REVIEW published: 04 June 2020 doi: 10.3389/fendo.2020.00301 Bisphenols and Male Reproductive Health: From Toxicological Models to Therapeutic Hypotheses Luca De Toni 1† , Maurizio De Rocco Ponce 2† , Gabriel Cosmin Petre 1 , Kais Rtibi 3 , Andrea Di Nisio 1 and Carlo Foresta 1* 1 Department of Medicine and Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy, 2 Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau, Barcelona, Spain, 3 Laboratory of Functional Physiology and Valorization of Bioresources, Higher Institute of Biotechnology of Beja, University of Jendouba, Beja, Tunisia Bisphenols, and in particular bisphenol A (BPA), have been widely used for the production of plastic manufacts in the last 50 years. Currently, BPA is present in a variety of daily use polycarbonate plastics and epoxy resins, and dietary ingestion is considered the main route of human exposure. Accordingly, BPA is the chemical pollutant with the widest exposure in humans, involving nearly 90% of general population, according to recent studies. Concerns about BPA effects on human health date back Edited by: to 1930s, when severe impact on male sexual development was suggested. Now, the David H. Volle, acknowledged biological effects of BPA are various. In regard to human fertility, BPA Institut National de la Santé et de la Recherche Médicale has been shown to disrupt hormone signaling even at low concentrations. Results from (INSERM), France human epidemiological studies have reported BPA interference with follicle stimulating Reviewed by: hormone, inhibin B, estradiol, testosterone levels, and sexual function in male subjects. Laura Maria Mongioì, University of Catania, Italy Moreover, recent studies have reported an association between BPA levels and reduced Giulia Rastrelli, sperm concentration, motility, normal morphology, sperm DNA damage, and altered University of Florence, Italy epigenetic pattern, resulting in trans-generational legacy of BPA effects. In this review, *Correspondence: the recognized effects of BPA on male reproductive health are described, from the most Carlo Foresta carlo.foresta@unipd.it recent issues on experimental models to epidemiological data. In addition, the very recent † These interest about the use of nutraceutical remedies to counteract BPA effects are discussed. authors have contributed equally to this work Keywords: endocrine discruptors, semen parameters, endocrine axes, drug metabolism, exposure markers Specialty section: This article was submitted to INTRODUCTION Reproduction, a section of the journal Bisphenols, and in particular the phenol compound 2,2 Bis (4-hydroxylphenyl)–propane, Frontiers in Endocrinology universally known as Bisphenol-A (BPA), are widely used as additives for the production of plastic Received: 04 March 2020 materials, such as polycarbonate, phenol and epoxy resins, and polyesters and polyacrylates, as Accepted: 20 April 2020 well as an antioxidant in foodstuffs and cosmetics (1, 2). Specifically, nearly 75% of the industrial Published: 04 June 2020 production of BPA is intended for the manufacture of polycarbonate-based products, which find Citation: wide application in food industry, such as in containers for food and beverages, in plastic dishes, in De Toni L, De Rocco Ponce M, kitchen utensils, in containers for microwave cooking, and until 2011, in bottles (3). Of note, BPA Petre GC, Rtibi K, Di Nisio A and is also used in epoxy resin films used as binary patina: the internal coatings in the cans for canned Foresta C (2020) Bisphenols and Male food (4). Reproductive Health: From Toxicological Models to Therapeutic BPA is a solid at 25◦ C with a melting temperature of 156◦ C, insoluble in water but soluble Hypotheses. in alcohol, ethers, and fats. Accordingly, BPA can migrate for continuity in food and drinks by Front. Endocrinol. 11:301. direct contact with plastic container under certain conditions. Prolonged storage times, exposure doi: 10.3389/fendo.2020.00301 to high temperatures (e.g., >70◦ C), and the presence of foods with a significant lipid component Frontiers in Endocrinology | www.frontiersin.org 1 June 2020 | Volume 11 | Article 301 De Toni et al. BPA and Male Reproduction represent some of these conditions. Consequently, BPA enters narrative review will cover available evidence regarding the the food chain due to the massive use of plastics, as containers male reproductive outcomes associated with the exposure to or technological packaging, and as a function of increasing the BPA. In addition, possible remedies to counteract BPA effects shelf life of foods (5). A recent report from the European Food are discussed. Safety Agency (EFSA) showed that the highest concentrations of BPA were found in packaged products (on average 18.68 µg/kg) compared to unpackaged