- Open Access
Bisphenol a and the female reproductive tract: an overview of recent laboratory evidence and epidemiological studies
Reproductive Biology and Endocrinology volume 12, Article number: 37 (2014)
Bisphenol A (BPA) is a high production volume monomer used for making a wide variety of polycarbonate plastics and resins. A large body of evidence links BPA to endocrine disruption in laboratory animals, and a growing number of epidemiological studies support a link with health disorders in humans. The aim of this review is to summarize the recent experimental studies describing the effects and mechanisms of BPA on the female genital tract and to compare them to the current knowledge regarding the impact of BPA impact on female reproductive health. In particular, BPA has been correlated with alterations in hypothalamic-pituitary hormonal production, reduced oocyte quality due to perinatal and adulthood exposure, defective uterine receptivity and the pathogenesis of polycystic ovary syndrome. Researchers have reported conflicting results regarding the effect of BPA on premature puberty and endometriosis development. Experimental studies suggest that BPA’s mechanism of action is related to life stage and that its effect on the female reproductive system may involve agonism with estrogen nuclear receptors as well as other mechanisms (steroid biosynthesis inhibition). Notwithstanding uncertainties and knowledge gaps, the available evidence should be seen as a sufficient grounds to take precautionary actions against excess exposure to BPA.
There is growing concern regarding the impact of environmental pollutants on animal and human reproduction . For instance, a substantial number of laboratory rodent studies suggest that the plasticizer Bisphenol A (BPA) may act as a reproductive toxicant, although many uncertainties remain as to the actual risk for humans . BPA is one of the highest volume chemicals produced world-wide and is used in the manufacture of plastics and epoxy resins that are pervasive in our environment and in our daily lives . BPA has estrogenic activity and binds to the α- and, to a lesser extent, β-estrogen receptors (ER) in vitro and in vivo. Moreover, BPA can also inhibit the activity of endogenous estrogens and/or disrupt estrogen nuclear hormone receptor action . There is additional clear evidence of a 17β-estradiol, BPA, and diethylstilbestrol (DES) membrane-binding site with a pharmacologic profile that differs from the classical ER. This membrane receptor may be implicated in triggering non-genomic actions of xenoestrogens and it has been demonstrated its existence both in pancreatic β cells and in pancreatic α cells .
BPA also affects other relevant endocrine activities, including the thyroid hormone pathway and binding to glucocorticoid and androgen receptors as well as more complex interferences with the central nervous system and immune system [3, 5].
In experimental studies, BPA has been shown to affect many reproductive indices, such as ovary, uterus and vagina weights (indicating estrogenic action); egg shape; fertilization rate; number of live-born neonates per litter; distance between the genital pore and the anus in newborns (indicating the degree of masculinization or feminization of external genitalia); time of vaginal opening (indicating the start of female puberty); and onset of the estrous cycle (indicating sexual maturity) [2, 7–9]. The evidence in the literature suggests that BPA exposure in humans may impair fertility .
In fact, we recently observed that women with BPA concentrations above the limit of detection were significantly more represented in the infertile population than in healthy controls . In the last years, a few reviews have been published regarding the impact of BPA on human health [12–14]. These data are mainly derived from epidemiological studies, even though cross-sectional analyses cannot establish causality . Furthermore, in human studies the possibility of an additive effect with other prevalent endocrine disrupting compounds should not be overlooked .
To the best of our knowledge, despite the vast literature of experimental animal and mechanistic studies, there are no reviews summarizing the toxicological studies regarding BPA’s effect on the female reproductive system. The aim of the present review is to synthetize and evaluate the experimental evidence regarding the impact of BPA on the female genital tract and to relate this evidence to the current knowledge of BPA’s effect on human reproduction.
In particular, we focused on the effect of BPA on the hypothalamic-pituitary-ovarian axis (HPOA), the ovary, the uterus and the development of diseases, such as polycystic ovarian syndrome and endometriosis.
A systematic MEDLINE (PubMed) search was performed using the following keywords: “BPA”, “endocrine disruptors”, “fertility”, “reproductive health”, “genital tract”, “BPA and fertility”, “GnRH alterations and BPA”, “BPA and puberty onset”, “BPA and oocytes”, “BPA and primordial follicles”, “BPA and uterus”, “BPA and polycystic ovarian syndrome” and “BPA and endometriosis”. Relevant articles published in the last 10 years (from 2004 since November 2013) were selected. We considered experimental studies, epidemiological studies and previous reviews. Criteria for inclusion and exclusion were established before the bibliographic search. Studies published in languages other than English were considered if an English abstract was available. When evaluating experimental studies, we did not consider studies in which the effects of perinatal exposure were analyzed on the second generation. Moreover, studies in which BPA was administered with other endocrine disruptors were not considered as the aim of this study was to examine the potential direct association of BPA with female reproductive disorders; therefore, a discussion on the complex issue of the “cocktail” effects of endocrine disorders is outside the scope of this paper.
BPA actions on the hypothalamic-pituitary-ovarian axis
During critical periods of prenatal and postnatal development, the hormonal milieu is crucial for the correct organization of neuroendocrine circuits that coordinate sex-specific physiology . BPA exposure has been associated with alterations in brain sexual differentiation and modifications in the expression of gonadotropin-releasing hormone (GnRH), hypothalamic ER and luteinizing hormone (LH) [16–18].
Altered brain sexual differentiation has been demonstrated in perinatally treated rodents. In particular, BPA has been shown to alter the composition of the following two sexually dimorphic areas located in the hypothalamus: the sexually dimorphic nucleus (SDN) and the anteroventral periventricular nucleus (AVPV) . BPA’s endocrine disrupting action could explain this effect; however, an epigenetic mechanism has been hypothesized as well . Indeed, Kundakovic et al.  observed that in the hypothalamus of female offspring treated during gestation, the ER-α gene (Esr1) was hypomethylated for a downregulation of DNA methyltransferase 1 (DNMT1), an epigenetic regulator. However, unexpectedly, hypomethylation was associated with decreased Esr1 mRNA levels, suggesting that additional mechanism are involved in the transcriptional regulation of this gene .
