Doses Of Bisphenol A Research Articles

Bisphenol-A disturbs hormonal levels and testis mitochondrial activity, reducing male fertility.

How does bisphenol-A (BPA) influence male fertility, and which mechanisms are activated following BPA exposure? BPA exposure causes hormonal disruption and alters mitochondrial dynamics and activity, ultimately leading to decreased male fertility. As public health concerns following BPA exposure are rising globally, there is a need to understand the exact mechanisms of BPA on various diseases. BPA exposure causes hormonal imbalances and affects male fertility by binding the estrogen receptors (ERs), but the mechanism of how it mediates the hormonal dysregulation is yet to be studied. This study consisted of a comparative study using mice that were separated into a control group and a group exposed to the lowest observed adverse effect level (LOAEL) (n = 20 mice/group) after a week of acclimatization to the environment. For this study, the LOAEL established by the US Environmental Protection Agency of 50 mg/kg body weight (BW)/day of BPA was used. The control mice were given corn oil orally. Based on the daily variations in BW, both groups were gavaged every day from 6 to 11 weeks (6-week exposure). Before sampling, mice were stabilized for a week. Then, the testes and spermatozoa of each mouse were collected to investigate the effects of BPA on male fertility. IVF was carried out using the cumulus-oocyte complexes from female hybrid B6D2F1/CrljOri mice (n = 3) between the ages of eight and twelve weeks. Signaling pathways, apoptosis, and mitochondrial activity/dynamics-related proteins were evaluated by western blotting. ELISA was performed to determine the levels of sex hormones (FSH, LH, and testosterone) in serum. Hematoxylin and eosin staining was used to determine the effects of BPA on histological morphology and stage VII/VIII testicular seminiferous epithelium. Blastocyst formation and cleavage development rate were evaluated using IVF. BPA acted by binding to ERs and G protein-coupled receptors and activating the protein kinase A and mitogen-activated protein kinase signaling pathways, leading to aberrant hormone levels and effects on the respiratory chain complex, ATP synthase and protein-related apoptotic pathways in testis mitochondria (P < 0.05). Subsequently, embryo cleavage and blastocyst formation were reduced after the use of affected sperm, and abnormal morphology of seminiferous tubules and stage VII and VIII seminiferous epithelial cells (P < 0.05) was observed. It is noteworthy that histopathological lesions were detected in the testes at the LOAEL dose, even though the mice remained generally healthy and did not exhibit significant changes in BW following BPA exposure. These observations suggest that testicular toxicity is more than a secondary outcome of compromised overall health in the mice due to systemic effects. Not applicable. Since the protein expression levels in the testes were validated, in vitro studies in each testicular cell type (Leydig cells, Sertoli cells, and spermatogonial stem cells) would be required to shed further light on the exact mechanism resulting from BPA exposure. Furthermore, the BPA doses employed in this study significantly exceed the typical human exposure levels in real-life scenarios. Consequently, it is imperative to conduct experiments focusing on the effects of BPA concentrations more in line with daily human exposures to comprehensively assess their impact on testicular toxicity and mitochondrial activity. These findings demonstrate that BPA exposure impacts male fertility by disrupting mitochondrial dynamics and activities in the testes and provides a solid foundation for subsequent investigations into the effects on male reproductive function and fertility following BPA exposure, and the underlying mechanisms responsible for these effects. In addition, these findings suggest that the LOAEL concentration of BPA demonstrates exceptional toxicity, especially when considering its specific impact on the testes and its adverse consequences for male fertility by impairing mitochondrial activity. Therefore, it is plausible to suggest that BPA elicits distinct toxicological responses and mechanistic endpoints based on the particular concentration levels for each target organ. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1A6A1A03025159). No competing interests are declared.

