Fertility of prenatal BPA-exposed offspring was further evaluated in vitro. (C) Sperm acrosome integrity of control and prenatal BPA-exposed offspring. (B) Sperm morphology of control and prenatal BPA-exposed offspring. (A) Sperm motility of control and prenatal BPA-exposed offspring. In contrast, linearity (LIN) and straightness (SRT) were higher in BPA exposured mice, while beat cross frequency (BCF) was not affected by prenatal BPA exposure (Fig. 3C). Metabolism of BPA is limited compared with gavage administration when BPA is absorbed through the skin (153), which may be a contributing factor in elevated BPA exposure in cashiers who handle these receipts all day (157, 158). A single gavage administration per day does not take into account the markedly different toxicokinetics of BPA after transdermal absorption (153), which is expected from exposures due to handling of BPA-containing thermal receipt paper (154, 155) and use of cosmetics (156). Gavage increases stress hormones, and intragastric gavage bypasses absorption in the mouth (152). Why was there such a disconnect between measurements of BPA in human samples and the estimates of BPA intake? Therefore, to ascertain whether BPA induces lesions at specific concentrations, we examined the morphology of the testis and kidney. The two-cell embryos were then transferred to 50 μl of BM supplemented with 0.4% BSA under 5% CO2 at 37°C. After 18 h, the cleavage rate was measured by counting the number of two-cell embryos compared to the number of zygotes. Superovulation was induced via an intraperitoneal injection of pregnant mare serum gonadotropin (PMSG; 5 IU) followed 48 h later by human chorionic gonadotropin (hCG; 5 IU). If you heat your food in plastic you mix Add Now your food with BPA but there’s more than that. I never buy my food in a store and I never will. It tastes better and it’s better for your overall health. It’s better to buy fresh or frozen food, fruit and vegetables. Yes, these contain high levels of BPA and that’s why I avoid them. From here, GnRH reaches the anterior pituitary (adenohypophysis) and mediates the discharge of pituitary gonadotropins (i.e. LH and FSH) into the main circulation; as a consequence, the gonads produce sex steroid hormones, testosterone and estradiol.Ptak et al. (2014) have reported that elevated BPA level induces matrix metalloproteinase-2 (MMP-2) and MMP-9 and CDH2 in turn facilitates cell migration (Ptak et al. 2014).Methodological heterogeneity and limited human longitudinal data constrain translational relevance.In vitro and in vivo studies have shown that BPA exposure has a pro-carcinogenic influence in hormone-dependent and hormone-independent cancers (Gao et al. 2015; Seachrist et al. 2016).According to the available data, environmental pollution is a serious problem all over the world.While there is a growing body of literature suggesting adverse relationships with fertility and birth outcomes in relation to BPA exposure, human studies remain extremely limited and highlights the need for more epidemiological research.The majority of chemicals and work environments have not been investigated for their potential to harm reproductive systems up to this point.BPA concentration less than 10-4 M enhances the migration and invasion of A549 cells (Zhang et al. 2014).In summary, it seems clear that BPA exposure induces electrical changes in cardiac muscle cells and vascular SMC, with L-type Ca2+ channels and voltage-dependent K+ channels being the most affected by BPA (Table 1). A systematic review of Medline for terms including ejaculation, orgasm or hematospermia. BPA disrupts endocrine pathways, because it has weak estrogenic, antiandrogenic, and antithyroid activities. Everyone is exposed to BPA through skin, inhalation, and digestive system. Bisphenol A (BPA) has been used since the 1950s, in food packaging, industrial materials, dental sealants, and personal hygiene products. This chemically stable compound has estrogenic and/or anti-androgenic properties and can leach into food and water, both under normal condition and at elevated temperature 3,4 , and can consequently be accumulated in animal body 5,6. The collaboration involved the National Institute of Environmental Health Sciences (NIEHS), which funded 14 academic programs to examine gene and protein expression, epigenetic markers, morphometric analyses, and neuroendocrine and behavioral responses using tissues from rats produced by the FDA’s National Center for Toxicological Research (NCTR).Results from preclinical research clarified possible mechanisms by which BPA can interfere with the regulation of spermatogenesis (Castellini et al.; De Toni et al.).In particular, BPA is commonly considered to have estrogenic and antiandrogenic effects able to disrupt the hypothalamic-pituitary-gonadal axis, and the ability to alter normal epigenetic patterns with impairing consequences on the reproductive system.Researchers measured sexual function based on in-person interviews using a standard male sexual function inventory that measures four categories of male sexual function including erectile function, ejaculation capability, sexual desire, and overall satisfaction with sex life.In contrast, Roelofs et al. reported that exposure to BPF and BPS for 48 h caused an increase in the level of testosterone in the MA-10 LC culture.BPA and its analogues are also reported to exert oxidative stress in the plasma, testis, and sperm, resulting in spermatogenesis disturbance 51,52.MPs originate from anthropogenic, marine, terrestrial and atmospheric sources, frequently interacting within intricate environmental systems. These transformations are mediated by microbial genes encoding metal reductases, oxidases, and transporters, which may be enriched in the gut microbiome under chronic exposure scenarios. These findings suggest that mercury exposure compromises intestinal barrier function, providing an entry point for systemic toxicity. Mercury can be converted in the environment into methylmercury (MeHg), a highly toxic and bioaccumulative compound that enters the human body primarily through consumption of fish, particularly large predatory species (Wang et al., 2020a; Nielsen et al., 2018). Overexpression of HOTAIR resulted in cisplatin resistance by regulating the expression of p21 and downregulation of microRNA-130a by activating NF-κB, PIK3R3, and MAPK1 63, 64. Conversely, BPA could suppress the expression of proapoptotic factors including caspase-3 and caspase-7 through ERK1/2 signaling pathway . Such low doses of BPA can increase the proliferation and migration of several ovarian cancer cell lines. However, in humans, evidence for the persistence of such changes remains scarce, and further longitudinal and interventional studies are warranted to better elucidate the temporal stability of pollutant-driven dysbiosis. Future research should prioritize integrating multi-omics approaches, such as metagenomics, metabolomics, and transcriptomics with