It has been demonstrated that exposure to 25–250 ng/kg BPA per day in the prenatal period in rats can induce changes in the gross ovarian anatomy (31). It is well documented that exposure to BPA in the prenatal period is associated with cystic endometrial hyperplasia, ovarian cysts, and a reduction in the primordial pool of follicles in mouse ovaries, indicating an association between BPA and increased proliferation of ovarian cells mediated by the estrogenic pathway (31,32). Studies have shown an increase in the percentage of ovarian tissue that is occupied by antral follicles and also a decreased percentage of corpora lutea in rats groups treated with BPA for 3 months compared with controls, which is suggestive of a reduced number of oocytes (31,32). Prenatal exposure to BPA can also result in a notable increase of unilateral or bilateral ovarian bursae filled with blood, which is a sign of reproductive ageing in 6-month-old mice (33). Furthermore, other studies have suggested that following accidental exposure to BPA, there is an increase in meiotic disturbances in mice, such as aneuploidy in oocytes (34,35).

Ovarian cancer was reported in 2018 to be the seventh leading cause of cancer-associated mortality worldwide, and its 5-year survival rate is <20% in women (36). Several studies have suggested an association between exposure to BPA and ovarian malignancy, as BPA mimics the effects of estrogen (37,38). In addition, human ovarian cancer cells express elevated levels of estrogen receptors (ERs) compared with normal or benign ovarian lesion cells (36). Long-term exposure to BPA could lead to an increased incidence of cystic endometrial hyperplasia or ovarian cysts, which are premalignant lesions (39,40). In both normal and malignant ovarian cells, there are two isoforms of ERs, ERα and ERβ, and ERβ expression in both normal and benign lesion cells is higher compared with ERα (41–43). The expression of ERα is higher in malignant tumors cells (44). ERα acts as an oncogene, while ERβ acts like a tumor suppressor. In normal cells, the expression of ERβ is significantly higher compared with ERα, but in ovarian tumoral cells the expression of ERα is 40–60% higher than ERβ (44). ERα expression is higher in malignant cells compared with normal cells, while ERβ expression is higher in normal cells compared with malignant cells (44). Multiple studies have shown that ERβ is considered to offer a protective role against cancer by promoting inhibition of cell migration and proliferation, or by inducing apoptosis (36,45). Increased levels of both ER isoforms can be found in ovarian cancer compared with normal non-neoplastic ovaries, and the expression of this receptor is associated with unfavorable progression (46). Studies have reported that estrogens are capable of activating the proliferation of surface epithelial cells of ovaries and also mediating growth response and gene expression to produce changes in cancer cells (47,48). In addition, it is understood that in postmenopausal women, estrogens can induce an increasing incidence of ovarian cancer (49,50). Furthermore, multiple studies on animal models suggest that continuous exposure to BPA from the early stages of life can lead to a higher prevalence of alterations in the estrous cycle. Thus, BPA induces changes in ovarian morphology and ovulation, but also an increased incidence of endometriosis, cystic endometrial hyperplasia, proliferation lesions of the oviduct, stromal polyps, atypical hyperplasia, leiomyomas or adenomyosis (39,51).

Analysis via PCR has shown that mRNA is altered at different levels during the processes of ovarian tumorigenesis. Upregulated mRNAs, such as CDK4, cyclin D1, cyclin A, proliferating cell nuclear antigen, E2F transcription factor (E2F)3 and E2F1, are associated with the cell cycle and cell proliferation, while other downregulated mRNAs, such as p21, GADD45 and Weel-1, are also associated with cell proliferation; and all of these cell cycle genetically-programed mechanisms have been shown to be modified by exposure to BPA (52). Multiple studies have demonstrated that BPA plays an important role in ovarian cancer by inducing activation of cell signaling pathways, such as the MAPK/ERK and PI3K/AKT pathways (53). Prenatal exposure to BPA can lead to inhibition of the expression of apoptotic genes, such as CAD, FAS, RAIDD, FADD, BOK and caspase, and can induce the expression of pro-survival genes, such as Mcl-1 and Bcl-x1, and also the growth of ovarian cancer cells via the specific signaling axis ER-CXCL12-CXCR-4 (54,55).