foods (on average 1.50 µg/kg) (6). METHODS To this regard, the most relevant concentrations of BPA (>30 PubMed, Scopus and Web of Science databases were used to µg/kg) were observed in packaged food, such as cereals, meat perform a literature search on the time interval 2000–2019. and fish, ready-to-use foods, snacks, and sweets. As for other The following terms were included: “bisphenol male fertility,” bulk foods, the presence of the contaminant is most likely due to “bisphenol testis,” “bisphenol reproductive outcome,” “bisphenol the production processes. Among unpackaged foods, the highest semen parameters,” “bisphenol spermatozoa,” “bisphenol concentrations were found in fish, with average values of 9.40 nutraceuticals,” “bisphenol dietary supplements,” “bisphenol µg/kg. These data strongly suggest a major role of massive plastic antioxidant,” “bisphenol medicinal plants.” We included studies pollution in waterways (7). on cell models, studies on murine models, and observational As a result, there is a significant risk of human exposure to studies in humans. BPA through ingestion, skin contact, or inhalation (8, 9). Once The overall 6,865 records were then screened for relevance accessed into the body, nearly the 12% of BPA is metabolized to the topics, for a total of 77 studies finally considered for the in the liver by glucuronidation, providing more water-solubility review. Data from eligible studies were considered separately, and quicker excretion in urine, even if the concentrations in according to the different following topics: “data from animal plasma and urine are very low and difficult to detect (10, 11). In studies,” “data from human studies,” and “nutritional remedies addition, the conjugated form of BPA is equally accounted in the to BPA related disorders.” pool of the active forms (12). For this reason, total urinary BPA, including both conjugated and unconjugated BPA, is generally used as a biomarker of exposure to BPA (13). Epidemiological Disrupting Effects of BPA on Male Fertility: data from the United States have reported detectable levels Data From Animal Studies of BPA in urine samples from more than 90% of general A wide amount of data from animal studies shows a clear effect population, resulting a major problem of exposure to chemical of BPA on male reproductive system, even at very low doses. substance (14). One of the first investigations on this topic relied of the fact that Concerns about BPA issues on the human health date back BPA is massively used in sealant made of resin-based composite to 1930s, when severe impact on male sexual development materials for dental use, with the consequent oral ingestion of had been suggested. From a mechanistic point of view, the BPA. Al-Hiyasat et al. were among the first to investigate the most relevant risks associated with the exposure to BPA are reproductive outcome in male mice exposed to BPA by oral mainly due to its action as an endocrine disruptor (ED), being ingestion, suggesting possible issues for infertility, genital tract able to interfere with the balance of the hormonal system and malformations and increased cancer rates in estrogen sensitive thus causing harmful effects on the whole body (15). Available target tissues (26). BPA doses >25 ng/kg were associated with reports in late 1990s firstly documented a stimulating activity reduced sperm count, both at epididymal and ejaculated level, of BPA on estrogen receptor α that differed, however, from the and with significant reductions of the absolute weights of the classical pattern observed in weak estrogens, partial agonists, testes and seminal vesicles. These early results were confirmed by and pure antagonists (16, 17). This evidence was confirmed more recent studies reporting decreased sperm count associated by subsequent investigations, reporting that BPA binds several with the exposure of BPA in rodent models, suggesting major nuclear receptors, mimicking the action of endogenous steroids, impairment of the spermatogenetic process. (27–33). In addition, maintaining the target molecule in active conformations or lower levels of exposure were equally associated with reduced blocking the access of endogenous 17β-estradiol to receptor’s semen quality, particularly with regard to motility parameters binding site by competition (18–20). In addition, unconjugated and markers of adequate cell-redox balance (27, 29, 31, 33, 34). BPA showed a binding activity to other two receptors: the G Furthermore, the exposure to BPA has been associated with the protein-coupled estrogen receptor 30 (GPR30), also known as alteration of other non-conventional markers of sperm quality membrane estrogen receptor alpha (mERα) (21, 22) and the such as the index of DNA fragmentation, suggesting a possible