environmental exposure assessment to unravel the causal pathways linking PPCPs to host-microbiota dysregulation. Notably, most functional studies to date are limited to in vivo rodent models or aquatic species, with fewer high-resolution, longitudinal studies in human cohorts (Jiang et al., 2023). In zebrafish models, fluoxetine exposure led to increased abundance of Actinobacteria and shifts in amino acid biosynthesis pathways, potentially linking microbiota changes to neurobehavioral phenotypes (Pinto et al., 2024). Mounting evidence suggests that PPCPs can disrupt gut microbiota composition, diversity, and function, even at environmentally relevant concentrations. BPS promotes apoptosis by up-regulating IL-6, cleaved caspases, and a spike in sperm DNA fragmentation. Male offspring prenatally exposed to BPS (0.4 μg/kg) had higher plasma testosterone than BPA and control. However, a significant inverse association was found between urinary BPA concentration and FAI levels and the FAI/LH ratio, as well as a significant positive association between BPA and SHBG. These concentrations are also designated using pharmacological concentrations and cause more accurate results than lower concentrations . BPA exposure impairs not only cardiac electrophysiology, but also Ca2+ signaling, leading to arrhythmias and changes in contractile functions (contraction and relaxation) (Figure 3). However, to our knowledge, these authors were the only ones to evaluate the effects of BPA in the postpartum period. It has recognized activity as an endocrine-disrupting chemical and has suspected roles as a neurological and reproductive toxicant. It is plausible that BPA induces toxicity with a higher sensitivity specifically in the testes of mouse suggesting that the toxicity of the testis is not a secondary consequence of unhealthy mice resulting from systemic effects. In numerous studies, lower concentrations of BPA than the LOAEL have been reported to elicit toxicity. Thus, BPA exposure may negatively impact spermatogenesis, leading to lower sperm numbers and decreased motility (Rahman et al., 2021). After studying this chapter, you will be able to: It upregulates the expression of tight junction proteins such as occludin and claudin, strengthening intercellular connections and preventing paracellular leakage (Xu et al., 2023). For barrier protection, the microbiota maintains the integrity of the intestinal mucus layer, which prevents harmful substances from directly contacting epithelial cells. For instance, it regulates the balance between T helper 17 (Th17) cells and regulatory T (Treg) cells—Th17 cells defend against pathogens, while Treg cells suppress excessive immune responses to maintain homeostasis (Yuan et al., 2023). In terms of immune modulation, the gut microbiota trains the innate immune system, promoting immune cell development and functional maturation. By elucidating these molecular and ecological connections, this review underscores the gut microbiotaas a key target and therapeutic entry point for mitigating the health impacts of environmental pollution and guiding microbiota-based interventions for disease prevention. In a long-term study, C57BL/6 mice exposed to 0, 5, or 10 ppm sodium arsenite (NaAsO2) via drinking water for 6 months developed significant liver injury and microbial dysbiosis (Li H. et al., 2024). Epidemiological studies have shown that high arsenic exposure correlates with distinct alterations in gut microbial composition. Path analysis revealed that changes in these two microbial taxa explained approximately 24%−29% of the association between TRAP exposure and elevated fasting glucose levels (Alderete et al., 2018). Epidemiological data show that exposure to traffic-related air pollution (TRAP) correlates with both gut microbiome composition and fasting blood glucose levels. Association of bisphenol a exposure with line-1 hydroxymethylation in human semen. Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men. Male exposure to bisphenol a impairs spermatogenesis and triggers histone hyperacetylation in zebrafish testes. Role of DNA methylation in bisphenol A exposed mouse spermatocyte. Epigenetics presents any process that influences gene expression without changing the DNA sequence and leads to modifications that can be inherited. Examples of inducers and effectors of cell proliferation and apoptosis 43,48,49. Intrinsic pathway (or mitochondrial pathway) of apoptosis occurs through the activation of caspases—enzymes catalyzing the cleavage of the cell proteins. Akt activates several target proteins involved in cell determination, metabolism, and protein synthesis . In male animals, exposure to environmental contaminants can impact the reproductive organs and in turn fertility (for a review see ). These non-monotonic relationships indicate that the effects of low and high dose exposure are not always constant between outcome measures and that studying only high dose responses, as is common in toxicological studies, is not sufficient. A second reason why previous studies have not found low dose effects of BPA exposure may be because most of these focused primarily on the deactivated metabolite, bisphenol A-glucuronide. There are multiple reasons as to why previous human and animal studies have failed to report the low dose effects of BPA exposure. Similarly, in prostate cancer cells, the exposure to DEHP, BBzP, and DBP stimulated cell proliferation via ERK5 and p38 . In ovarian cancer cells, the exposure to DEHP activated ER and cyclin D via the MAPK pathway. They observed that the DnBP exposed the LNCaP prostatic carcinoma cells (DnBP dose at 10−6–10−5 M) activated TGFβ signaling via the MAPK signaling pathway . Phthalates also affect the cells related to the reproductive system by other mechanisms. This impairment can be observed mainly in gonadal cells or cells related to the reproductive system. Hence, this review was performed to connect the HPG axis, testicular steroidogenesis, and spermatogenesis outcomes after exposure to BPA and its analogues, leading to male reproductive toxicity These analogues may demonstrate the same adverse effects as BPA on the male reproductive system; however, toxicological data explaining the male reproductive hormones’ physiological functions are still limited. BPA is identified as an endocrine-disrupting chemical that deteriorates the physiological function of the hormones of the male reproductive system. In men, hormone-disrupting chemicals found in plastics have been linked to erectile dysfunction, reduced sperm counts and health, and many other reproductive abnormalities linked to infertility. Phthalates’ Action on Female Reproductive Health In summary, this review discusses the various sources of exposure to PFOS/PFOA, leading to their high concentrations in the general population and in occupational groups. Reports from animal and epidemiological studies implicate PFAS as an endocrine disruptor 15,34,36,41,42. In our review, rodent