WITHDRAWN: Letter to editor: Evidence evaluated by EFSA does not support lowering the temporary tolerable daily intake for bisphenol A

The European Food Safety Authority (EFSA) recently derived a tolerable daily intake (TDI) for bisphenol A (BPA) of 0.2 ng/kg bw/day. There are several issues with EFSA's hazard assessment review process, including that it was based on a limited subset of relevant studies. Multiple public commenters on EFSA's draft evaluation of BPA, including several European regulatory agencies, noted these issues, yet they were not adequately addressed by EFSA in the final evaluation. The TDI for BPA was based on an intermediate immunotoxicity endpoint in mice that has not been observed in other species; there is no evidence that it is a precursor event to any downstream pathological outcome. The TDI is several orders of magnitude lower than estimates of safe doses of BPA established by agencies worldwide, including EFSA's temporary TDI (t-TDI) for BPA established in 2015. Overall, the EFSA hazard assessment review process has led to a conclusion that there are low-dose effects of BPA based on very few, lower quality experimental animal studies. This conclusion is not supported by the totality of the available evidence, which includes multiple high quality studies not considered by EFSA and indicates that the t-TDI established in 2015 is protective of human health.

Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model

Early embryonic development represents a sensitive time-window during which the foetus might be vulnerable to the exposure of environmental contaminants, potentially leading to heart diseases also later in life. Bisphenol A (BPA), a synthetic chemical widely used in plastics manufacturing, has been associated with heart developmental defects, even in low concentrations. This study aims to investigate the effects of environmentally relevant doses of BPA on developing cardiomyocytes using a human induced pluripotent stem cell (hiPSC)-derived model. Firstly, a 2D in vitro differentiation system to obtain cardiomyocytes from hiPSCs (hiPSC-CMs) have been established and characterised to provide a suitable model for the early stages of cardiac development. Then, the effects of a repeated BPA exposure, starting from the undifferentiated stage throughout the differentiation process, were evaluated. The chemical significantly decreased the beat rate of hiPSC-CMs, extending the contraction and relaxation time in a dose-dependent manner. Quantitative proteomics analysis revealed a high abundance of basement membrane (BM) components (e.g., COL4A1, COL4A2, LAMC1, NID2) and a significant increase in TNNC1 and SERBP1 proteins in hiPSC-CMs treated with BPA. Network analysis of proteomics data supported altered extracellular matrix remodelling and provided a disease-gene association with well-known pathological conditions of the heart. Furthermore, upon hypoxia-reoxygenation challenge, hiPSC-CMs treated with BPA showed higher rate of apoptotic events. Taken together, our results revealed that a long-term treatment, even with low doses of BPA, interferes with hiPSC-CMs functionality and alters the surrounding cellular environment, providing new insights about diseases that might arise upon the toxin exposure. Our study contributes to the current understanding of BPA effects on developing human foetal cardiomyocytes, in correlation with human clinical observations and animal studies, and it provides a suitable model for New Approach Methodologies (NAMs) for environmental chemical hazard and risk assessment.

#5402 ASSOCIATION BETWEEN URINARY N-ACETYL-β-D-GLUCOSAMINIDASE AND BISPHENOL AND ITS SUBSTITUTE EXPOSURE IN TAIWANESE ADULTS

Abstract Background and Aims Urinary N-acetyl-β-D-glucosaminidase (NAG) is a sensitive and reliable indicator of renal damage, like proximal tubular cell injury. Bisphenol A (BPA), a known endocrine disruptor, or its substitute has been reported as a risk factor that caused kidney damage in experimental studies. We aimed to investigate the correlation between urinary NAG and Bisphenol and its Substitute Exposure in Taiwanese Adults. Method We collected urine samples including 271 adults (145 female and 126 men) from Taiwan Environmental Survey for Toxicants 2013, and analyzed for three urinary BPA, BPS and BPF by using ultraperformance liquid chromatography–tandem mass spectrometry. The bisphenol and their substitutes in the human urine samples were converted into daily intake (DI) values. We measured by the indicators of renal function, included urine creatinine (crea, mg/dL), microalbumin (mg/dL), NAG (IU/L), etc. We used logistic regression analysis to elucidate their correlations and adjustment for significant covariate. Results We found the median levels were 7.96 for BPA, 7.89 for BPF, and 1.96 (μg/L) for BPS, respectively, and yielded a median estimate daily intakes were 3.01 (BPA), 2.99 (BPF), and 0.76 (BPS) (ng/kg/day) in the Taiwanese adults. We found that the ratio of urinary NAG and creatinine (NAG/crea) was a significantly increased trend with exposure doses of BPA, BPF and BPS whereas no similar trend for ACR. After adjustment for age, sex, BMI and other covariate, we found that DI of BPA increased the risk of NAG/crea by 5.8 times (ORAdj: 5.8, p&amp;lt;0.01, 2nd tertile) and 9.6 times (ORAdj: 9.6, p&amp;lt;0.01, 3rd tertile). Conclusion Our findings supported that the exposure of bisphenol and its substitute may increase the risk of renal tubular injury. Further large and longitudinal studies are warrant.