Ovarian cancer is considered to be highly fatal as it is often diagnosed in terminal stages when intraperitoneal metastasis is present (56). Intraperitoneal metastasis is induced by a decrease of E-cadherin, which leads to a loss of cell adhesion (57). The switch from E-cadherin to N-cadherin expression is a key element in the dynamics of neoplastic cells (57). N-cadherin can induce the overexpression of matrix metalloproteinases (MMPs), which alters the extracellular matrix and the basal membrane, therefore promoting tumor invasion (57). MMP-9 and MMP-2 differ from other types of MMPs due to their ability to degrade type IV collagen (58,59). It has been demonstrated that BPA stimulates granulosa lutein cells so that they express MMP-9, and elevated levels of MMP-9 and MMP-2 are associated with the metaplastic transformation of normal ovarian cells (39,60–62).

Not only BPA is associated with the occurrence of ovarian cancer; other EDCs, such as methoxychlor [1,1,1-trichlor-2,2-bis-(4-methoxyphenyl)ethane; MXC] and triclosan (TCS) act synergistically. These chemical compounds are ubiquitous in everyday products, such as toothpaste, deodorants and hygiene products (23). Recent studies have shown these two compounds at relatively low doses can induce the growth of BG-1 ovarian cancer cells by regulating p21, cyclin D1 and Bax genes, which are associated with the cell cycle and apoptosis (62,63). In experimental models, BG-1 cells treated with TCS or MXC resulted in cyclin D1 upregulation, p21 downregulation and activation of Bax gene transcription. In addition, the ER antagonist ICI 182,780 can reverse the MXC and TSC-induced alterations of these particular genes, which suggests that the actions of these compounds are mediated by signaling pathways that are ER-dependent (63).

Although endogenous estrogen has a higher potency compared with xenoestrogen, the latter is ubiquitous in nature and is more dangerous due to its resistance to enzymatic or chemical degradation (64).

Breast cancer is considered to be the most prevalent cancer type in female patients, and the main risk factors are due to genetic, lifestyle or environmental influences (65). EDCs are considered to contribute to the increasing incidence of breast cancer, particularly in critical periods of breast development, when mammary gland cells are the most predisposed to atypical differentiation (66–68). In vitro studies have demonstrated that exposure of human mammary gland cancer cells to BPA increases proliferation and oxidative stress, even at low doses (demonstrated for 10⁻¹⁰ M) for long-period exposure, of minimum 60 days (69,70).

In immunohistochemical analysis of animal model, mammary gland tumors are investigated for the presence or the absence of three key receptors. In experimets with animal models, the long term effect of BPA was observed in gestational monkeys, demonstrating a significant increase in the density of mammary buds, and also an overall increase in the volume of mammary epithelium in newborns (71). A study on rats revealed that exposure during intrauterine life to different doses of BPA (2.5, 25, 250 and 1,000 µg/kg/day) can lead to an exponential increase in the number of hyperplastic ducts at postnatal day 50 in a dose-independent manner and also a significant increase in these numbers even at a low dose at postnatal day 90 (72). Another study on rats demonstrated that the incidence of mammary tumors would increase following the administration of different doses of BPA (0.25, 2.5, 25 and 250 µg/kg/day) during both the gestational and lactation periods. Preneoplastic lesions were already observed at day 50. Atypical ductal hyperplasia or neoplastic modifications, like ductal carcinomas in situ, in mammary gland cells were diagnosed in the rats exposed to BPA. At postnatal day 200, malignant tumors were observed in female rats exposed to a low BPA dose of only 0.25 µg/kg/day, which were histopathologically diagnosed as benign fibroadenoma or adenocarcinomas. These findings demonstrate a direct association between BPA and breast cancer (73).