studies are examined for common threads and possible endocrine disruptor activities of PFAS. Some studies have shown a strong association between male subfertility and subsequent risk of testicular cancer 26,27,28, suggesting common etiologic factors for infertility and testicular cancer. The reason why phthalates interfere with steroid hormones lies in a similar chemical structure. Phthalates influence not only the expression of peptide receptors but also the activity of nuclear receptors. Altered hormonal balance can be influenced by the phthalates’ impact on the intracellular signaling. Exposure to BPA alters DNA methylation and is proposed as a mechanism for increased risk of BC (Fernandez 2012). Studies have reported exposing breast cancer cell lines to BPA causes cell proliferation, migration, and invasion (Kim et al. 2017). BPA-induced changes in the mammary gland tissues include enhanced estradiol sensitivity and increased progesterone receptors. Estrogen exerts its effects via nuclear ERα and ERβ or via mERs such as GPER/GPR50 (Prossnitz and Barton 2011). Global BPA production gradually increased from 5 to 8 million tons between 2010 and 2016 and is estimated to reach 10.2 million by 2023. BPA does not occur freely in nature, and when exposed to air, it undergoes photo-oxidation and degradation, resulting in a low half-life (0.2 days) . BPA, also designated by IUPAC as 4-2-(4hydroxyphenyl)propan-2-ylphenol, is an endocrine disruptor that has estrogenic activity . Despite being consumed in low doses, it can stimulate cellular responses and affect body functions . Supplementary data UGT in the human foetal liver is present at a concentration five times lower than in the adult liver; this means that a foetus may face a higher risk of deleterious effects 9,10. Therefore, from the aquatic environment, the ingestion of freshwater fish or seafood contaminated with BPA may be the main route of contamination for humans 10,25. Its presence in edible products is related to the exposure of animals and raw materials to BPA, the accumulation of BPA in the environment, and the contact of food with polymers containing this substance . In 2012, the CLARITY-BPA study was created specifically to address the divide concerning BPA safety, and directly compare the results from a guideline study (eg, a regulatory study conducted by FDA scientists) and hypothesis-driven endpoints conducted by academic investigators using tissues from randomly selected animals from the same cohort. The estimated “safe” dose is calculated based on the assumption that a dose 1000-fold lower than the LOAEL should be without effect if oral exposure occurred each day over the lifetime (3). This manufactured controversy was initiated by the plastic industry, and subsequently has been perpetuated by regulatory agencies that have ignored findings from thousands of mechanistic in vitro and low-dose animal experiments, as well as significant findings from more than 100 epidemiological studies. Ultimately, CLARITY-BPA has shed light on why traditional methods of evaluating toxicity are insufficient to evaluate endocrine disrupting chemicals. BPA exposure alters core histone proteins, which could ultimately lead to male infertility15, and may also result in a significant decrease of H3K9me2 activity in the testes, leading to the loss of spermatogonia and meiotic germ cell16. However, some studies have shown that the effects of BPA exposure during organ development may not be detectable immediately but become apparent in subsequent adulthood. Many studies have indicated that BPA can cause abnormalities in health, including male and female infertility, many kinds of malignant tumors, neuroendocrine issues, thyroid problems, metabolism disorder and obesity, and cardiovascular endocrine issues1,2,3. While research highlights various side effects of plastic containers, their impact on human health extends beyond infertility. Other contributing factors include stress, pollution, and exposure to pesticides, which can adversely affect reproductive health. One chemical in plastics, Bisphenol A (BPA), is particularly concerning due to its effects on reproductive health. 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. For obvious ethical reasons, controlled studies of the long-term exposure effects cannot be performed on pregnant women or children. The report describes a wealth of evidence supporting direct cause-and-effect links between the toxic chemical additives in plastics and specific health impacts to the endocrine system.Conservative estimates point to more than a thousand manufactured chemicals in use today that are EDCs. Our data showed that the total number of sperm was decreased and the morphology was impaired in BPA-exposed mice. Although similar results have been shown in mice, this is the first such study in humans. New research shows an intriguing correlation between prenatal exposure to phthalates and effects on anogenital distance in baby boys. In neonatal rats, BPA exposure has been linked to altered DNA methylation at key cell signaling genes, increasing the likelihood of developing precancerous prostatic lesions in adulthood 82,83. Epigenetics is a large field of study regarding the molecular processes responsible for heritable and stable changes in gene expression that do not involve changes to the DNA sequence . This not only highlights the sexually dimorphic effects of BPA exposure, but also the non-linear dose response curves typical of EDCs. Specifically, low dose (1 µg/mL) exposure to BPA significantly increases female adipose tissue weight, while high dose (10 µg/mL) exposure has no effect. In this study, as in the Murature study, the measurement of phthalate diesters raises concern with sample contamination from the ubiquitous presence of the diester in the environment. The concentration of phthalates was inversely correlated with sperm morphology but not correlated with ejaculate volume, sperm concentration or motility. In another small study, conducted in India, Rozati et al. (2002) studied 21 infertile men with poor semen quality and 32 ‘control’ men with normal semen parameters. The study had a number of limitations, including a small number of participants, the failure to adjust for potential confounders and measurement of the parent compound, which may be subject to sample contamination. This study demonstrates inverse associations between AGD, penile width and testicular descent and one or more metabolites of DEHP, as well as between AGD and both MEP and MBP. This mini-review describes more than 20 years of controversy over the effects of BPA at low doses relevant to human exposure.Aging affects the endocrine glands, potentially affecting hormone production and secretion, and can cause disease.The consumers were satisfied by RAC, ensuring the risk of BPA exposure through the thermal paper was controlled.Read ahead to explore the research on BPA, its effects on male reproductive health, and what