PBTK-TD model of the phagocytosis activity in three-spined stickleback exposed to BPA

Due to the high production volume and persistence in the environment of bisphenol A (BPA) and its substitutes, realistic exposure scenarii were proposed in some species to better understand the relationship between external and internal concentrations. For example, a recent PBTK model has been developed and adapted to BPA ADME (Absorption, Distribution, Metabolization, and Excretion) processes in three-spined stickleback. These substances have an impact on organism physiology including reproductive and immune functions. In this context, physiologically-based toxicokinetic models coupled with toxicodynamics (PBTK-TD) have proven to be valuable tools to fill the knowledge gap between external exposure and effect dynamics. The aim of the current work was to explain the impact of BPA on the immune response by determining its temporality. In addition, the relationship between BPA dose and these responses was investigated using a PBTK-TD model. Two experiments were performed on stickleback to characterize their biomarker responses, (i) a short exposure (14 days) at 0, 10 and 100 µg/L, including a depuration phase (7 days), and (ii) a long exposure (21 days) at 100 µg/L to measure the immunomarker dynamic over a long period. The fish spleens were sampled to analyze immune responses of stickleback at various times of exposure and depuration: leucocyte distribution, phagocytic capacity and efficiency, lysosomal presence and leucocyte respiratory burst index. At the same date, blood, muscle, and liver were sampled to quantify BPA and their metabolites (BPA monoglucuronide and BPA monosulfate). All these data enabled the development of the indirect pharmacodynamic models (PBTK-TD) by implementing the responses of biomarkers in the existing BPA PBTK of stickleback. The results shown a high induction of phagocytosis activity by BPA in the two exposure conditions. Furthermore, the immunomarkers exhibit very different temporal dynamics. This study demonstrates the need of a thorough characterization of biomarker response for a further use in Environmental Biomonitoring.

Propuesta de ruta de degradación del BPA durante la reacción del ozono

Endocrine-disrupting compounds (EDC) are present in surface water bodies that supply water to the population. One of them is bisphenol A (BPA), which is listed as a carcinogen. This research addresses its degradation through the ozone reaction and presents a likely pathway established by analyzing products and degradation products using gas chromatography-mass spectrometry (GC-MS). BPA degradation was carried out under pseudo-first-order conditions, where liquid phase ozone was the limiting reactive, in doses of ≈2.29 × 10-4 M and BPA doses of 1.25 × 10-4, 17.5 × 10-4, and 35.0 × 10-4 M, looking to have molar ratios [BPA]&gt; [O3]; the oxidation reaction was carried out in a stopped-flow system that allows obtaining results in the order of seconds. The degradation pathway obtained shows the rupture of one of the benzene rings, decreasing the phenolic toxicity of the BPA compound. The proposed pathway can contribute to the understanding of the degradation of BPA in the environment and tertiary treatment processes with the use of ozone. Likewise, it is intended to contribute with new data to the issues of drinking water treatment to offer safe water to the population.

Bisphenol A has a sex-dependent disruptive effect on hepatic lipid metabolism in zebrafish

Bisphenol A (BPA) is an endocrine disruptor that has adverse effects on lipid metabolism. However, most of the current studies on the effects of BPA on lipid metabolism in fish have focused on middle- and short-term exposure tests. The aim of this study was to investigate the effects of long-term BPA exposure on liver lipid metabolism in zebrafish. Post-fertilization embryos were exposed to environmentally relevant concentrations of BPA for 120 days, and the changes in triglyceride (TG), total cholesterol (TC) levels, and gene expression related to liver lipid metabolism were investigated in both male and female fish. The results showed that long-term exposure to BPA led to lipid deposition in liver, and there was a sex difference. In the liver of female fish, there was higher lipid transport and synthesis at low concentration of BPA, while overall metabolic levels were increased at high concentration of BPA. In contrast, BPA showed a dose-dependent effect on the lipid deposition in male fish. The expression of mRNA of TG transport-related and lipid synthesis-related genes was significantly up-regulated and the expression of genes related to lipid catabolism, was significantly down-regulated with increasing BPA dose. Taken together, our results indicate that long-term exposure to BPA can increase lipid deposition in a gender-specific manner. This may be due to the different responses of lipid metabolism related genes to BPA in male and female zebrafish. These results will provide a new reference for a deeper understanding of the ecotoxicological effects of BPA on aquatic animals.

