisphenol A causes decreased lutei­
nizing hormone as well as abnormal oestrus cycle and reduced fertility.
A study by Neff et al. [105] found that chronic exposure to low doses of
BPA (60 µg/kg/d) resulted in abnormal endometrial proliferation.
Moreover, BPA has been shown to increase FGF production, leading to
activation of the FGF receptor in the uterus of non-pregnant animals. At
the same time, a decrease in HAND2 expression was obtained, which
corresponded to an increase in FGF production. The authors concluded
that such pathway activation is the cause of uterine hyperplasia [105].
In addition, disturbances in the action of progesterone and estradiol
contribute to the development of uterine fibroids [108]. Leiomyomas
have their pathogenesis in EDC-induced female hormone imbalance
[109]. The research conducted by Zhang et al. [109] investigated the
effect of exposure to phthalates, toxic metals, and equol on the occur­
rence of leiomyomas and endometriosis in women aged 20–54 years.
The authors obtained the influence of the studied endocrine-disrupting
chemicals on the occurrence of fibroids, but no effect on endometri­
osis. Mercury (Hg) and equol had the greatest effect on fibroids [109].
Changes in the uterine endometrium are epigenetically regulated
[10,44,76]. Xiong et al. [10] proved that BPA alters histone modification
during endometrial decision-making, leading to impaired processes and
failure of embryo implantation. In their studies, the authors examined
the effect of bisphenol A on MLL1 (mixed-lineage leukemia 1) and EZH2
(enhancer of zeste homolog 2) in human endometrium stromal cells in
vitro. MLL1 and EZH2 are histone methylation transferases and play an
important role in endometrial proliferation and development [10].
MLL1 is a histone methyltransferase that can trimethylate histone H3.
BPA was shown to inhibit the expression of MLL1 at the concentrations
of 10 and 100 nM [10]. Furthermore, 10 nM and 10 µM BPA have an
influence on the morphology of endometrial cells during decision
making. EZH2, together with the catalytic subunit of the polycomb 2
repressive complex (PRC2), participates in the suppression of the gene
by the methylation of histone H3 in lysine 27. Lowering the level of
EZH2 leads to a reduction in the work of DNA damage in the uterine
muscle, which is involved in the neoplasm [10,44,76]. Furthermore, in
the studies conducted, the expression of the serine-threonine protein
kinase (SGK1) protein was found to be reduced by the estrogen receptor
in endometrial cells, leading to implantation failure in the mouse model
[10]. SGK1 transmits a growth factor signal from phosphoinositide 3-ki­
nase (PI3K) during implantation in response to embryonic serine pro­
teases [110]. Exposure to very small amounts of bisphenol A (<1 nmol)
has been shown to increase the production of reactive oxygen species
(ROS), damaging genetic material, and the expression of inflammatory
factors in the uterus [10].
Endometriosis is an estrogen-dependent endocrine disorder charac­
terized by endometrial hyperplasia with pain, bleeding, and infertility as
A. Kowalczyk et al.
common complications [48,111]. This condition is associated with an
increased risk of developing epithelial ovarian cancer. Environmental
factors such as endocrine-disrupting chemicals are believed to
contribute to the development of the endometriosis [111–113].
Bisphenol A, polychlorinated biphenyls, dioxins, organochlorine pesti­
cides, and phthalate esters are associated with the appearance of
endometriosis, but also primary and ovarian failure or miscarriage [48,
112,114]. In the studies conducted by Ao et al. [115] on women who
had miscarried before the 20th week of pregnancy, the effect of EDCs on
miscarriage was examined. During the study, urine samples were
collected and tested for BPA, bisphenol AF (BPAF), and BPS. In all tested
samples, bisphenols were detected at the level of 78–90 %, of which BPA
was the most frequently detected (87 %). Studies have shown an asso­
ciation between these bisphenol analogues and the risk of unexplained
miscarriage [115]. DEHP, which is one of the phthalate esters, has a
much higher concentration in the plasma and urine of women suffering