this means for fertility.Critical effects of BPA toxicity mostly occur during fetal development and postnatal development.Gestational, perinatal and neonatal exposures to BPA affect developmental processes, including brain development and gametogenesis, with consequences on brain functions, behavior, and fertility.In addition, weight-of-evidence studies conducted in 2006 and updated in 2009 reviewed a large number of studies and found no low-dose effects of BPA; there may be conflict of interest issues that underlie these interpretations 168,169,170.The findings highlight that BPA exposure during critical periods of fetal growth, such as the reproductive programming window, is linked to disruptions in hormone levels, early puberty, and potential alterations in key reproductive markers like AGD, penis length, and testicular function.Mammadov E, Uncu M, Dalkan C. High prenatal exposure to bisphenol A reduces anogenital distance in healthy male newborns. The action of PDE helps to ensure that a target cell’s response ceases quickly unless new hormones arrive at the cell membrane. The effects vary according to the type of target cell, the G proteins and kinases involved, and the phosphorylation of proteins. In the cAMP second messenger system, a water-soluble hormone binds to its receptor in the cell membrane (Step 1 in Figure 3. (Binding of Water-Soluble Hormones)). Except for thyroid hormones, which are lipid-soluble, all amino acid–derived hormones bind to cell membrane receptors that are located, at least in part, on the extracellular surface of the cell membrane. Hydrophilic, or water-soluble, hormones are unable to diffuse through the lipid bilayer of the cell membrane and must therefore pass on their message to a receptor located at the surface of the cell. Hormonal stimuli are changes in hormone levels that initiate or inhibit the secretion of another hormone. In contrast, hydrophilic hormones must interact with cell membrane receptors. Hydrophobic hormones are able to diffuse through the membrane and interact with an intracellular receptor. Research suggests that BPA is an endocrine disruptor, meaning that it negatively interferes with the endocrine system, particularly during the prenatal and postnatal development period. An endocrine gland may also secrete a hormone in response to the presence of another hormone produced by a different endocrine gland. Women in our study were originally recruited in the first phase of the Study for Future Families (SFFI), a multicentre pregnancy cohort study. In adult men, Hauser et al. (2004) reported high day-to-day and month-to-month variability in a person's urinary monoester concentrations, but demonstrated that a single sample may adequately predict average monoester concentrations over a three-month period. Several recent studies have explored temporal variability of urinary phthalate metabolites, and high within-individual variability has been reported over the course of several days (Fromme et al. 2007). Over the last 50 years, the 32.5% decrease in sperm concentration in men has been remarkable. In 2015, 8–12% of couples worldwide were infertile or had decreased fecundity , and 6.7% of females were infertile . At the hormonal level, phthalates can modify the release of hypothalamic, pituitary, and peripheral hormones. What You Can Do To Limit Your Exposure To Xenoestrogens Other evidence derived indirectly from cells or tissues of different lineages are discussed in the main text. Conversely, BPA can induce cell cycle inhibition in prostate cancer cells by activating androgen receptor (AR) and pathways involving estrogen receptor beta (ERβ)/EGFR complexes, ERK, and p53 . Low doses of BPA can also induce resistance in many types of cancer cells to classical chemotherapeutics such as doxorubicin, cisplatin, carboplatin, tamoxifen (TAM), bevacizumab, PARP inhibitors, vinblastine and other drugs both in vitro and in vivo (Table 1). EDCs interfere and prevent the binding of natural hormones to their receptors and/or can act as a hormone mimics; consequently, they exaggerate the effects of endogenous hormones 2, 8. Our research (Figure 1) has found that the effects of PFOA exposure on germ cells are more complex and depend on the stage of the differentiating germ cells. A more thorough investigation of the expression of nuclear receptors estrogen receptor beta, AR, and aromatase in the PFOS/PFOA-exposed dividing, differentiating, and maturing germ cells, as well as Leydig and Sertoli cells within the seminiferous tubule, is thus lacking. Any changes in the hormone levels or receptor expression could result in impaired spermatogenesis. Additionally, the expression levels of testicular receptors for gonadotropin, growth hormone, and IGF-1 were considerably reduced in mice exposed daily to PFOS . Interestingly, the BPA-GPR30 complex induces testicular seminoma cell proliferation in vitro, and incubation with G15, a GPR30 antagonist, reverts this effect . GPR30 is widely expressed in different cell types and cancer cell lines and is overexpressed in endometrial, breast, and ovarian cancers 75,76. In parallel, Garcia-Arevalo et al. shed light on BPA interference with glucose metabolism, showing that BPA exposure causes impaired glucose tolerance, body weight gain, and reduced insulin secretion in mice 73,74. Indeed, Wang et al. have indicated that GPR30 knockout (GPRKO) female mice are protected from high-fat diet (HFD)-induced obesity, blood glucose intolerance, and insulin resistance . Impact of microplastics via poultry food chain on human health It enters the human body via inhalation, ingestion (consumption of contaminated food and water), and through dermal exposure (TSAI 2006). Herein, we review the current literature on the role of BPA in hormone-dependent and hormone-independent human cancers, their mechanism of action, and their potential impact on cancer development. In vitro and in vivo studies have shown that BPA exposure has a pro-carcinogenic influence in hormone-dependent and hormone-independent cancers (Gao et al. 2015; Seachrist et al. 2016). Pupo et al. demonstrated that BPA activates G protein-coupled estrogen receptor 1 (GPER, ERK 1/2, EGFR) signaling pathway in cancer cells via inducing the expression of target genes coupled with G protein receptor (Pupo et al. 2012). This finding seems to be at the variance with the assumption that BPA is rapidly eliminated after ingestion and that the digestive tract represents the main source of exposure. Interestingly, when NHANES data were adjusted for the fasting hours preceding the collection of the urinary samples, no clear inverse relationship between fasting hours and urinary BPA levels was found (36). According to a recent study by Gerona et al. (35), these epidemiological data could even be underestimated. European Union and Brazil have set the permissible limit of 600 μg/kg in infant foods. Higher exposure rates of BPA are reported in Infants and children compared to adults. Simultaneously, the chance of getting BPA exposure from cashiers was not declared adequately in control. The consumers were satisfied by RAC, ensuring the risk of BPA exposure through the thermal paper was controlled. Bisphenol A reduces fertilizing ability and motility by compromising mitochondrial function of sperm. In vitro molecular mechanisms of bisphenol a action. Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys, and man. Anti-androgenic mechanisms of bisphenol a involve androgen receptor signaling pathway. Some studies have observed that early vaginal opening occurs in BPA-treated rodents (a sign of advanced puberty onset) 9,21. 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. Monje et al. even found that rats exposed in the neonatal period were incapable of producing an estradiol-induced LH surge. Indeed, during critical periods of perinatal development, aromatase is present in specific brain regions . Furthermore, the exposed workers had decreased FSH levels, while there was no difference between LH and FT levels compared to the controls . The results showed that bisphenol A diglycidyl ether can generate BPA endogenously with higher BPA levels in the urine of the epoxy resin workers when compared to controls. Similar hormonal changes were also detected in a study by Liu et al. that recruited 592 workers, with and without occupational exposure to BPA, and collected urine and blood samples. The main source of BPA in people is thought to be from residues in food, leaching out of certain types of polycarbonate and resin packaging. The US Food and Drug administration has committed itself to reducing BPA residues in food. It has previously caused concerns over health risks to babies, as it is present in some baby's bottles. BPA is a controversial chemical commonly used in food and drink containers. Researchers analysed data from the InCHIANTI study, an Italian population sample. In addition, since epigenetic changes can be potentially treated, target therapies could represent a very interesting topic of study in order to preserve fertility in subsequent generations.Polystyrene and polyvinyl chloride have been demonstrated to generate hazardous monomers that contribute to carcinogenesis and reproductive deformities in humans (Wang et al. 2016).This is in contrast to a previous study by Hauser et al. (2005), where they found interactions of MBP and MBzP with congener PCB 153 in relation to sperm motility.In particular, the patterns of epigenetic alterations in colorectal cancers suggests a link to environmental exposure in some groups 72, 74.Additionally, some foods that are often thought to raise estrogen levels, such as hops and fennel, may actually have a beneficial effect on hormone balance when consumed in moderation.The results showed that the global average sperm count dropped by half and that the sperm motility, viability, and acrosomal integrity significantly decreased.Sub-toxic doses of BPA could also enhance the glycolysis in an ERα-dependent manner resulting in higher levels of intracellular ATP production in ovarian cancer cells . The widespread use of BPA in a multitude of consumer products, particularly those related to food and beverage storage, has resulted in widespread human exposure. Furthermore, exploring effective interventions, increasing public awareness, and implementing regulatory measures are crucial steps in mitigating BPA’s adverse effects on reproductive health. Additionally, research is needed to address critical gaps in knowledge regarding the cumulative effects of low-dose exposure, transgenerational impacts, and the specific effects on male fertility. This interference poses risks to reproductive health, especially among younger individuals, as it may result in irregular menstrual cycles, ovulation issues, and compromised spermatogenesis. Therefore, even though promising research suggests that BPA can be biodegraded by certain types of bacteria, fungi, and algae , there is potential for environmental accumulation due to the substantial quantities released into the environment. However, recent studies suggest that certain strains (i.e., Bacillus) are able to effectively biodegrade BPA at high rates (10 mg/dm3) under anaerobic conditions . Under aerobic conditions, BPA appears to biodegrade quickly, as compared to other bisphenols, but under anaerobic conditions it does not degrade or does so very slowly . Not surprisingly, BPA has been detected in indoor air, dust, soil, water (dinking, surface, and ground), sediment, municipal and industrial waste, and food (for a review see ). In literature various studies indicate that reproductive and endocrine-related endpoints are important in risk assessment of BPA.15,16 In addition to presenting different genetic predispositions and daily life habits, the studies group men from a large age range and not by age group, considering that hormone levels vary over age. It was also related to changes in other hormone levels that may also contribute to male infertility. These compositional changes result in lower levels of butyrate and propionate, key metabolites that regulate intestinal epithelial energy supply and systemic glucose homeostasis through the GPR41/43–AMPK axis (Zhang et al., 2022). While these mediators are essential for pathogen clearance, their persistent expression transforms transient immune defense into chronic inflammation. Following oxidative stress and barrier disruption, environmental pollutants initiate a cascade of immune activation that can progress from acute mucosal inflammation to chronic systemic dysregulation (Samak et al., 2014). Results showed significantly higher urinary concentrations for all the phthalates in cases compared to controls, except for monoethylphthalate and BPA. All data were statistically elaborated considering information about clinical situation, life habits, occupational activity, and, for cases, semen parameters (volume, sperm concentration, total count of spermatozoa, and sperm motility). The urinary levels of seven phthalates and BPA were analyzed through HPLC/MS/MS. Moreover, the cause-effect relationship cannot be established due to the cross-sectional design of the studies as well as the large spontaneous between- and within-subject variability of semen parameters. • Increases cell proliferation, migration, most likely through AR-T877A • Increases aromatase (CYP19A) activity, androgen receptor (AR) expression in the ventral prostate, and also increases centrosome number • Decreases miR-149 expression and downregulates DNA repair gene (ARF6) and p53 and upregulates CCNE2 Studies revealed that fat in foods also contributes to the migration of particles. It depends on different factors, including the composition of different food items, duration of contact time, the food temperature during contact, and packaging material type refs. The migration of particles from the wrapping material to the food material is quite a complex phenomenon. It is due to the