The AVPV nucleus is fundamental for gonadotropin release and the LH surge [16–18]. The neural circuit that coordinates reproductive function is sexually differentiated; the female AVPV is nearly twice the size of the male AVPV, and neurons that express tyrosine hydroxylase (TH, rate-limiting enzyme for dopamine synthesis) are more abundant [17, 19]. These sex differences are due to female development occurring in the absence of estrogen, whereas the perinatal male brain is exposed to high levels of estrogens synthesized locally through the aromatization of testicular testosterone . Indeed, during critical periods of perinatal development, aromatase is present in specific brain regions .
Contrasting results have been reported regarding the effect of BPA on the number of TH-positive cells. Rubin et al.  observed a significant decrease in the number of TH-positive cells in the female population and no differences in males, while Patisaul  found an increased in the number of TH-positive cells in the male population. Such differences may be attributed to the species (rat or mouse in  and , respectively) or to the developmental exposure window (only neonatal or from organogenesis to neonatal in  and , respectively). AVPV-TH-containing neurons interact with GnRH fibers and modulate GnRH production . GnRH secretion is pulsatile and acts on gonadotrope cells of the anterior pituitary to stimulate the synthesis and release of LH and follicle-stimulating hormone (FSH). The frequency of the GnRH pulses determines the predominant hormone produced. LH is produced with fast GnRH pulses, and FSH is favored with slow pulse frequencies . Fernandez et al.  observed that female rats exposed to BPA during the neonatal phase had a higher GnRH pulse frequency and an increased number of peaks. Nevertheless, LH release in their study was lower basally and after GnRH stimulation, suggesting a qualitative, rather than quantitative, alteration in the gonadotrope hormone production. Monje et al.  even found that rats exposed in the neonatal period were incapable of producing an estradiol-induced LH surge. The decrease in basal and GnRH-induced LH release caused by BPA may be the consequence of the increased GnRH pulse frequency leading to a desensitization of the pituitary. Alternatively, a direct effect of BPA on LH secretion may occur . Kisspeptins (KiSS) are critical hypothalamic regulators of GnRH secretion . BPA exposure in rodents may alter the KiSS-regulation of the LH-surge system via a different mechanism that is dependent on the developmental window. Acute neonatal exposure seems to lead to downregulation , whereas prolonged perinatal (prenatal to neonatal) treatment seems to elicit an up-regulation of KiSS-positive AVPV cells in male rats . Indeed, Xi et al.  observed that in mouse pups exposed to BPA both in utero (starting from gestation day 1) and postnatally (21–49), the expression levels of KiSS-1 mRNA were increased. Conversely, for pups exposed only postnatally (21–49) no noticeable changes in gene expression levels were detected, indicating a higher susceptibility during the prenatal window.
Overall, an influence of BPA-induced HPOA changes on the time of pubertal onset is plausible. Some studies have observed that early vaginal opening occurs in BPA-treated rodents (a sign of advanced puberty onset) [9, 21]. This event may be explained by a premature hypothalamic-pituitary maturation induced by BPA treatment during the pre- and/or postnatal windows. However, the few human studies do not provide consistent results regarding a possible effect of BPA on pubertal development. Wolff et al.  investigated the association of exposure to phenols, phthalates, and phytoestrogens with pubertal stages in a multiethnic longitudinal study of 1,151 girls. They found that these endocrine-active agents had only limited association with pubertal development. In particular, the authors observed some weak association with phthalates and phytoestrogens but not with phenols. Conversely, in a case–control study by Qiao et al. , girls with premature puberty had significantly higher BPA serum levels. Therefore, the relationship between exposure to BPA and puberty onset in humans is still largely unknown. It should be noted that most animal studies were planned to gain mechanistic insights; thus, subcutaneous injection was often used, and in some cases, the administered doses were quite high. Upon real-life exposure by ingestion, dermal contact or inhalation, the majority of BPA is conjugated to BPA-glucuronide in the liver, which is a form devoid of interaction with nuclear receptors . More experimental studies are needed to investigate BPA effects on HPOA and puberty onset using treatment routes and dose levels relevant to human environmental exposures. Table 1 shows BPA effects on the hypothalamic-pituitary-ovarian axis in animal experiments.
BPA actions on the ovary
As already noted for the actions on the HPOA, BPA has different effects on the ovary depending on the time of exposure.
Maternal exposure affects the earliest stages of oogenesis in the developing fetal ovary. The resulting meiotic defects increase the likelihood that embryos produced by the exposed females in adulthood will be chromosomally abnormal. In particular, several studies on in utero exposure of mice as well as rhesus monkeys revealed disturbances during the prophase events of meiosis and an increase in multiple oocyte follicles (MOFs) [29–31].
Disturbances during prophase events seem to mainly involve synapsis and recombination between homologous chromosomes. An interesting study by Susiarjo et al.  on pregnant mice exposed to BPA revealed synaptic abnormalities, such as “incomplete synapsis” (partial or complete synaptic failure of a single chromosome pair), end-to-end associations between non-homologous chromosomes and an increased risk of aneuploidy.
MOF occur due to improper cyst breakdown. In fact, in rodents, oocytes at birth are clustered in cysts and individual primordial follicles become detectable only when the cysts breakdown 3–5 days after birth. Usually, the cyst breakdown is initiated upon decreased estrogen levels after birth. BPA, acting as a synthetic estrogenic compound, may counteract this event [29, 32, 33]. Furthermore, gene ontology analysis suggests that BPA acts to downregulate genes involved in the mitotic cell cycle, raising the possibility that fetal BPA exposure may limit expansion of the primordial germ cell population .