Bisphenol A disruption promotes mammary tumor microenvironment via phenotypic cell polarization and inflammatory response.

Inflammation in the established tumor microenvironment (TME) is often associated with a poor prognosis of breast cancer. Bisphenol A (BPA) is an endocrine-disrupting chemical that acts as inflammatory promoter and tumoral facilitator in mammary tissue. Previous studies demonstrated the onset of mammary carcinogenesis at aging when BPA exposure occurred in windows of development/susceptibility. We aim to investigate the inflammatory repercussions of BPA in TME in mammary gland (MG) during neoplastic development in aging. Female Mongolian gerbils were exposed to low (50 µg/kg) or high BPA (5000 µg/kg) doses during pregnancy and lactation. They were euthanized at 18 months of age (aging) and the MG were collected for inflammatory markers and histopathological analysis. Contrarily to control MG, BPA induced carcinogenic development mediated by COX-2 and p-STAT3 expression. BPA was also able to promote macrophage and mast cell (MC) polarization in tumoral phenotype, evidenced by pathways for recruitment and activation of these inflammatory cells and tissue invasiveness triggered by tumor necrosis factor-alpha and transforming growth factor-beta 1 (TGF-β1). Increase of tumor-associated macrophages, M1 (CD68 + iNOS+) and M2 (CD163+) expressing pro-tumoral mediators and metalloproteases was observed; this aspect greatly contributed to stromal remodeling and invasion of neoplastic cells. In addition, the MC population drastically increased in BPA-exposed MG. Tryptase-positive MCs increased in disrupted MG and expressed TGF-β1, contributing to EMT process during carcinogenesis mediated by BPA. BPA exposure interfered in inflammatory response by releasing and enhancing the expression of mediators that contribute to tumor growth and recruitment of inflammatory cells that promote a malignant profile.

Забруднювач довкілля бісфенол А порушує програмування статевої поведінки у жіночого потомства щурів

Bisphenol A (BPA) is a common environmental pollutant and, due to its estrogenic properties, can cause disorders of the reproductive and other physiological systems of the body, especially in males. It is known that in male rats it disrupts the sexual differentiation of the brain (SDB) of the fetus in utero. Studies of the effects of perinatal exposure of fetuses and newborn females through the mother’s body under the conditions of long-term administration of BPA during pregnancy and lactation did not reveal significant changes in SDB. Identification of long-term endocrine, neuromorphological, and behavioral consequences of exposure of female rat fetuses to a low dose of BPA administered to mothers during the last week of pregnancy, which corresponds to the temporal period of SDB, was the aim of this study. Rats were orally administered BPA suspended in Dorfman gel at a daily dose of 25 μg/kg b.w., which is 200 times less than the NOAEL (no observed adverse effect level) for rats, via a gavage, or, as a positive control, estradiol diacetate (E2D) subcutaneously at a dose of 10 μg/kg b.w., during 15-21 days of pregnancy. Control animals received gel without BPA. The levels of estradiol, testosterone, and corticosterone in blood plasma, the response of the hypothalamic-pituitary-adrenal (HPA) axis to acute immobilization stress, sexual behavior, and the histological structure and karyometric parameters of neurocytes of the medial-preoptic nuclei (MPN) of the hypothalamus were studied in adult female offspring. Prenatal exposure to BPA or E2D decreased the concentration of estradiol in the blood plasma, while the levels of testosterone and corticosterone remained normal. In the females of the BPA and E2D groups, a masculinization of sexual behavior (mounting to a receptive female, approaching her, etc.) was observed, which, according to the number of lordosis reactions in the presence of a sexually experienced male, not accompanied by her defeminization. Changes in the morphology of the MPN, which belongs to the sex-dimorphic area of the brain, conformed to the masculinization of female sexual behavior due to prenatal exposure to a low dose of BPA. Karyometry of neurocytes of the hypothalamic MPN of rats revealed no difference between the control and the BPA group. The response of the HPA axis to immobilization stress did not change in both experimental groups. It is found for the first time that maternal exposure of in utero female rat fetuses to an ultra-low relative to the NOAEL dose of BPA during the last gestational week, which corresponds to the critical period of SDB impairs programming of sexual behavior in the direction of its masculinization and causes hypoestrogenemia at adulthood. Disorders of sexual behavior conformed to morphological changes of the hypothalamic MPN. The unidirectionality of functional disorders induced by prenatal exposure to BPA and the reference estrogenic drug E2D indicates that they are caused by the estrogenic properties of both substances.