penetration of BPA from packaging into foodstuff and beverages (40, 41). BPA has influenced the pathogenesis of several reproductive health diseases, which include fibroids, polycystic ovarian syndrome (PCOS), endometriosis, female infertility, primary ovarian insufficiency (POI), etc., as well as led to an increase in the presentation of male infertility. Although substantial evidence from animal and in vitro studies supports the detrimental effects of BPA, there is a need for more human-focused research, particularly in developing countries, to confirm these findings. BPA's pervasive presence and its harmful effects on reproductive health underscore the need for global regulation and public awareness. In females, there was an association of BPA exposure with hormonal imbalances, reduced ovarian reserve, and increased likelihood of conditions such as fibroids, polycystic ovarian syndrome, endometriosis and infertility. Overall, while preclinical research has provided compelling evidence that bisphenols can negatively interfere with male reproduction, clinical studies have produced quite inconclusive results. The cells of the zona fasciculata produce hormones called glucocorticoids because of their role in glucose metabolism. When blood calcium levels are high, calcitonin is produced and secreted by the parafollicular cells of the thyroid gland. The thyroid gland also secretes a hormone called calcitonin that is produced by the parafollicular cells (also called C cells) that stud the tissue between distinct follicles. However, relying solely on mouse models may not fully capture the complexity of human reproductive physiology. In conclusion, differentially expressed proteins mediating the BPA-induced decline in Leydig cells were identified. Prenatal BPA exposure also disturbed steroidogenesis and arrested the meiotic zygotene-pachytene transition during spermatogenesis. There is an elevated proportion of headless and incomplete acrosome sperms, leading to decreased sperm-egg binding ability and disorders in early embryonic development, likely due to oxidative stress and DNA damage during spermatogenesis44. The men’s health topics we’re talking about.Now, the acknowledged biological effects of BPA are various.The monomeric form can leach from its source into adjacent materials such as into water or into the food products from the lining of the can.The ubiquitous presence and environmental persistence of BPA, along with its reputation of being an endocrine disruptor, is generating worldwide concerns about the possible links with a spectrum of human health disorders, including infertility.The study may inform future policy and practice, supporting more targeted, inclusive, and sustainable HIV responses.Major individual exposure occurs through ingestion, inhalation, or dermal absorption, and humans are exposed to these chemicals through multiple complex routes (Fig. 1).Gestational exposure to vinclozolin (100 mg/kg/day) was found to cause long lasting effects in reproductive organs (prostate, testes) as well as immune and kidney function in males from F1 to F4 . However, recent studies have shown that the lowest observed adverse effect level (LOAEL), which serves as the reference ADI, is much lower than currently accepted (20,000-fold lower). Summary representation of Bisphenol A (BPA) exposure pathways and main mechanisms involved in BPA-induced cardiotoxicity. In summary, the use of a high concentration range is crucial to determine the occurrence of toxic effects of substances, such as for BPA. Male sexual development and function rely on a fine balance of hormones throughout life, and therefore male fertility is potentially vulnerable to exposure to plastic compounds that are known as EDCs. Even if a correlation between specific metabolites and semen parameters did not emerge, we cannot exclude the impact of multiple exposure on the observed health effects, particularly on sperm motility (which is the most critical parameter). More specifically, BPA exposure can induce a disorganization and degeneration of sperm cells , a fragmentation of pyknotic nuclei, and a significant reduction in sperm cell number 40,41. Some authors have found an association between increased protamine levels mediating sperm apoptosis and DEHP exposure. In contrast, phthalates induce the delayed onset of puberty in some studies.A group of 308 healthy, young men from the general population have been chosen to examine the correlation between urinary BPA concentrations and semen quality or reproductive hormones.The authors conclude that in mice, BPA disrupts fetal liver maturation in a sex-specific manner and hypothesize that the decrease in C/EBPα may be responsible for the altered expression of albumin, alpha-fetoprotein, and glycogen synthase .Some 90 percent of the U.S. population carries detectable levels in the urine.By replacing the Zn atom with Ni or copper, binding of the estrogen receptor to the DNA hormone responsive elements in the cell nucleus is prevented.There is a lot of evidence that, when F0 pregnant S–D rats are exposed to BPA during gestation and lactation, sperm of adult F1 male rats and islets of male F2 offspring feature Igf2 hypermethylation and decreased expression. BPA exerts endocrine disruptor action due to its weak binding affinity for the estrogen receptors ERα and ERβ. Lindsey Manshack, a graduate student in Rosenfeld's lab in MU's Bond Life Sciences Center authored the study. "After analyzing the genes, we were able to link gene expression changes to behavioral changes." The gene expression changes identified in the BPA group were found to significantly alter mitochondrial and ribosomal pathways. Researchers examined whether BPA and ethinyl estradiol (EE), a hormone found in birth control pills, affect the global regulatory pathways of the brain. Another study on rats showed that exposure to BPA, as well as exposure to fungicides and pesticides, appears to cause ovarian cysts and fewer eggs in offspring—as many as three generations down the line (a rat’s great “grandchildren”). Before studies were conducted on humans, dozens of studies were conducted and are still being conducted in the lab. It is called an “endocrine disruptor” because it affects the body’s own hormones (its endocrine system) in ways that could be potentially harmful. Harvard Health Publishing provides trustworthy, evidence-based health content with the authority you demand and the impact you need. Gene-editing therapy lowers harmful blood fats in early study Choose the plan that fits your health goals. In conclusion, understanding the gut microbiota's role in pollutant toxicity not only deepens our insight into environmental pathophysiology but also opens new avenues for microbiota-targeted prevention, therapy, and policy innovation. Based on broad-spectrum usage the concerns about increased exposure to BPS have been resonating during the past years. A growing body of evidence indicates that BPA action is initiated