from endometriosis compared to healthy women [116]. In the study
conducted by Nazir et al. [116] on 50 women aged 20–40 struggling
with endometriosis, it was shown that sick women had a higher con­
centration of phthalate esters compared to healthy women. The authors
found an association between DEHP exposure and endometriosis [116].
3.4. Pregnancy
Exposure to EDCs during critical stages of development, such as
embryogenesis, and implantation, can modulate the immune response,
and promote inflammation that during pregnancy leads to preterm
birth, pre-eclampsia, or reduced fetal growth [7,48].
During early pregnancy, a series of events occur that begin with
conception, then the blastocyst develops and implants in the uterus,
which gradually becomes susceptible to the implantation process [75,
117]. Uterine receptivity, i.e. the ability to accept the embryo, occurs in
the middle luteal phase, during which progesterone and estrogen are
crucial, and then decisive takes place [118]. During which an increase in
progesterone levels is observed, endometrial cell differentiation is
induced, and the uterus becomes susceptible to embryo implantation.
Estrogen and progesterone modulate the production of cytokines,
growth factors, and prostaglandins that are important for the implan­
tation [117,118]. Another key factor is calcium, which is also involved
in fertilization. These factors contribute to the preparation of the
endometrium for the implantation [118]. During implantation, molec­
ular events are also crucial [117,118]. Any disruption of genes encoding
factors and calcium channels (cationic channel of the transient receptor
potential cation channel subfamily V (TRPV) member 5 and 6 (TRPV5
and TRPV6), or mucin 1 (MUC1), leukemia inhibitory factor (LIF), ho­
meobox A10 (HOXA10), needed for implantation, resulting in infertility
and implantation disorder [117,118]. Homeobox 10 and LIF are markers
of embryo implantation that are involved in endometrial decisionuali­
zation and receptivity [119]. Mucin 1, on the other hand, is a trans­
membrane proteoglycan that regulates uterine perceptiveness and
enables implantation [117]. TRPV is involved in the exchange of cal­
cium ions [118]. Exposure to endosulfan, an organochlorine pesticide,
has been shown to result in dysregulation and expression of HIXA10 and
has been associated with implantation failure [119]. In turn, studies in
mice showed that 2 mg/kg of body weight 1-nitropyrene (1-NP)
inhibited the leukemia inhibitory factor (LIF) pathway, as well as
reduced the expression of estrogen and progesterone receptors, thus
interfering with endometrial proliferation and implantation capacity
[120]. It has been proven that abnormal expression of RPV5, TRPV6,
PMCA1, and NCX1 genes caused by exposure to EDCs negatively affects
calcium ion transport and interferes with implantation, and may even
lead to apoptosis and necrosis [118]. Plasma membrane Ca2+-ATPase 1
(PMCA1) and Na+/Ca2+ exchanger 1 (NCX1) participate in the flow of
calcium ions [118].
In the studies on pregnant sow and 10 day blastocyst, the effect of
17β-estradiol was analyzed [121]. Furthermore, the intergenerational
9
Biomedicine & Pharmacotherapy 155 (2022) 113730
influence of E2 in the livers of one-year-old female offspring (F1) was
also studied. The animals were divided into groups according to the
doses of E2 – the first group took the acceptable daily intake (ADI) of
0.05 μg/kg body weight/day, and the second group get a dose similar to
the level of no observed effects level (NOEL) equal to 10 μg/kg body
weight/day, the last one – high dose of 1000 μg/kg body weight/day,
and the control group which was not supplemented with E2. During the
analysis of gene expression, as well as the analysis of DNA methylation
changes, including in the liver, and endometrium of sows, induction of
tissue-specific changes in the expression of cell cycle regulatory genes (e.
g., DCKN2D, CDC42EP4, GADD45A, MGMT, CCN1, etc.), tumor sup­
pressor genes (e.g. HIC1, BGN, PSAT1, etc.), two genes specific for
methylation - DNMT3a, MeCP2 in the studied pigs compared to the
control group. The highest increase of CDKN2D expression in the
endometrium was shown for groups of animals with NOEL and HIGH