orphan nuclear estrogen-related receptor gamma (ERR-gamma) role as mutagen (29, 31, 34–42). Also, in a recent study from (23, 24). Finally, experimental animal studies demonstrated that Wisniewski et al. acrosomal integrity, an overall marker of the BPA binds also to the androgen receptor (AR), to the peroxisome fertilization potential, was significantly reduced by PBA exposure proliferator-activated receptor gamma (PPAR-gamma), and the in murine models (27). thyroid hormone receptor (19). As outlined by the aforementioned studies, BPA showed On these bases, the exposure to BPA is increasingly suspected major abilities to interfere with spermatogenesis and germ to exert major reproductive issues, such as the impairment cell maturation, a process largely regulated by the synthesis of semen production in men as well as alteration of the of testosterone (T) from the Leydig cell population of the hormonal cycle and oocyte maturation in women (25). This testis under the direct control of pituitary luteinizing hormone Frontiers in Endocrinology | www.frontiersin.org 2 June 2020 | Volume 11 | Article 301 De Toni et al. BPA and Male Reproduction (LH) (43). Several studies have been performed to disclose the motility with no significant histologic changes of testes (62). Jiang possible disruption of the hypothalamus/hypophysis/testis axis et al. observed ultrastructural lesions in Sertoli and Leydig cells (HHTA) associated with BPA exposure in animal models, with after the administration of 5 mg/kg/day of BPA to rats for 8 the result of a fairly complex picture that invariably leads to weeks (63). the impaired production of T (28, 44). In this regard, both Of note, very recent studies disclosed some transgenerational direct effects on Leydig cells and indirect effects on HHTA effects associated with BPA exposure. Manikkam et al. showed were recognized. Among the direct effects, a study conducted that the early exposure of female gestating rats to a cocktail of in the classical murine Leydig MA-10 cell model, Lan et al. plastic additives, including BPA, was associated with a significant showed that BPA forces a detour of the normal steroidogenic increase of the prevalence of diseases and abnormalities in F1 and activity by stimulating, on one hand, the production of 17- F3 generation males, particularly pubertal abnormalities, testis hydroxy-pregnenolone and T from cholesterol, but on the other disease and obesity (64). Likewise, similar effects were exerted by hand, the expression of CYP19A1, the aromatase activity that replacement bisphenols, namely compounds structurally similar converts T into 17-β estradiol, resulting in a overproduction to BPA used in “BPA-free” products (65). Subsequent studies of this latter (45). Other studies suggested that BPA triggers were able to detect major genetic abnormalities associated with multi-level dysfunction in Leydig cells, altering either insulin exposure to BPA. Firstly, BPS showed a mutagen effect on male signaling and glucose transport or the mitochondrial activity, germ cells, resulting in blocked meiotic progression of germ with a resulting downstream redox imbalance and altered cells (31, 66). Furthermore, Shi et al. showed that both BPA and steroidogenesis (46, 47). As anticipated, BPA was also suggested replacement bisphenols are able to modify the expression of DNA to indirectly suppress the pituitary LH release through the methyltransferases and the pattern of histone methylation in the massive aromatase upregulation in the testes; the consequent neonatal and adult testes (67). increase of serum estrogens would then exert a negative However, earlier studies by Hass et al. on this topic (68) hormonal feedback at central level (48). Importantly, because of reported that male offspring from pregnant Wistar rats, gavaged its high lipid solubility, BPA undergoes to trans-placental transfer with bisphenol A from gestation day 7 to pup day 22, in animal models with a consequent detection in cord blood, showed a significant reduction of the sperm count only at an evidence reported also in humans (49–52). Accordingly, the lowest bisphenol A dose (25 µg/kg/day). Higher doses BPA exposure during the prenatal period was associated with had no effect on either sperm parameters or the weight and the impairment of both fetal development and the endocrine histology of the reproductive organs. These results suggest a function of the testis, with reduced Leydig cell proliferation likely transgenerational toxicity of bisphenols, with a possible and fetal testosterone production (53–55). Additional data from mechanistic involvement of epigenetics on the impairment of animal models suggests that the endocrine disruption associated male reproductive functions. However, a more complex scenario with