through binding to relatively specific hormone receptors, including sex hormone receptors (ERs and ARs), thereby directly regulating gene expression (Cimmino et al. 2020). Child and adolescent male and female participants were selected in the next study carried out by Scinicariello and Buser (2016). The average value of total urinary BPA concentrations was 0.55 ng/ml in this experimental study. Semen quality was evaluated by measuring total sperm count, sperm concentrations, and sperm morphology or motility. Foods that Raise Estrogen Levels in Males The controversial studies can be justified through the different experimental approaches that are applied, as well as changes in the levels of doses, duration of exposure, or even the experimental model used. The ranges of these pharmacological concentrations are those that are required to cause effects at the cellular level, and are normally bigger than those required to cause harmful effects in vivo. It has become clear that BPA, even acting at lower doses as an EDC, can cause adverse effects on cardiovascular health, especially at more susceptible stages of development, such as pregnancy. Male reproductive functions are an important area affecting men’s overall health and well-being. Still, many people are concerned about the potential effects of even minimal exposure. Studies of exposure to lower levels of BPA have produced decidedly inconsistent results. (c). Human developmental studies BPA and its analogues, BPF and BPAF, also caused a decrease in testosterone levels in the plasma or testis of male rats and zebrafish 42,72,74,75,76. Furthermore, exposure to BPF and BPS for 28 days in male rats also decreased testicular and plasma testosterone 52,68,69,70. Therefore, from the previous findings, we may assume that BPA and its analogues at a lower dosage may increase LH and FSH levels via Kiss1 expression. Some phthalates exhibit estrogenic properties, which increase levels of endogenous estradiol. A systematic review by Fu et al. involved nine studies with 6579 probands. In addition, a US study recruited 3003 women aged 25–85, most of whom were non-Hispanic white, whereby 20 of them were diagnosed with ovarian cancer. Then, a US multiethnic study included 57 women diagnosed with leiomyoma aged 26–54. BPA acts like estradiol, stimulating different cell responses, although its affinity for the estrogen receptor is lower and its activity is approximately 10,000 to 100,000 times weaker compared to the natural hormone 17 beta estradiol (E2) 46,48. Low doses of this compound induce adverse effects on reproduction and regulation of the immune system, hormone-dependent cancers, and metabolism . BPA belongs to the endocrine-disrupting class of compounds and exhibits hormone-like properties. The public concern about the potentially harmful health effects of BPA resulted in a ban on many plastic products, particularly those used for infants and young children . Indeed, upon 10 months exposure to BPA, CD-1 mice feature a decrease of DNA methyltransferase levels, accompanied by hypomethylation and overexpression of genes involved in lipid synthesis, such as Srebf1 and Srebf2. Li et al. have demonstrated that chronic exposure of female mice to BPA (60 or 600 μg/kg/day) decreases HAND2 expression in uterine stroma, affecting embryo implantation and formation of the decidua during early phases of pregnancy . Among the HOX genes, HOXA9, HOXA10, HOXA11, and HOXA13 are expressed in the female reproductive system, while HOXB9 and HOXC6 are involved in the development of the mammary gland 116,117. In contrast, PPARγ does not emerge as an essential mediator of BPA action in human adipose-derived stem cells . Sarcopenic obesity (SO) is a serious public health concern, few studies have examined the clinical implications of SO in newly-diagnosed type 2 diabetes mellitus (T2DM) patients. The mean±standard deviation soluble DPP-4 levels in our study sample were 645±152 ng/mL. In this retrospective analysis, soluble DPP-4 levels were measured in preserved sera from 140 patients with type 2 diabetes mellitus who had participated in our previous coronary artery calcium (CAC) score study. This study examined the association between the serum soluble DPP-4 levels and renal function or cardiovascular risk in patients with type 2 diabetes mellitus. The study subjects were 13,908 male and 18,697 female adults aged 30 years or older who were free of liver cirrhosis. The exposed workers were exposed to very high BPA levels in their workplace. But the findings raise questions about whether exposure at lesser levels can affect sexual function, Li said. The workers had levels of exposure to BPA that were 50 times what an average U.S. man faces. "While the exact outcomes may differ in humans, there is reason for concern that sex-specific behavioral alterations are a significant risk following prenatal exposure to BPA," said Dr. Rodney Dietert, professor of immunotoxicology at Cornell University. Similarly, PFAS exposure pre-puberty and during puberty could be an important determinant to show more consistent associations between PFAS, testosterone levels, and sperm counts or impaired spermatogenesis in rodents. Additionally, exposure levels during “windows of susceptibility”, when the organ is more susceptible to hormonal effects, may give more consistent dose outcome results, rather than at the disease endpoint. The endocrine disruptor function of a chemical depends on its concentration within the system and can cause fluctuations in responses and non-monotonic responses, an inherent problem for both human epidemiological studies and for animal studies. As described in Table 3 and Table 4, changes in steroidogenic enzyme levels have been reported 93,116 for PFOS exposure, which could be due to loss of Leydig cell function 30,113. As described in Table 1, Table 2, Table 3 and Table 4 in more detail, for some studies, the levels of either serum or testicular testosterone appeared to decrease 32,36,92,93,108,111,112,113,114,115,116; in others, the level of estrogen increased 36,117. The estimated average dietary exposure of U.S. adults from the consumption of various protein sources exceeds 11,000 MP particles per year (Milne et al., 2024). Reported contamination levels range from 0.03 ± 0.04 to 1.19 ± 0.72 particles per gram in chicken meat (Abd El-Hack et al., 2025), 0.16–0.48 particles per gram in quail meat (Doğan et al., 2024), and approximately 11.7 particles per gram in chicken eggs (Amanatidou et al., 2024). For example, Japanese quail chicks that exhibited plastic consumption showed a higher frequency of male epididymis intraepithelial cysts compared to those that did not consume plastic (Roman et al., 2019). Studies indicate that the ingestion of MPs may pose risks to the reproductive systems of birds (de Souza et al., 2022; Roman et al., 2019). MPs damage the testicular tissue of male chickens and cause oxidative stress and inflammatory infiltration (Hou et al., 2022). Based