Low Dose of BPA Induces Liver Injury through Oxidative Stress, Inflammation and Apoptosis in Long–Evans Lactating Rats and Its Perinatal Effect on Female PND6 Offspring

Bisphenol A (BPA) is a phenolic compound used in plastics elaboration for food protection or packaging. BPA-monomers can be released into the food chain, resulting in continuous and ubiquitous low-dose human exposure. This exposure during prenatal development is especially critical and could lead to alterations in ontogeny of tissues increasing the risk of developing diseases in adulthood. The aim was to evaluate whether BPA administration (0.036 mg/kg b.w./day and 3.42 mg/kg b.w./day) to pregnant rats could induce liver injury by generating oxidative stress, inflammation and apoptosis, and whether these effects may be observed in female postnatal day-6 (PND6) offspring. Antioxidant enzymes (CAT, SOD, GR, GPx and GST), glutathione system (GSH/GSSG) and lipid-DNA damage markers (MDA, LPO, NO, 8-OHdG) were measured using colorimetric methods. Inducers of oxidative stress (HO-1d, iNOS, eNOS), inflammation (IL-1β) and apoptosis (AIF, BAX, Bcl-2 and BCL-XL) were measured by qRT-PCR and Western blotting in liver of lactating dams and offspring. Hepatic serum markers and histology were performed. Low dose of BPA caused liver injury in lactating dams and had a perinatal effect in female PND6 offspring by increasing oxidative stress levels, triggering an inflammatory response and apoptosis pathways in the organ responsible for detoxification of this endocrine disruptor.

Cucumeropsis mannii seed oil ameliorates Bisphenol-A-induced adipokines dysfunctions and dyslipidemia.

This study demonstrated the therapeutic potentials of Cucumeropsis mannii seed oil (CMSO) capable of alleviating BPA-induced dyslipidemia and adipokine dysfunction. In this study, we evaluated the effects of CMSO on adipokine dysfunctions and dyslipidemia in bisphenol-A (BPA)-induced male Wistar rats. Six-week-old 36 albino rats of 100-200 g weight were assigned randomly to six groups, which received varied doses of BPA and/or CMSO. The administration of BPA and CMSO was done at the same time for 42 days by oral intubation. The adipokine levels and lipid profile were measured in adipose tissue and plasma using standard methods. BPA induced significant (p < .05) increases in triglycerides, cholesterol, leptin, LDL-C, and atherogenic and coronary risk indices in adipose tissue and plasma, as well as a decrease in adiponectin and HDL-C levels in Group II animals. BPA administration significantly (p < .05) elevated Leptin levels and reduced adiponectin levels. BPA plus CMSO reduced triglycerides, cholesterol, leptin, LDL-C, and atherogenic and coronary risk indices while increasing adiponectin levels and HDL-C in adipose tissue and plasma (p < .05). The results showed that BPA exposure increased adipose tissue as well as serum levels of the atherogenic index, triglycerides, cholesterol, coronary risk index, LDL-C, leptin, and body weight with decreased adiponectin levels and HDL-C. Treatment with CMSO reduced the toxicities caused by BPA in rats by modulating the body weight, adiponectin/leptin levels, and lipid profiles in serum and adipose tissue. This study has shown that CMSO ameliorates BPA-induced dyslipidemia and adipokine dysfunctions. We suggest for further clinical trial to establish the clinical applications.