BPA exposure in male fetuses negatively affects fertility should be hypothesized given the observed non-monotonic in adult life. To this regard, in a study by Salian et al., dose–response relationship. maternal exposure to BPA was associated with reduced sperm count and motility in male offspring and, in turn, with post implantation loss and decreased litter size (56). However, the DISRUPTING EFFECTS OF BPA ON MALE mechanisms by which BPA interferes with testis development FERTILITY: DATA FROM HUMAN STUDIES and function, whether in fetal or in adult life, seem to be wider than the exclusive endocrine disruption of the HHTA. In fact, Despite the large availability of data in animal models, fewer exposure to BPA alters the glucose homeostasis in germ cells studies assessed the possible relationship between BPA exposure through the decreased expression of GLUT-8 glucose transporter, and semen quality in humans. The first reports on this particularly in spermatocytes and spermatids (39). In addition, topic dealt with occupational medicine; particularly, Li et al. an increased oxidative stress in the testis was claimed as the found a negative association between urinary BPA and sperm responsible for the impaired seminal quality associated with concentration, total sperm count, viability, and motility in exposure to BPA (35, 57). For example, excessive production 215 factory workers, further distinguished into occupationally of reactive oxygen species (ROS) and consequent mitochondrial exposed to high or low levels of BPA. However, in the subgroup dysfunction induced by BPA, was associated with Sertoli cells with lower creatinine-adjusted urinary BPA, the only significant apoptosis (58). BPA was also suggested to directly interfere with association was with reduced sperm concentration. Notably, apoptotic signaling and to induce the morphological changes in urinary BPA levels were not associated to altered morphology Sertoli cell mitochondria, the triggering of Pten/Akt signaling in this study (69). As for data in animal models, other studies pathway, or the activation of the JNKs/p38 MPAK pathway, with investigated the possible association of BPA exposure with the consequent nuclear translocation of NF-kB and Fas/FasL alterations of sperm DNA. Meeker et al. explored the possible system (59–61). Despite this severe interference with Sertoli correlation between urinary BPA concentration and sperm DNA cell cycle, a morphological alteration of testicular histologic damage, evaluated by neutral comet assay, in a cohort of 190 architecture was not observed frequently, largely depending on subfertile male patients (70). Urinary BPA concentration was the protocol of administration. In fact, Aikawa et al. showed that associated with reduced sperm concentration, motility, and the experimental exposure of male mice to 50 µg BPA for 5 days morphology, whereas a positive association with sperm DNA after birth caused a decrease in normal morphology and sperm damage was observed. However, two independent studies on Frontiers in Endocrinology | www.frontiersin.org 3 June 2020 | Volume 11 | Article 301 De Toni et al. BPA and Male Reproduction male partners from infertile couples attending infertility clinics the possible relationship between time to pregnancy (TTP) and were not able to retrieve any significant association between urine levels of more than 15 environmental pollutants, including BPA urinary concentration and altered semen parameters. BPA, in both males and females. Urinary BPA concentration in Importantly, a relatively high variability of exposure markers was either males or females was not associated with increased TTP, observed, since the mean urinary BPA concentration in these two which was instead correlated with male urinary concentration of studies were, respectively, 1.5 and 0.6 ng/mL (71, 72). monomethyl, mono-n-butyl, and monobenzyl phthalates. Another field of investigation pursued was the possible Overall, available data are supportive of detrimental role correlation between exposure to BPA and alteration of the of BPA on semen parameters, but this is not accompanied endocrine pattern, but widely varying scenarios can be observed. by clear data on sex hormones and on fertility outcomes. Hanaoka et al. conducted a study on 42 workers occupationally As suggested by other authors (79), within the limits of the exposed to BPA through the handling of epoxy resin spray availability of data in humans, a possible reconciling explanation containing BPA (73). Interestingly, authors have found lower could rely on a greater direct toxicity of BPA on germ line serum levels of follicle-stimulating hormone (FSH) in exposed cells, rather than in an albeit important endocrine disruption workers compared to those non-exposed, although