Intrauterine exposure to BPA elicits analogous effects on early oogenesis and follicle formation in mice [29, 31] as in rhesus monkeys . This mammal is considered a valid model for human reproductive physiology ; hence, the findings of experimental studies raise concerns about the impact of BPA exposure on human reproductive programming.
Most studies conducted on rodents exposed to BPA during the early postnatal period report an initial follicle recruitment with a consequent decrease in the primordial follicle reserve as well as an increased incidence of MOFs [33, 35, 36]. These results were obtained even in a study conducted on lambs, a species in which the follicular development trajectory is similar to humans . Follicle activation has been confirmed by Chao et al. , who found that upon BPA exposure, mouse ovaries had significantly decreased primordial follicles but increased primary, secondary and antral follicles. In contrast with other studies, Karavan et al.  observed an increased percentage of primordial follicles in neonatal mice injected with BPA during the first four postnatal days and examined on postnatal day 5. Table 2 shows effects of pre and postnatal BPA exposure on oocytes
In a recent study conducted by Lee et al. on adult female rats (8 weeks of age) exposed orally to 1 μg/kg body weight (BW) or 100 μg/kg BW for 90 days, caspase-3 activation was significantly increased by BPA exposure, causing an augmentation of follicular atresia and luteal regression . BPA-induced apoptosis in granulosa cells has already been reported by Whetherill et al. , but the precise mechanism remains unclear. In addition, Lee et al. observed that 17β-estradiol synthesis was decreased via downregulation of aromatase. The steroidogenic acute regulatory protein (StAR) and aromatase cytochrome P450 (P450arom) appeared to be targeted by BPA . The occurrence of negative effects on the ovary using lower doses of BPA (1 μg/kg BW), rather than the doses used in other experiments, should trigger further studies.
In vitro studies have demonstrated that BPA can interfere with ovarian hormone production.
A study conducted on antral follicles isolated from 32-day-old mice proved that BPA significantly decreased progesterone, dehydroepiandrosterone, androstenedione, estrone, testosterone, and estradiol production . Because the BPA’s mechanism of action of is life stage-dependent, it cannot be excluded that BPA exposure close to or during sexual maturity mainly elicits an inhibiting action on steroid biosynthesis. This inhibitory effect has been observed even in isolated porcine granulosa cells  and in human luteal cells obtained from the corpora lutea of woman undergoing surgery for non-endocrine gynecological diseases . In both studies, incubating cells with 0.1, 1, and 10 μM of BPA induced a significant decrease in progesterone production. Conversely, no inhibitory action was observed in a study by Dominuigez et al.  conducted on human granulosa-lutein cells collected from women undergoing in vitro fertilization (IVF) treatments. Instead, an increased metalloproteinase 9 (MMP-9) secretion was observed, suggesting a BPA effect on the stability of the ovarian extracellular matrix.
In vitro studies have also been conducted on human oocytes [42, 43]. Genes involved in DNA double-strand generation, signaling and repair were up-regulated in fetal oocytes exposed to BPA . Machtinger et al.  treated human oocytes obtained from patients undergoing IVF cycles with 0, 20, and 200 ng/ml BPA. In accordance with animal studies, they observed a negative effect on cell cycle progression, spindle architecture and chromosome organization.
The oocyte alterations observed in animal experiments and on human oocytes in vitro may explain the poor ovarian response to IVF treatments and the recurrent miscarriages observed in women with higher serum BPA concentration . In particular, increased BPA levels are correlated with a decrease in peak estradiol levels and decreased oocyte retrieval number [10, 44]. A similar mechanism of action may underlie the association between female infertility and higher BPA levels that has been consistently reported in the results of the Italian biomonitoring study PREVIENI[11, 45]. Interestingly, in this study, the higher serum BPA levels in infertile women were also correlated with upregulation of some nuclear receptors (ERα, ERβ, Androgen receptor, and Pregnane-X receptor) in the serum mononuclear cells [11, 45]. It is still unclear whether chemical compounds are linked with first-trimester spontaneous abortion . Some studies reported a higher serum BPA concentration in women with recurrent miscarriages compared to healthy controls [46, 47]. Zheng et al.  even observed that the risk of unexplained recurrent spontaneous abortion increased progressively with increasing serum BPA levels. Sugiura-Ogasawara et al.  suggested that the mechanism leading to an increased incidence of miscarriages from BPA exposure is an increase in embryonal chromosome abnormalities.
BPA and its actions on the uterus
Mendoza-Rodriguez et al.  showed that when BPA was administered to rats in their drinking water (approximate dose 1.2 mg/kg BW/day) during pregnancy and lactation, there was a resultant significant increase in the thickness of the uterine epithelia and stroma in the adult female offspring. The majority of BPA-exposed offspring also had reduced epithelial apoptosis and a downregulation of α-estrogen receptor expression in epithelial cells during estrus. In vitro studies show that BPA in other endometrial cells seems to induce different effects. Indeed, decreased proliferation was observed both in human endometrial fibroblasts isolated from hysterectomy specimens  and in human endometrial endothelial cells . In particular, in the latter case, the authors found that mRNA levels of gene products involved in the cell cycle, cell division and cytoskeletal organization were affected .
Although BPA is not a genotoxic carcinogen, a possible endocrine-related tumorigenic effect might be elicited by BPA exposure during critical periods of differentiation. Atypical hyperplasia, stromal polyps of the uterus as well as sarcoma of the uterine cervix were observed in adult female offspring of mice injected with BPA during organogenesis. These lesions were completely absent in controls: however, the incidence was low and did not show a meaningful dose–response relationship; therefore, no conclusion could be drawn . Nevertheless, the increased proliferative activity and reduction of programmed cell death in uterine epithelial cells upon intrauterine exposure, as observed in BPA-exposed rats by Mendoza-Rodriguez et al. , may support an increased predisposition to cancer and/or a tumor-promoting effect . In contrast with these results, human epidemiological studies do not seem to support the relationship between BPA and endometrial disorders . Indeed, Hiroi et al.  unexpectedly found that in patients with complex endometrial hyperplasia, serum BPA was significantly lower compared to both the control and simple endometrial hyperplasia groups. Even in postmenopausal endometrial cancer patients, serum BPA was significantly lower than either the control or simple endometrial hyperplasia groups.