doses (9.0, 15.2 times increased). In turn, exposure to NOEL and HIGH
doses of E2 induced hypomethylation in the liver tissues of sows and in
blastocysts. In the F1 generation, higher DNA hypomethylation was
found in the liver than in other tissues [121].
Endocrine-disrupting chemicals such as, for example, phthalates
have the ability to cross the fetal-placental barrier and interfere with
placental development and embryonic growth [7,75]. Toxic metals,
bisphenol A, polycyclic aromatic hydrocarbons, and phthalates present
in the blood of pregnant women negatively affect the birth weight of
children [122]. There are associated phthalates with fluctuations in the
concentrations of steroid hormones like estradiol and estriol during
pregnancy [122]. During the research, the prenatal exposure to the birth
weight of the newborn was assessed [123]. The study included 1857
pregnant women from whom urine and blood samples were collected
and analyzed for EDCs – OC, phenols, metals, PFAS. During the tests,
BPA (88 %) and PCB (74 %) were most often detected in the tested
samples. It was found that exposure to mixtures of OC and metals was
associated with lower birth weight, with trans-nanochlor and lead
having the greatest impact, reducing the mean birth weight by 38 g (95
%) and 39 g (95 %), respectively. In contrast, PFAS, phenols, and
phthalates were not associated with birth weight [123]. In turn, expo­
sure to organochlorine pesticides may be associated with decreased
fertility, including the inability to become pregnant [124].
EDCs have been suggested to cause preterm birth that occurs before
37 weeks gestation and is associated with health complications and in­
fant mortality [125]. Exposure to phthalates and parabens has been
shown to increase the risk of preterm birth, as shown in studies on
pregnant women. During the research, the impact of using hair oils
containing parabens and phthalates was analyzed on the time of birth
[125]. Phthalates alter the inflammatory pathways associated with
preterm birth, while parabens disrupt the signaling of estrogen and
progesterone receptors. Of the 154 tested pregnant women, 7 % gave
birth prematurely and used the oils before [125]. In addition, these
substances endanger embryos and fetuses during pregnancy, limiting
their development [3].
3.4.1. Embryo
During embryonic development, which is critical for genome pro­
gramming, environmental changes that occur may result in changes in
gene expression or cell function, affecting cell metabolism [7]. During
embryogenesis, cell differentiation is controlled by growth factors as
well as hormones, and this can be interfered with by EDCs [7]. The
success of embryo development depends on the previous stages of
oogenesis and therefore depends on the quality of the oocytes [126].
Early developmental exposure to these substances is of key importance
as embryos and fetuses are very sensitive to toxins and changes in
endocrine management [7]. BPA has been detected in the amniotic fluid,
newborn blood, and placenta. Low-dose (nM) BPA has been found to
have a similar affinity to 17β-estradiol in stimulating a cellular response.
There is a relationship between high levels of BPA and phthalates in the
urine and preterm birth [7].
A. Kowalczyk et al.
In the research conducted by Zhou et al. [127] in rat embryos, it was
found that EDCs to which mothers were exposed exhibited an effect of
increasing the thickness of the interventricular septum. Moreover, the
exposure of females during pregnancy to endocrine-disrupting chem­
icals results in low birth weight of the offspring as well as a risk of
premature birth [3]. In addition, exposure to endocrine disruptors of the
embryo may be associated with birth defects (teratogenic), impaired
fertility during sexual maturity, and an increased risk of neurological
and cardiovascular diseases [106,128]. The embryo exposed to EDCs
shows reduced development and growth. In turn, studies on chickens
proved that the exposure to 220 ppm of BPA in chicken embryos
increased their mortality by 60 %, and the remaining embryos were
characterized by malformations or deformation of the bones and skull
[128].
In studies on bovine embryos, 0.05 mg/ml of biphenyl A and
biphenyl S (BPS) were tested for the oocyte maturation process and