non-obvious of the HHTA. This hypothesis is somewhat supported by very differences in plasma LH and free T levels were observed. Also, few studies reporting the interference of BPA on germ cell Galloway et al. investigated the relationship between urinary BPA development in human fetal testis and on mitochondrial and male reproductive hormones in a cohort of 715 healthy activity and energy metabolism in ejaculated human adults aged 20–74 years from the general population (74). sperms (57, 80, 81). Surprisingly, urinary BPA levels were positively and significantly associated with serum T levels, but no associations with either 17-β estradiol, sex hormone-binding globulin (SHBG), or free T were observed. On the other hand, Lassen et al., in a study on NUTRACEUTICAL APPROACHES TO 308 healthy males from the general population, found increased OVERCOME BPA EFFECTS serum T, free T, LH, and estradiol in subjects pertaining to higher urinary BPA concentrations quartile, compared with the Given the large availability of evidence reporting detrimental lowest quartile. Subjects in the highest urinary BPA quartile also effects of BPA on testis function, especially in animal models, this showed reduced progressive sperm motility compared with the chemical has progressively gained a role as a reference substance, lowest quartile (75). Also, Mendiola et al. performed a similar able to induce endocrine disruption in several experimental study on 375 fertile men recruited from prenatal clinics, finding models, from laboratory animals to in vitro cell cultures (82). that urinary BPA concentrations were positively associated On this basis, some recent studies have focused on possible with serum SHBG levels and inversely correlated with free approaches to treat or prevent BPA-induced derangements and androgen index (FAI), calculated as total T × 100/SHBG and testicular toxicity. Since the direct toxicodynamics of PBA on the FAI/LH ratio. However, serum FSH, LH, total T, inhibin B, both Leydig and germ cells of the testis were largely related and free T levels showed no obvious correlation with urinary to the impairment of cell redox system, most of the treatment BPA concentration (72). In addition, Meeker et al. found a approaches relied on the use of natural sources of antioxidants. negative association between urinary BPA levels and both serum Based on the fact that the expression of the enzymes inhibin B levels and 17-β estradiol/T ratio in male partners of glutathione peroxidase and glutathione reductase are regulated subfertile couples attending a fertility clinic; however, BPA was by melatonin, a study from Anjum et al. aimed to disclose the positively associated with both FSH and FSH/inhibin B ratio possible effect of melatonin on mitochondrial lipid peroxidation (76). observed in mouse testis after BPA exposure (41). Interestingly, Finally, few studies aimed to assess the possible impact of BPA the treatment with melatonin reduced mitochondrial lipid exposure on the overall fertility potential in males through the peroxidation, restored the overall mitochondrial enzyme overall evaluation of the relationship between BPA levels and machinery and improved the mitochondrial antioxidant pool the reproductive outcome in the setting of assisted reproduction compromised by BPA. However, major limitations of the study facilities. In a study enrolling 215 infertile couples undergoing were represented by the high dosage of melatonin administered assisted reproduction techniques, with roughly equal distribution intraperitoneally. In 2012, El-Beshbishy et al. demonstrated between in vitro fertilization and intrauterine insemination, some mitigation of the mitochondrial toxicity exerted by BPA Dodge et al. (77) investigated the possible correlation between exposure in rats, by the co-administration of lipoic acid (44). urinary concentrations of parabens and BPA with the live- Also, Khalaf et al. (83) recently reported a protective effect of birth rate. Authors found minimal association between paternal selenium (Se) against BPA-induced testis impairment in albino urinary propyl paraben levels and reduced live-birth rate in a male rats. In particular, co-administration of Se attenuated correlation model corrected by possible confounders. However, the reproductive issues induced by BPA toxicity through the no significant association emerged between paternal urinary BPA restoration of testicular antioxidant activity and the amelioration and reproductive outcomes after fertility treatments (77). On the of sperm genetic abnormalities observed in BPA exposed animals other hand, Buck-Louis et al. in the Longitudinal Investigation (83). Similar results were obtained by Kaur et al. who reported of Fertility and the Environment (LIFE) Study, a multicenter