There is a growing body of literature to suggest that BPA exposure may lead to defective uterine receptivity [53–55]. Varayoud et al.  observed a lower pregnancy rate and a reduction of implantation sites (live fetuses plus resorption sites) in female rats injected with BPA during the first postnatal week. Downregulation of homeobox A10 (Hoxa10) expression may explain, at least in part, the defective uterine receptivity. A different effect was observed by Bromer et al.  in mice from dams injected in utero during organogenesis (gestation days 9–16). In these cases Hoxa10 up-regulation and increased binding of ERα to the Hoxa10 Estrogen Responsive Element (ERE) were observed. As in other instances, it cannot be excluded that the discrepancy between effects observed in  and  is due to the different exposure windows, i.e., neonatal vs. prenatal, respectively. Alternatively, the drop in implantation rate could be due to a direct BPA effect on the development and transport of the pre-implantation embryo . However, this possible explanation is less likely because the adverse effects of BPA mostly result from endocrine modulation rather than from target cell toxicity. An influence of BPA exposure on implantation success can also be surmised. Indeed, it has been observed that women with higher urinary BPA had higher implantation failure during IVF treatments . Table 3 shows BPA effects on the uterus in animal experiments
BPA and polycystic ovary syndrome (PCOS)
PCOS is the most common endocrinopathy among women of reproductive age. It is characterized by hyperandrogenism, insulin resistance and chronic anovulation. A role for BPA as an endocrine disruptor in the pathogenesis of PCOS has been recently proposed . Several studies have reported higher BPA levels in premenopausal women with PCOS when compared to regularly ovulating women [57, 58]. In addition, BPA treatment in rats, both during gestation or during the neonatal period, induced the development of a PCOS-like syndrome in adulthood [49, 59].
A bidirectional mechanism has been hypothesized to underlie the relationship between PCOS and BPA, involving both BPA-increased insulin resistance and free androgen index as well as chronic, low-grade inflammation . In fact, Kandaraki et al.  found a significant positive association between testosterone and androstenedione with BPA levels in women with PCOS. The increase in the androgen level may be explained by different mechanisms. The exposure of rat ovarian theca-interstitial cells to BPA in vitro results in elevated testosterone synthesis . The increase in GnRH/LH pulse frequency observed in BPA experiments, as mentioned above, may be involved in this event . Moreover, BPA alters androgen metabolism in the liver and acts as a potent ligand of sex hormone-binding globulin (SHBG); thus, it can displace androgens from SHBG resulting in increased levels of serum free androgens . However, some studies have hypothesized that elevated BPA is a consequence and not a cause of PCOS because women with PCOS have higher circulating testosterone levels than do healthy women, and elevated androgen concentrations decrease BPA clearance .
BPA and endometriosis
Endometriosis is a gynecological disorder characterized by endometrial glands and stroma that grow outside the uterine cavity. This ectopic endometrium responds to hormonal signaling; therefore, fetal exposure to estrogen is positively associated with endometriosis in adulthood [60, 61].
Due to its ability to interact with ERs, BPA may be involved in the occurrence of estrogen-dependent pathologies. Strong epidemiological data link in utero exposure to the potent estrogen-mimicking drug DES and the occurrence of endometriosis later in adult life ; however, much less is known about exposure to BPA. In a pilot study, Cobellis et al.  investigated the possible relationship between serum levels of both BPA and the closely related, albeit much less investigated, bisphenol B (BPB) and the occurrence of endometriosis. These authors did not find BPA or BPB in any of the sera of healthy control women (n = 11). In contrast, the researchers found at least one of the bisphenols in 63.8% of sera of the 58 patients with endometriosis; 51.7% and 27.6% of these samples had detectable BPA or BPB levels, respectively, while 15.5% of patients had detectable levels of both bisphenols. In a study conducted on 465 women undergoing laparoscopy/laparotomy and 131 patients with endometriosis diagnosed by pelvic resonance imaging, Buck Louise et al.  found a positive association between urinary phthalates and endometriosis, while urinary BPA was not associated with endometriosis. In addition, Itoh et al.  analyzed the total urinary BPA concentration of 166 infertile patients and did not observe any association with endometriosis. It cannot be overlooked that different biomarkers of exposure may have different meanings. Therefore, the urinary BPA concentration (as used in  and ) provides information on the overall environmental exposure, while serum BPA  may be a more direct indicator of the internal exposure of target tissues, as outlined in the PREVIENI study on infertile Italian women [11, 44].
A study on mice suggested a possible mechanism by which exposure to BPA may result in a predisposition to endometriosis. Signorile et al.  injected pregnant mice with BPA (100 and 1000 μg/kg/day) from day 1 of gestation to 7 days after delivery and found endometriosis-like structures in the adipose tissue surrounding the genital tract of a number of their sexually mature (3 month-old) offspring. Only one case was observed in the control group. Therefore, the authors suggested that endometriosis may be caused by alterations in the proper axial development of the Mullerian system during embryogenesis by changes in genetic-epigenetic programming. As previously mentioned, studies using parenteral routes of administration may have limited, or even no, relevance to human risk assessment. On the other hand, contrary to experimental studies, the human cross-sectional studies cannot give any insight on a possible effect on programming.
Considering the conflicting results, the hypothesis of a relationship between BPA and endometriosis needs to be further explored by robust and soundly designed human biomonitoring studies.