further for in vitro embryonic development [126]. For the study, oocytes
were aspirated post-mortem from cows’ ovaries to the nutrient medium
and then matured. Mature cumulus-oocyte complexes (COCs) were
subjected to IVF, after fertilization, the blastocysts were retained at the
2–4 cell stage, 8–16 cell stage, and the morula stage. 0.05 mg/ml BPA
and 0.05 mg/ml BPS were tested on these groups [126]. Granular cells
secrete Anti-Mullerian Hormone (AMH), which mediates communica­
tion with the oocyte and the maturation process. Incubation of oocytes
with 0.05 mg/ml BPA and BPS during oocyte maturation decreased the
amount of AMH and inhibited the growth and development of cow
embryos as well as fragmentation of their DNA due to bisphenol [126].
Organochlorine pesticides and atrazine have a strong influence on
blastocyst formation and development, and MXC may directly influence
genetic abnormalities during embryo development [96].
3.4.2. Fetus
Fetal growth depends on fetal factors, endocrine regulation, and
interaction between the placenta, mother, and fetus [7129,130].
Essential hormones in fetal growth are insulin-like growth factors (IGF1,
IGF2), insulin, thyroid hormones, growth hormone, leptin, progester­
one, estrogen, and cortisol [122,129]. Disturbances in the content of
these compounds result in disorders in the fetal growth [129].
During pregnancy, hormonal disorders lead to difficulties in the
maintenance and development of pregnancy, and even to its loss [18,
131]. EDCs are transmitted to the fetus via the placenta [7]. The fetus is
protected at an early stage from exogenous estrogens by
alpha-fetoprotein, which is an estrogen-binding plasma protein. It is
noted that some endocrine disruptors may have a low affinity for this
protein and thus be unprotected. The fetus will then be exposed to these
substances. EDCs, through their receptor affinity, are able to bind to
hormone receptors and thus be transferred to the fetus. Moreover,
endocrine-disrupting chemicals negatively affect cell differentiation,
and any defects in the tissues and their genome can be passed on to the
offspring [58]. However, the fetus is very sensitive to toxic substances,
and its exposure negatively affects subsequent reproductive abilities, but
also cognitive and behavioral disorders, such as autism, attention deficit
hyperactivity disorder, or cardiovascular diseases, including hyperten­
sion, and coronary artery disease [7,18,130,131].
EDCs are toxic to the placenta, disrupting its functioning, and this
translates directly into the development of the fetus [18]. EDCs can
negatively affect birth weight, and placental weight [131]. The use of
personal care products containing phthalates, parabens, and biphenyls
has been shown to affect the development of the fetus and placenta
through the presence of these substances in the circulatory system
[7131]. The placenta, as an organ necessary for the development of the
fetus, is involved in the transport between the mother and the fetus. The
placenta of fetal origin develops from the blastocyst trophectoderm,
which is made up of stem cells (cytotrophoblast cells – CTB). EDCs have
been shown to limit the differentiation of CTB cells through epigenetic
changes or changes in gene regulation. Also, the expression of steroid
10
Biomedicine & Pharmacotherapy 155 (2022) 113730
hormone receptors in the placenta influences the susceptibility of the
structure to hormonal disorders. BPA has the ability to methylate as well
as apoptosis of placental cells [131]. Exposure to polycyclic aromatic
hydrocarbons and polybrominated diphenyl ethers has been shown to
modify the IGF2 content in the placenta, which disrupts the balance
between the developing fetus and the mother [75,129]. In studies in
mice, IGF2 overexpression has been found to lead to placental and fetal
hypertrophy [132]. EDCs are able to alter imprinting in the placenta of
mice, resulting in altered placental function in mice [75]. Moreover,
epigenetic changes caused by EDCs contribute to the occurrence of ab­
normalities and neoplasms in the placenta [75]. Epidermal growth
factor (EGF) and epidermal growth factor receptor (EGFR) are important
to placental physiology, which stimulates placental growth and func­