on the results of cohort studies, we could not draw conclusions on the relationship between the phthalate exposure and effects on FSH and LH levels in men.They used a rat known as the Charles River Sprague Dawley and it doesn’t respond to synthetic hormones like BPA.Studies have shown the increased serum level of estradiol in females and reduced testosterone in males due to BPA (79, 80).EDCs disrupt sex hormone synthesis and balance, thereby perturbing endocrine, reproductive, cardiovascular, immune, and central nervous systems.Finally, to better investigate the possible role of occupational activity on reproductive health, ORs for infertility were calculated considering differences between cases and controls (Table 7).Expression ERα, ERβ, AR, AhR and PXR genes was positively correlated with BPA levels, suggesting their possible use as biomarkers for BPA intoxication.They found no significant difference between the PCOS and non-PCOS groups in recreational marijuana/cannabis use in the Australian cohort aged 24 to 30 years, but the study did find an increased prevalence of unhealthy lifestyle behaviors in women with PCOS compared with women without PCOS.The first guideline GLP-complaint study was conducted at RTI, a commercial animal testing firm, and was funded by the plastics industry lobbying arm (127).The association between BPA and ovarian cancer as well as the mechanisms of ovarian cancer development by BPA remain unclear. However, little attention has been paid to the effects of prenatal exposure on the reproductive potential of offspring mice. Bisphenol S(BPS) is a novel BPA analogue, can induce ROS in immature Leydig cells and directly inhibit the avtivity of 17β-hydroxysteroid dehydrogenase 3, leading to hypergonadotropic androgen deficiency in male rats41. Moreover, the proteins cyclin-H and cyclin-L2 were also downregulated upon BPA exposure, correlating with cell cycle arrest observed in our study. Our findings indicated that BPA exposure disrupted the protein expressions of the estrogen receptor and the steroid hormone receptor ERR2, aligning with our PCR outcomes for the genes Cyp11a1, Cyp17a1, Hsd3b1, and Hsd3b6. This can cause premature maturation of Leydig cells, characterized by an abnormal intratesticular paracrine milieu and disturbing proper development of germ cells40. FC, IS, and AC contributed to the conception and design of the study. Further research is needed to define the mechanisms underlying BPA-related epigenetic changes in paternal sperm and offspring phenotype and to find appropriate therapies to reduce the impact of BPA-induced dysfunctions. In addition, since epigenetic changes can be potentially treated, target therapies could represent a very interesting topic of study in order to preserve fertility in subsequent generations. The disturbances of these proteins lowered the integrity of BTB, which was proven by the reduction in cell viability and androgen receptor (AR) after 6 h of BPA exposure . The reduction of occludin was also found in the SCs, which were exposed to BPA in in vitro studies 82,83. However, the testosterone hormone helps release the mature spermatozoa into the lumen of the seminiferous tubule, thus preventing spermatozoa from being engulfed by the SC . In accordance, in Ob/Ob mice that lacking leptin gene, are affected by both obesity and hypogonadotropic hypogonadism; low expression rate of Kiss1 gene has been observed within the ARC of this animal model . This ensures that reproduction proceeds only when metabolic and environmental conditions are favorable. BPA has suggested obesogenic effects and raises the risk of obesity and weight gain interfering in adipogenesis, energy homeostasis, liver lipid composition, and insulin signaling within insulin-sensitive organs such as the liver, muscle tissue, and adipose tissues 24, 175. Accordingly, by means of calcium imaging, Klenke et al. (2016) demonstrated the direct inhibitory effects of BPA on the activity of GnRH neurons by mechanisms independent from ERβ, GPR30 and ERRγ which are expressed in GnRH neurons, and thus requiring non canonical signaling pathways . Two recent studies demonstrated the direct influence of BPA on the activity of Kiss/GnRH secreting neurons. Focusing on male reproductive health, phthalates have been suggested to produce adverse effects on gonadal and non-gonadal tissues. The mechanisms leading to male infertility are not completely clear, though changes in hormonal balance, particularly during sperm cell development, might affect the quality of spermatozoa. Routes of exposure to BPA and the accompanying effect on human reproductive health. Therefore, human reproductive health and development have been adversely affected by BPA. Furthermore, although seemingly subtle, small changes in hormone levels resulting from exposure may be of public health importance when considering the prevalence of exposure to plastic additives and EDCs among entire populations. Recently, the negative impact of BPA has been widely reported by scientists and has been identified as a well-known endocrine-disrupting chemical (EDC) 30,31,32. The most alarming concern is that BPA has also been detected in human biological samples, such as in the blood, urine, sweat, breast milk, and in the umbilical cord 19,20,21. Polycarbonate plastic is also used as packaging or as containers for many daily consumable products, such as vegetables, fruits, milk bottles, plastic bags, and food and beverage containers. Poultry can also be exposed to MPs through contaminated drinking water originating from agricultural runoff or environmental pollution as well as from airborne dust and deposition on feed, litter and birds. Global food security, nutrition and economic development largely depend on poultry production. Plastic residues in expired packaged foods may act as exposure sources for poultry (Cornelis et al., 2021). Additionally, it will provide mechanistic insights into how these MPs can be transferred from poultry to humans, posing significant health risks, and discuss the challenges in addressing this issue. Consequently, present evaluations of human exposure via poultry products predominantly depend on extrapolations from models that are either non-poultry or non-terrestrial in nature. Adiponectin—another hormone synthesized by adipose cells—appears to reduce cellular insulin resistance and to protect blood vessels from inflammation and atherosclerosis. One important example is leptin, a protein manufactured by adipose cells that circulates in amounts directly proportional to levels of body fat. An example of a hormone secreted by the stomach cells is gastrin, a peptide hormone secreted in response to stomach distention that stimulates the release of hydrochloric acid. The endocrine cells of the GI tract are located in the mucosa of the stomach and small intestine. In response, specialized cells in the wall of the atria produce and secrete the peptide hormone atrial natriuretic peptide (ANP).