An increasing number of studies indicate that exposure to BPA is associated with a variety of disorders of the female reproductive system. Toxicological risk assessment of the potential human health effects rely mainly on experimental studies that should be methodologically robust and provide information on exposure routes and levels relevant to humans but also on epidemiological studies, when available . In this appraisal of the recent literature, we aimed to integrate and compare the results of both laboratory and human studies on BPA, which is among the most widespread endocrine disrupters. In relation to effects on the HPOA, animal experiments revealed alterations in brain sexual differentiation, higher GNRH pulsatility, alterations in the estradiol-induced LH surge and advanced puberty onset, as demonstrated by an early vaginal opening [16–18, 21]. However, in women, the influence of BPA on the pathogenesis of premature puberty has not been confirmed. Some authors found a correlation between pubertal stages and the BPA serum level , while others observed conflicting results .
The higher risk of infertility and poor ovarian response to IVF treatments described in women with higher BPA concentrations suggest effects on oocyte quality and ovarian function in women [4, 10, 12, 44, 45]. In experimental studies, perinatal exposure has revealed disturbances in prophase events, and an increase in MOFs and initial follicle recruitment with increased numbers of primary, secondary and antral follicles [29–33, 35, 36]. In vitro studies on ovarian cells isolated from the ovary of both animals and women have also demonstrated an inhibiting action on steroid biosynthesis [38–40]. Thus, human and animal data show a degree of consistency.
BPA may reduce apoptosis and increase proliferation in the endometrium of perinatally exposed rats ; however, no tumorigenic effect of BPA on the uterus has been shown in adult women . Additionally, rodent studies reported a defective uterine receptivity [53, 55]; this event may be related to the higher risk of infertility or implantation failure observed during IVF treatments.
It has been suggested that BPA may be involved in the occurrence of some gynecological diseases. The association between BPA exposure and PCOS is supported by both human studies [57, 58] and in vivo animal studies [49, 59]. Indeed, BPA may induce an increase in androgen levels, while androgens decrease BPA clearance [57–59]. On the other hand, the involvement of BPA in the pathogenesis of endometriosis is doubtful; endometriosis-like structures were detected in mice perinatally injected with BPA . Conversely, epidemiological studies did not yield consistent results [63, 64]. Differences between laboratory evidence and epidemiological study results may be due to BPA dose, to the route of administration and to the time of exposure. Humans are exposed to BPA in a continuous manner and the main source of exposure is ingestion of contaminated food or water. Conversely, in most of the experimental studies reported in this review, BPA is administered only for a limited period through parenteral treatments. On the other hand, experimental studies allow a more detailed study of molecular events in target tissues, and, most important, allow for the investigation of long term effects of developmental exposures, which are important for BPA as well as for other endocrine disrupters. For obvious ethical reasons, controlled studies of the long-term exposure effects cannot be performed on pregnant women or children. The experimental studies provide some important information, namely, the BPA mode of action in some reproductive tissues may be highly dependent on the window of exposure [17, 18, 53, 54]. The effects on HPOA [16–18, 21], steroid biosynthesis in the ovary [37–40], or androgen-SBHG binding [57, 58] clearly show that the potential harmful effects of BPA on female reproduction are more complex than “estrogenic” action. As for human biomonitoring studies, more insight would be gained by a consistent use of the biomarkers of exposure, e.g., urine vs serum [62–64]; the integration of the biomarkers of exposure with molecular markers of endocrine action [11, 45, 58]; and the use of bio-banks to investigate long-term effects.
Although the association between BPA exposure and some gynecological disorders is still doubtful, there is currently sufficient evidence to prompt precautionary actions against excess exposure to BPA.
NDS, Maddalena M and VG are interns of the Department of Gynecologic-Obstetrical and Urological sciences, S. Andrea Hospital. AM is the director of the Food and Veterinary Toxicology Unit, Food Safety and Public Health Dept, Istituto Superiore Sanità, Roma. RM is a PhD, M.D and professor at “Ferrara University”. DC and Massimo M are PhD, M.D., and full professors at “Sapienza” University of Rome (Department of Gynecologic-Obstetrical and Urological sciences, S. Andrea Hospital). DC, AM and RM have previously collaborated on the “Previeni Project”, study in model areas on the environmental and health impact of some endocrine disrupters: living environment, reproductive outcomes and repercussions in childhood.
Anteroventral periventricular nucleus
Estrogen responsive element
Estrogen receptor α gene
In vitro fertilization
Multiple oocyte follicles
Polycystic ovarian syndrome
Aromatase cytochrome P450
Sexually dimorphic nucleus
Sex hormone-binding globulin
Ssteroidogenic acute regulatory protein
Gregoraszczuk EL, Ptak A: Endocrine-Disrupting Chemicals: Some Actions of POPs on Female Reproduction. Int J Endocrinol. 2013, 2013: 828532-
Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, Vandenbergh JG, Walser-Kuntz DR, Vom Saal FS: In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007, 24: 199-224. 10.1016/j.reprotox.2007.06.004.
Rubin BS: Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol. 2011, 127: 27-34. 10.1016/j.jsbmb.2011.05.002.
Caserta D, Mantovani A, Marci R, Fazi A, Ciardo F, La Rocca C, Maranghi F, Moscarini M: Environment and women's reproductive health. Human Reprod Update. 2011, 17: 418-33. 10.1093/humupd/dmq061.
Wetherill YB, Akingbemi BT, Kanno J, McLachlan JA, Nadal A, Sonnenschein C, Watson CS, Zoeller RT, Belcher SM: In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol. 2007, 24 (2): 178-98. 10.1016/j.reprotox.2007.05.010.
Alonso-Magdalena P, Laribi O, Ropero AB, Fuentes E, Ripoll C, Soria B, Nadal A: Low doses of bisphenol A and diethylstilbestrol impair Ca2+ signals in pancreatic alpha-cells through a nonclassical membrane estrogen receptor within intact islets of Langerhans. Environ Health Perspect. 2005, 113: 969-77. 10.1289/ehp.8002.
Cabaton NJ, Wadia PR, Rubin BS, Zalko D, Schaeberle CM, Askenase MH, Gadbois JL, Tharp AP, Whitt GS, Sonnenschein C, Soto AM: Perinatal exposure to environmentally relevant levels of bisphenol A decreases fertility and fecundity in CD-1 mice. Environ Health Perspect. 2011, 119 (4): 547-52.