decreased lipid peroxidation in mouse testis associated with the investigation involving 501 infertile couples from 16 targeted co-administration of Se and BPA, compared with sole exposure counties in the middle-east of the United States (78), evaluated to BPA (84). Frontiers in Endocrinology | www.frontiersin.org 4 June 2020 | Volume 11 | Article 301 De Toni et al. BPA and Male Reproduction TABLE 1 | Summary of the references supporting the possible effects of bisphenols on male reproductive health. Animal Model Human Model Outcome In vitro In vivo In vitro In vivo Testis Histology (62) ↔ (63) ↓ Effect on sperm count (26) ↓ (71) ↔ (29) ↓ (69) ↓↔ (28) ↓ (95) ↓ (61) ↓ (↓Sertoli cell function) (72) ↔ (32) ↓ (33) ↓ (30) ↓ (31) ↓ (59) ↓ (↓Sertoli cell function) (60) ↓ (↓Sertoli cell function) (27) ↓ Effect on sperm (39) ↓ (↓ Germ/Sertoli cells metabolism) (57) ↓ (71) ↔ motility/mitochondrial function (29) ↓ (35) ↓ (75) ↓ (34) ↓ (80) ↓ (95) ↓ (33) ↓ (81) ↓ (72) ↔ (31) ↓ (27) ↓ Sperm DNA Fragmentation (41) ↑ (70) ↑ (35) ↑ (39) ↑ (29) ↑ (42) ↑ (40) ↑ (36) ↑ (34) ↑ (37) ↑ (31) ↑ (38) ↑ Testosterone Production (46) ↓ (↓ redox balance) (53) ↓ (↓Fetal testis development) (74) ↑ (47) ↓ (↓ redox balance) (44) ↓ (73) ↔ (45) ↓ (↑ CYP19) (28) ↓ (75) ↑ (55) ↓ (↓Fetal testis development) (76) ↓ (54) ↓ (↓Fetal testis development) (72) ↓↔ (48) ↓ (↓ LH by estrogens) Fertility Outcome (78) ↔ (77) ↔ Fertility in Offspring (66) ↓ (68) ↓↔ (64) ↓ (56) ↓ (↓ Fetal testis development) (67) ↓ (31) ↓ For each outcome considered, the respective references are listed according to the model used, animal or human, the in vitro or in vivo evidence and the observed effect (↓, decrease; ↑, increase; ↔↓, mild decrease or no effect). When available, mechanistic details are provided. Another key vitamin supplementation, namely vitamin D, damage induced by BPA in rats, or even exerted worsening showed a partial restore of testicular fibrosis in a complex effects (86). On the contrary, Rahman et al. (87), in an rat model of diabetes, obtained by streptozotocin treatment, in vitro experimental model on isolated mouse spermatozoa, associated with BPA-induced hypogonadism (85). Interestingly, showed that the combination of glutatione, vitamin C, and this effect appeared as the result of a direct downregulation of vitamin E effectively prevented the oxidative stress and nuclear factor kappa B exerted by vitamin D, rather than the the respective downstream tyrosine phosphorylation-signaling indirect involvement of the central pituitary/testis axis. pathway, avoiding the premature acrosome reaction and possibly Of note, the composition of the antioxidant mixture improving the fertilization capacity of sperm cells exposed to seems to have major relevance on the efficacy of the BPA. (87). treatment. In fact, the classical vitamin C administration Interestingly, a wide variety of phytochemicals and plant failed to produce any amelioration on the testicular oxidative extracts showed ameliorating effects of testis function in rodent Frontiers in Endocrinology | www.frontiersin.org 5 June 2020 | Volume 11 | Article 301 De Toni et al. BPA and Male Reproduction models exposed to BPA (88). Cordyceps militaris, a medical major impairment of the male hypothalamus/hypophysis/testis fungus largely employed in Chinese traditional medicine, axis has been recognized as associated with the exposure to BPA restored the histological architecture of seminiferous tubules during both the fetal and the adult life, resulting in altered testis and epididymis in male rats exposed to BPA, with a significant development, impaired endocrine function and infertility. In this recovery of the sperm count, through the likely reduction regard, direct disruption of sperm characteristics, such as reduced of the oxidative stress damage (89). Also, lycopene showed motility performances and development genetic abnormalities a detoxifying activity toward testicular damages associated have been identified. On the other hand, data obtained in humans with BPA exposure, as evidenced by the protection from are actually limited and poorly conclusive to identify a strict the loss of germ cell population, the reduction of testis and causal role of BPA in reduced male fertility potential. A summary epididymis weight, as well as the impairment of sperm motility, of references supporting each singular effects of bisphenols on exerted by the treatment of male rats with the sole BPA (90). male reproductive health is reported in Table 1. Furthermore, co-administration of quercetin, an antioxidant Methodological differences and different study populations phytochemical member of the polyphenolic flavonoid family, are factors that can explain some discrepancies. Moreover, amended the toxic effects on testis and epididymis