ERα and ERβ are expressed in greater than 60% of human breast cancers and are ligand-regulated transcription factors that control breast cancer proliferation (74,75). Multiple studies have suggested that progesterone and estradiol are key factors in the malignant transformation of mammary gland cells, by increasing division and proliferation of cells in both mature and immature human breast tissue (74,75). It has been demonstrated that the therapy of estrogen replacement in postmenopausal women leads to an increased proliferation of terminal duct lobular units that represent the target site of breast cancer (74,75). Additionally, breast cell proliferation increases in adulthood, when levels of progesterone and estradiol are higher. Estradiol determines the proliferation of mammary cells, which are positive for ERα expression. This effect is determined indirectly by growth factors, which are produced as a response to estrogenic regulation or directly by promoting the transcription of genes involved in the cell cycle, such as c-Myc (76). Furthermore, ERs are known to determine non-genomic signaling events in the extra-nuclear site of mammary cancer cells, which stimulate anti-apoptotic and proliferative signaling pathways as a response to growth factors or ligand binding. This non-genomic action is associated with the rapid response by activating estradiol pathways, which involves the action of MAPK, Src, PI3K, protein kinase-C and heterotrimeric G-proteins in the membrane or cytoplasm of target cells (77). Some biological effects, including cell growth, DNA synthesis, cell death and cell cycle progression, and also processes that are associated with ER cytoplasm re-localization, are attributed to activation by estradiol stimulation (78).

BPA functions as an xenoestrogen, and a number of studies with animal models have shown that it has important implications in breast cancer (79,80). Results from animals studies have been used to predict what may occur in the human body, which lead to finding that the greater risk of breast cancer is associated with mutations of the susceptibility genes BRCA1 and BRCA2 in mammary gland cancer cells. These two genes are considered to act as tumor suppressor genes, resulting in hereditary ovarian or breast cancer syndrome (HBOC) if they undergo mutations in the germline, which is inherited in an autosomal-dominant manner. Individuals that present HBOC syndrome also have a higher risk of developing prostate cancer (8.6% for BRCA1 mutations and 20% for BRCA2 mutations), pancreatic cancer (1–3% for BRCA1 mutations and 2–7% for BRCA2 mutations) and melanoma (81). The incidence of HBOC syndrome accounts for approximately 6% of all breast cancer cases; however, the incidence of breast cancer accounts for greater than 70% of all HBOC cancer cases (79–83). Previous studies have demonstrated that women that exhibit mutations in BRCA1 and BRCA2 have a higher susceptibility to the negative effects of exposure to environmental BPA (79,80,82). Furthermore, other studies have reported that the effects of BPA on adult breast tissue, both normal or cancerous, are associated with cell proliferation, the induction of chemoresistance in ER-positive cells and also the increase of mammosphere size (82,83).

BPA acts through activating vascular endothelial growth factor, which is associated with angiogenesis in breast tumor, activation of the MAPK signaling pathway, STAT3 signaling, DNA repair, and changes in genes associated with apoptosis by DNA methylation (84–87). The expression of the long non-coding RNA HOX transcript antisense RNA, a key player in different neoplasias, including breast and ovarian cancer, inactivation of p53, and cell death or modulation of proliferation kinetics in human breast epithelial cells are also stimulated by BPA (84–87). These studies on the effects of BPA in humans suggest that BPA can play an important role in breast epithelial cells and carcinogenesis.

Considering the carcinogenic effect of different plastics on the human body, BPA is not the only EDC with important effects on health. Studies suggest other polychlorinated biphenyls, such as PCB-153 at a relatively high concentration (35 µM), are associated with cell proliferation by regulating ERK1/2 activation (86–88). Furthermore, multiple studies suggest that organochlorine insecticides, such as p,p′-DDT (dichloro-diphenyl-tri-chloroethane) (DDT), p,p′-DDE and chlordane, are risk factors for breast cancer (87,88). It has been suggested that DDT can lead to cancer progression by interfering with androgen signaling pathways and promoting the proliferation of breast cancer cells (88). Notably, it has been reported that in patients with breast cancer, exposure to DDT has negative effects on overall survival (88). Most available data in the literature suggest that organochlorine compounds influence the progression and pathogenesis of breast cancer.