Maffini MV, Rubin BS, Sonnenschein C, Soto AM: Endocrine disruptors and reproductive health: the case of bisphenol-A. Mol Cell Endocrinol. 2006, 254–255: 179-86.
Nah WH, Park MJ, Gye MC: Effects of early prepubertal exposure to bisphenol A on the onset of puberty, ovarian weights, and estrous cycle in female mice. Clin Exp Reprod Med. 2011, 38: 75-81. 10.5653/cerm.2011.38.2.75.
Ehrlich S, Williams PL, Missmer SA, Flaws JA, Ye X, Calafat AM, Petrozza JC, Wright D, Hauser R: Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF. Hum Reprod. 2012, 27: 3583-92. 10.1093/humrep/des328.
Caserta D, Ciardo F, Bordi G, Guerranti C, Fanello E, Perra G, Borghini F, La Rocca C, Tait S, Bergamasco B, Stecca L, Marci R, Lo Monte G, Soave I, Focardi S, Mantovani A, Moscarini M: Correlation of endocrine disrupting chemicals serum levels and white blood cells gene expression of nuclear receptors in a population of infertile women. Int J Endocrinol. 2013, 2013: 510703-
Rochester JR: Bisphenol A and human health: A review of the literature. Reprod Toxicol. 2013, 42: 132-55.
Cantonwine DE, Hauser R, Meeker JD: Bisphenol A and Human Reproductive Health. Expert Rev Obstet Gynecol. 2013, 8 (4): 329-335. 10.1586/17474108.2013.811939.
Balabanič D, Rupnik M, Klemenčič AK: Negative impact of endocrine-disrupting compounds on human reproductive health. Reprod Fertil Dev. 2011, 23: 403-16.
Talsness CE, Andrade AJ, Kuriyama SN, Taylor JA, Vom Saal FS: Components of plastic: experimental studies in animals and relevance for human health. Philos Trans R Soc Lond B Biol Sci. 2009, 27: 2079-96.
Monje L, Varayoud J, Munoz-de-toro M, Luque EH, Ramos JG: Exposure of neonatal female rats to bisphenol A disrupt hypothalamic LHRH pre-mRNA processing and estrogen receptor alpha expression in nuclei controlling estrous cyclicity. Reprod Toxicol. 2010, 30: 625-34. 10.1016/j.reprotox.2010.08.004.
Patisaul HB, Fortino AE, Polston EK: Neonatal ginestein or bisphenol-A exposure alters sexual differentiation of the AVPV. Neurotoxicol Teratol. 2006, 28: 111-118. 10.1016/j.ntt.2005.11.004.
Rubin BS, Lenkowski JR, Schaeberle CM, Vandenberg LN, Ronsheim PM, Soto AM: Evidence of altered brain sexual differentiation in mice exposed perinatally to low environmentally relevant levels of bisphenol A. Endocrinology. 2006, 147: 3681-3691. 10.1210/en.2006-0189.
Wolstenholme JT, Rissman EF, Connelly JJ: The role of Bisphenol A in shaping the brain, epigenome and behavior. Horm Behav. 2011, 59: 296-305. 10.1016/j.yhbeh.2010.10.001.
Kundakovic M, Gudsnuk K, Franks B, Madrid J, Miller RL, Perera FP, Champagne FA: Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure. Proc Natl Acad Sci U S A. 2013, 110 (24): 9956-61. 10.1073/pnas.1214056110.
Fernandez M, Bianchi M, Lux-Lantos V, Libertun C: Neonatal exposure to bisphenol A alters reproductive parameters and gonadotropin releasing hormone signalling in female rats. Environ Health perspect. 2009, 117: 757-762. 10.1289/ehp.0800267.
Maranghi F, Mantovani A: Targeted toxicological testing to investigate the role of endocrine disrupters in puberty disorders. Reproductive Toxicology. 2012, 33: 290-6. 10.1016/j.reprotox.2012.01.009.
Navarro VM, Sánchez-Garrido MA, Castellano JM, Roa J, García-Galiano D, Pineda R, Aguilar E, Pinilla L, Tena-Sempere M: Persistent impairment of hypothalamic KiSS-1 system after exposures to estrogenic compounds at critical periods of brain sex differentiation. Endocrinology. 2009, 150: 2359-67. 10.1210/en.2008-0580.
Bai Y, Chang F, Zhou R, Jin PP, Matsumoto H, Sokabe M, Chen L: Increase of anteroventral periventricular kisspeptin neurons and generation of E2-induced LH-surge system in male rats exposed perinatally to environmental dose of bisphenol-A. Endocrinology. 2011, 152: 1562-71. 10.1210/en.2010-1042.
Xi W, Lee CK, Yeung WS, Giesy JP, Wong MH, Zhang X, Hecker M, Wong CK: Effect of perinatal and postnatal bisphenol A exposure to the regulatory circuits at the hypothalamus-pituitary-gonadal axis of CD-1 mice. Reprod Toxicol. 2011, 31: 409-17. 10.1016/j.reprotox.2010.12.002.
Wolff MS, Britton JA, Boguski L, Hochman S, Maloney N, Serra N, Liu Z, Berkowitz G, Larson S, Forman J: Environmental exposures and puberty in inner-city girls. Environ Res. 2008, 107: 393-400. 10.1016/j.envres.2008.03.006.
Qiao L, Zheng L, Cai D: Study on the levels of bisphenol A, octylphenol, 4-nonylphenol in serum of precocious girls. Wei Sheng Yan Jiu. 2010, 39: 9-12.
Doerge DR, Twaddle NC, Vanlandingham M, Fisher JW: Pharmacokinetics of bisphenol in neonatal and adult CD-1 mice: inter-species comparisons with Sprague–Dawley rats and rhesus monkeys. Toxicol Lett. 2011, 207: 298-305. 10.1016/j.toxlet.2011.09.020.