exerted by available clinical outcomes, such as semen parameters and time BPA (91). to pregnancy, are likely susceptible of variation related to many Our group recently showed that the metabolic/mitochondrial different confounding factors. It should be noted that, as for most disruption, induced by the in vitro exposure of human of chemical pollutants, the identification of a reliable marker of spermatozoa to BPA, was effectively compensated by low dose exposure remains a major issue. Specifically, for BPA, urinary treatment with aqueous extract from leaves of Eruca sativa, concentrations are surely reliable data from an analytical point of a plant of the Brassicaceae family widely represented in the view, but may not be representative of the real exposure to BPA Mediterranean region. Importantly, the characterization of the due to its short half-life. To this regard, Vitku et al. reported that extract showed to be extremely rich in natural antioxidants, BPA levels in blood plasma were positively correlated with BPA such as polyphenols and flavonoids. The treatment with levels in semen, but only seminal BPA was negatively associated high concentration of the aqueous extract was unexpectedly with seminal quality (96). Finally, the cross-sectional design of associated with severe disruption of both mitochondrial and the available studies surely provides proof of association, but cell membrane redox balance, resulting in a significant loss limited evidence of causality. of sperm motility (81). Importantly, these preliminary results One of the main problems associated with exposure to have been confirmed by a subsequent study performed on endocrine disruptors in general, and to BPA in particular, is Wistar rats (92). Consistent with in vitro data, the overall represented by the potential activity at low concentrations. hormonal and semen disruption associated with BPA exposure This represents a critical issue during the development phases, was significantly ameliorated by the low-dose administration of such as embryo/fetal life and newborn or peri-pubertal age, Eruca sativa aqueous extract, while it was worsened by high since the effects in these time windows may be irreversible dose treatment. and are generally detected only at adulthood (15). Accordingly, Despite these encouraging results, exogenous antioxidants populations at higher risk includes pregnant women, infants, and may exert a double-edged effect. In particular, the SELECT adolescents. On these bases, the current European law restricted study found that the supplementation of vitamin E significantly the use of BPA in the production of packaging and materials increased the risk of prostate cancer among healthy men (93). in direct contact with food by limiting migration rate to 0.05 Furthermore, more recently, it has been shown that vitamin E mg/kg of food and prescribing the total absence in products can act as pro-oxidant agent promoting DNA damage and cell for newborns, from food to food containers and clothes (6). In transformation (94). Thus, the use of antioxidants-based dietary addition, based on new toxicological data and methodologies, supplements for the prevention of disease states in general, and the European Authorities adjusted the tolerable daily intake from in particular for the compensation from altered states associated 50 to 4 µg/kg body weight/day with an overall lowering rate of with exposure to environmental factors, should be considered 12 times, highlighting the increasing level of attention for these with caution. health concerns. In conclusion, reproductive issues associated with bisphenol A exposure still remains an intense field of investigation, CONCLUSIONS AND FUTURE particularly dealing with health consequence reported in males. PERSPECTIVES Current challenges for the future are represented by the identification of efficient markers of exposure in order to address Bisphenol A represents one of the most controversial chemical the extent of health consequences in different age ranges. pollutants, with the typical features of an endocrine disruptor. Early toxicological evidence on BPA date back to nearly 30 AUTHOR CONTRIBUTIONS years ago, when major interference with estrogen signaling pathway was claimed. Since that time, a wide range of cell CF supervised manuscript drafting. MD reviewed clinical data. mechanisms of both endocrine and metabolic disruption have GP and KR reviewed data on nutraceuticals. AD reviewed been claimed by the use of experimental models. In particular, experimental data. LD drafted the manuscript. Frontiers in Endocrinology | www.frontiersin.org 6 June 2020 | Volume 11 | Article 301 De Toni et al. BPA and Male Reproduction REFERENCES studies. Reprod Toxicol. 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