tion, including proliferation, and EGFR is a marker of proliferation in
trophoblasts. Hypermethylation of EGF and EGFR following contact
with endocrine-disrupting chemicals has been shown to lead to com­
plications such as pre-eclampsia in pregnant females. The mechanism of
action of endocrine-disrupting chemicals on DNA methylation distur­
bance is not yet known [75]. In a study conducted by Shi et al. [73],
authors analyzed the influence of biphenyls in 0.5, 20, or 50 µg/kg/day
doses in pregnant mice. It has been proven, that prenatal exposure to
EDCs, particularly biphenyls, results in impaired estrous cycles, a
reduction in follicle count, and fertility in adult mice [73]. Moreover,
biphenyl stimulates germ cell breakdown in developing ovaries [73].
Imprinting is important in the regulation of the placental tran­
scriptome, where its loss results in an imbalance between the embryo
and the mother, and also results in a lower weight of the placenta [7,75].
microRNAs (miRNAs) play a role in the epigenetic control of gene
expression by acting post-transcriptionally inhibiting gene expression
[7]. These short, non-coding miRNAs are important in the proliferation,
embryonic development, embryonic development, and apoptosis of cells
whose synthesis is influenced by estrogen signaling. Therefore, BPA can
interfere with miRNA expression [7].
Exposure of the fetus to diethylstilbestrol (DES) results in the
development of pathology in adulthood. It has been proven that the risk
of developing clear cell adenocarcinoma (CCA) of the vagina and uterus,
the development of endometriosis, premature menopause, and
abnormal gametogenesis, is also associated with unfavorable indicators
of conception and pregnancy, and in men, it resulted in testicular hy­
perplasia and cryptorchidism [48,78,128]. DES was widely prescribed
to pregnant women in the 1970 s as a preventive measure for miscar­
riage [48]. There are also reports that exposure of prenatal to EDCs
results in DNA methylation of genes encoding steroid hormone re­
ceptors, which affects subsequent reproductive disorders [113].
The effect of EDCs on female reproduction is shown in Fig. 2 (Fig. 2).
4. Conclusions
Endocrine-disrupting chemicals adversely affect various body sys­
tems. In turn, in the reproductive system, they contribute, among others,
to premature aging of the ovaries, dysfunction, and pathology of the
ovaries and uterus, endometriosis, polycystic ovary syndrome, prema­
ture births, or epigenetic changes in DNA methylation disturbing cell
proliferation and even their apoptosis. The substances are common in
the environment and show the ability to accumulate. In females, they
were found in the follicular fluid, milk, and plasma. There is a need to
further investigate the effects of EDCs on the female reproductive sys­
tem. Despite the health risks presented, especially for female repro­
ductive health, the use of EDCs is increasing every day. Long-term
exposure to these substances of animals, humans, and the environment
is not yet fully understood. More research is needed to understand the
impact of EDCs on health and the environment and to develop methods
for the disposal of EDCs. Moreover, there is a need to develop technol­
ogies for the production of products without the addition of EDCs to
reduce human exposure to these substances.
A. Kowalczyk et al. Biomedicine & Pharmacotherapy 155 (2022) 113730

Fig. 2. The effect of ECDs on female reproduction [1–3,5–7,14,58,71,72].

Funding conceptualization and writing—original draft preparation; Alicja

Kowalczyk and Marcjanna Wrzecińska writing the final version of the
The APC/BPC is financed/co-financed by Wrocław University of manuscript. All authors have read and agreed to the published version of
Environmental and Life Sciences. the manuscript.

Ethics approval and consent to participate Coflict of interest statement

Not applicable. No potential conflict of interest was reported by the authors.

Consent for publication Data Availability

Not applicable. No data was used for the research described in the article.

Availability of data and material Acknowledgements

Not applicable. Not applicable.

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