Zhang HQ, Zhang XF, Zhang LJ, Chao HH, Pan B, Feng YM, Li L, Sun XF, Shen W: Fetal exposure to bisphenol A affects the primordial follicle formation by inhibiting the meiotic progression of oocytes. Mol Biol Rep. 2012, 39: 5651-7. 10.1007/s11033-011-1372-3.
Hunt PA, Lawson C, Gieske M, Murdoch B, Smith H, Marre A, Hassold T, VandeVoort CA: Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey. Proc Natl Acad Sci USA. 2012, 109: 17525-30. 10.1073/pnas.1207854109.
Susiarjo M, Hassold TJ, Freeman E, Hunt PA: Bisphenol A exposure in utero disrupts early oogenesis in the mouse. PLos Genet. 2007, 12: 3-
Rivera OE, Varayoud J, Rodríguez HA, Muñoz-de-Toro M, Luque EH: Neonatal exposure to bisphenol A or diethylstilbestrol alters the ovarian follicular dynamics in the lamb. Reprod Toxicol. 2011, 32: 304-12. 10.1016/j.reprotox.2011.06.118.
Karavan JR, Pepling ME: Effects of estrogenic compounds on neonatal oocyte development. Reprod Toxicol. 2012, 34: 51-6. 10.1016/j.reprotox.2012.02.005.
Lawson C, Gieske M, Murdoch B, Ye P, Li Y, Hassold T, Hunt PA: Gene expression in the fetal mouse ovary is altered by exposure to low doses of bisphenol A. Biol Reprod. 2011, 84: 79-86. 10.1095/biolreprod.110.084814.
Rodríguez HA, Santambrosio N, Santamaría CG, Muñoz-de-Toro M, Luque EH: Neonatal exposure to bisphenol A reduces the pool of primordial follicles in the rat ovary. Reprod Toxicol. 2010, 30 (4): 550-7. 10.1016/j.reprotox.2010.07.008.
Chao HH, Zhang XF, Chen B, Pan B, Zhang LJ, Li L, Sun XF, Shi QH, Shen W: Bisphenol A exposure modifies methylation of imprinted genes in mouse oocytes via the estrogen receptor signaling pathway. Histochem Cell Biol. 2012, 137: 249-59. 10.1007/s00418-011-0894-z.
Lee SG, Kim JY, Chung JY, Kim YJ, Park JE, Oh S, Yoon YD, Yoo KS, Yoo YH, Kim JM: Bisphenol A exposure during adulthood causes augmentation of follicular atresia and luteal regression by decreasing 17β-estradiol synthesis via downregulation of aromatase in rat ovary. Environ Health Perspect. 2013, 121: 663-9. 10.1289/ehp.1205823.
Peretz J, Gupta RK, Singh J, Hernandez-Ochoa I, Flaws JA: Bisphenol A impairs follicle growth, inhibits steroidogenesis, and downregulates rate-limiting enzymes in the estradiol biosynthesis pathway. Toxicol Sci. 2011, 119: 209-17. 10.1093/toxsci/kfq319.
Grasselli F, Baratta L, Baioni L, Bussolati S, Ramoni R, Grolli S, Basini G: Bisphenol A disrupts granulosa cell function. Domest Anim Endocrinol. 2010, 39: 34-9. 10.1016/j.domaniend.2010.01.004.
Romani F, Tropea A, Scarinci E, Dello Russo C, Lisi L, Catino S, Lanzone A, Apa R: Endocrine disruptors and human corpus luteum: in vitro effects of phenols on luteal cells function. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2013, 31: 170-80. 10.1080/10590501.2013.782180.
Dominguez MA, Petre MA, Neal MS, Foster WG: Bisphenol A concentration-dependently increases human granulosa-lutein cell matrix metalloproteinase-9 (MMP-9) enzyme output. Reprod Toxicol. 2008, 25: 420-5. 10.1016/j.reprotox.2008.05.059.
Brieño-Enríquez MA, Reig-Viader R, Cabero L, Toran N, Martínez F, Roig I, Garcia Caldés M: Gene expression is altered after bisphenol A exposure in human fetal oocytes in vitro. Mol Human Reprod. 2012, 18: 171-83. 10.1093/molehr/gar074.
Machtinger R, Combelles CM, Missmer SA, Correia KF, Williams P, Hauser R, Racowsky C: Bisphenol-A and human oocyte maturation in vitro. Human Reprod. 2013, 28: 2735-45. 10.1093/humrep/det312.
Bloom MS, Kim D, Vom Saal FS, Taylor JA, Cheng G, Lamb JD, Fujimoto VY: Bisphenol A exposure reduces the estradiol response to gonadotropin stimulation during in vitro fertilization. Fertil Steril. 2011, 96 (3): 672-677. 10.1016/j.fertnstert.2011.06.063.
Caserta D, Bordi G, Ciardo F, Marci R, La Rocca C, Tait S, Bergamasco B, Stecca L, Mantovani A, Guerranti C, Fanello EL, Perra G, Borghini F, Focardi SE, Moscarini M: The influence of endocrine disruptors in a selected population of infertile women. Gynecol Endocrinol. 2013, 29: 444-7. 10.3109/09513590.2012.758702.
Sugiura-Ogasawara M, Ozaki Y, Sonta S, Makino T, Suzumori K: Exposure to bisphenol A is associated with recurrent miscarriage. Hum Reprod. 2005, 20 (8): 2325-9. 10.1093/humrep/deh888.
Zheng YM, Wang Y, Zhao J, Dai YH, Luo XM, Shen ZJ, Chen X, Yuan W, Shen YP: Association between serum bisphenol-A and recurrent spontaneous abortion: a 1:2 case–control study, China [abstract]. Zhonghua Liu Xing Bing Xue Za Zhi. 2012, 33 (8): 841-5.
Mendoza-Rodríguez CA, García-Guzmán M, Baranda-Avila N, Morimoto S, Perrot-Applanat M, Cerbón M: Administration of bisphenol A to dams during perinatal period modifies molecular and morphological reproductive parameters of the offspring. Reprod Toxicol. 2011, 31: 177-83. 10.1016/j.reprotox.2010.10.013.
Aghajanova L, Giudice LC: Effect of bisphenol A on human endometrial stromal fibroblasts in vitro. Reprod Biomed Online. 2011, 22: 249-56. 10.1016/j.rbmo.2010.12.007.
Bredhult C, Sahlin L, Olovsson M: Gene expression analysis of human endometrial endothelial cells exposed to Bisphenol A. Reprod Toxicol. 2009, 28: 18-25. 10.1016/j.reprotox.2009.03.006.
Newbold RR, Jefferson WN, Padilla-Banks E: Prenatal exposure to bisphenol a at environmentally relevant doses adversely affects the murine female reproductive tract later in life. Environ Health Perspect. 2009, 117: 879-85. 10.1289/ehp.0800045.
Hiroi H, Tsutsumi O, Takeuchi T, Momoeda M, Ikezuki Y, Okamura A, Yokota H, Taketani Y: Differences in serum bisphenol a concentrations in premenopausal normal women and women with endometrial hyperplasia. Endocr J. 2004, 51: 595-600. 10.1507/endocrj.51.595.
Varayoud J, Ramos JG, Bosquiazzo VL, Lower M, Muñoz-de-Toro M, Luque EH: Neonatal exposure to bisphenol A alters rat uterine implantation-associated gene expression and reduces the number of implantation sites. Endocrinology. 2011, 152: 1101-11. 10.1210/en.2009-1037.
Bromer JG, Zhou Y, Taylor MB, Doherty L, Taylor HS: Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. FASEB J. 2010, 24: 2273-80. 10.1096/fj.09-140533.
Xiao S, Diao H, Smith MA, Song X, Ye X: Preimplantation exposure to bisphenol A (BPA) affects embryo transport, preimplantation embryo development, and uterine receptivity in mice. Reprod Toxicol. 2011, 32: 434-41.
Ehrlich S, Williams PL, Missmer SA, Flaws JA, Berry KF, Calafat AM, Ye X, Petrozza JC, Wright D, Hauser R: Urinary bisphenol A concentrations and implantation failure among women undergoing in vitro fertilization. Environ Health Perspect. 2012, 120: 978-83. 10.1289/ehp.1104307.
Tarantino G, Valentino R, Di Somma C, D'Esposito V, Passaretti F, Pizza G, Brancato V, Orio F, Formisano P, Colao A, Savastano S: Bisphenol A in polycystic ovary syndrome and its association with liver-spleen axis. Clin Endocrinol. 2013, 78: 447-53. 10.1111/j.1365-2265.2012.04500.x.
Kandaraki E, Chatzigeorgiou A, Livadas S, Palioura E, Economou F, Koutsilieris M, Palimeri S, Panidis D, Diamanti-Kandarakis E: Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab. 2011, 96: 480-4. 10.1210/jc.2010-1658.
Fernández M, Bourguignon N, Lux-Lantos V, Libertun C: Neonatal exposure to bisphenol a and reproductive and endocrine alterations resembling the polycystic ovarian syndrome in adult rats. Environ Health Perspect. 2010, 118: 1217-22. 10.1289/ehp.0901257.
Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Michels KB, Hunter DJ: In utero exposure and the incidence of endometriosis. Fertil Steril. 2004, 82: 1501-1508. 10.1016/j.fertnstert.2004.04.065.
Signorile PG, Spugnini EP, Mita L, Mellone P, D’Avino A, Bianco M, Diano N, Caputo L, Rea F, Viceconte R, Portaccio M, Viggiano E, Citro G, Pierantoni R, Sica V, Vincenzi B, Mita DG, Baldi F, Baldi A: Pre-natal exposure of mice to bisphenol A elicits an endometriosis-likephenotype in female offspring. Gen Comp Endocrinol. 2010, 168: 318-25. 10.1016/j.ygcen.2010.03.030.
Cobellis L, Colacurci N, Trabucco E, Carpentiero C, Grumetto L: Measurement of bisphenol A and bisphenol B levels in human blood sera from healthy and endometriotic women. Biomed Chromatogr. 2009, 23: 1186-90. 10.1002/bmc.1241.
Buck Louis GM, Peterson CM, Chen Z, Croughan M, Sundaram R, Stanford J, Varner MW, Kennedy A, Giudice L, Fujimoto VY, Sun L, Wang L, Guo Y, Kannan K: Bisphenol A and phthalates and endometriosis: the Endometriosis: Natural History, Diagnosis and Outcomes Study. Fertil Ster. 2013, 100: 162-9. 10.1016/j.fertnstert.2013.03.026.
Itoh H, Iwasaki M, Hanaoka T, Sasaki H, Tanaka T, Tsugane S: Urinary bisphenol-A concentration in infertile Japanese women and its association with endometriosis: A cross-sectional study. Environ Health Prev Med. 2007, 12: 258-64. 10.1007/BF02898033.
We thank the American Journal Experts for the editing of the manuscript.
The authors declare that they have no competing interests.
DC, Massimo M and RM conceived the study, participated in the study design, compiled the contents and critically reviewed the paper. NDS was responsible for the literature (Medline) search, compilation of the information, drafting and finalizing the paper. MM, VG and AM provided substantial contributions, ranging from study ideas, design and a critical review of the final paper. All of the authors read and approved the final manuscript.
About this article
Cite this article
Caserta, D., Di Segni, N., Mallozzi, M. et al. Bisphenol a and the female reproductive tract: an overview of recent laboratory evidence and epidemiological studies. Reprod Biol Endocrinol 12, 37 (2014) doi:10.1186/1477-7827-12-37
- Bisphenol A
- Endocrine disruptors
- Reproductive health
- Genital tract