Acute exposure to low-dose bisphenol A delays cardiac repolarization in female canine heart - Implication for proarrhythmic toxicity in large animals.

Bisphenol A (BPA) is a common environmental chemical with a range of potential adverse health effects. The impact of environmentally-relevant low dose of BPA on the electrical properties of the hearts of large animals (e.g., dog, human) is poorly defined. Perturbation of cardiac electrical properties is a key arrhythmogenic mechanism. In particular, delay of ventricular repolarization and prolongation of the QT interval of the electrocardiogram is a marker for the risk of malignant arrhythmias. We examined the acute effect of 10-9M BPA on the electrical properties of female canine ventricular myocytes and tissues. BPA rapidly delayed action potential repolarization and prolonged action potential duration (APD). The dose response curve of BPA on APD was nonmonotonic. BPA rapidly inhibited the IKr K+ current and ICaL Ca2+ current. Computational modeling indicated that the effect of BPA on APD can be accounted for by its suppression of IKr. At the tissue level, BPA acutely prolonged the QT interval in 4 left ventricular wedges. ERβ signaling contributed to the acute effects of BPA on ventricular repolarization. Our results demonstrate that BPA has QT prolongation liability in female canine hearts. These findings have implication for the potential proarrhythmic cardiac toxicity of BPA in large animals.

Mechanism of nephrotoxicity induced by chronic exposure of bisphenol A in mice based on oxidative stress and cell apoptosis

Bisphenol A (BPA) is widely used to produce epoxy resin and polycarbonate plastic products. In severe cases, these plastics may release BPA, which then infiltrates into the environment. Various concentrations of BPA have been found in most biological fluid. Its presence has been well shown to be closely related to many chronic diseases, including chronic kidney disease (CKD). However, little is known regarding the adverse effects of BPA exposure and its succedent cellular events on CKD. Hence, in the current in vivo study, we aimed to assess the effects of chronic exposure to BPA on animal nephrotoxicity through investigating oxidative stress and apoptosis. Upon exposure to BPA at 0.01, 0.1, and 1 mg/L via drinking water for four weeks, the mated and pregnant females were continuously exposed to BPA until weaning. Subsequently, three weeks old F1-male neonates were also orally challenged with the same three doses of BPA for ten weeks. The results showed that the kidneys of 0.1 and 1 mg/L BPA-treated mice were seriously damaged; the contents of serum renal function indexes and lipid peroxidation products were significantly increased, including urea nitrogen, creatinine, uric acid, and thiobarbituric acid reactive substances; the morphological structure of mouse kidneys was impaired; the expressions of antioxidant-related genes at mRNA and protein levels from mouse kidneys were markedly diminished, including glutathione-S-transferase, superoxide dismutase, and catalase; the expressions of genes and proteins related to apoptosis index (ratio of Bax/Bcl-1 and Caspase-3) were significantly enhanced. The data manifested that cumulative oxidative stress and apoptosis might play an essential role in the animal nephrotoxicity induced by chronic exposure to BPA.

The antioxidant effects of coenzyme Q10 on albino rat testicular toxicity and apoptosis triggered by bisphenol A.

Polycarbonate plastics for packaging and epoxy resins are both made with the industrial chemical bisphenol A (BPA). This investigation looked at the histological structure, antioxidant enzymes, and albino rats' testis to determine how coenzyme Q10 (CoQ10) impacts BPA toxicity. For the experiments, three sets of 18 male adult rats were created: group 1 received no therapy, group 2 acquired BPA, and group 3 got the daily BPA treatment accompanied by coenzyme Q10, 1h apart. The experimental period ran for 14days. The biochemical biomarkers catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) were altered as a result of BPA exposure. The testicular histological architecture, which is made up of apoptosis, was also exaggerated. Furthermore, rats given BPA and CoQ10 treatment may experience a diminution in these negative BPA effects. These protective properties of CoQ10 may be correlated with the ability to eliminate oxidizing substances that can harm living species. The outcomes might support the hypothesis that CoQ10 prevented oxidative damage and boosted rats' stress responses when BPA was introduced. Thus, by shielding mammals from oxidative stress, CoQ10 aids in the growth and development of the animals. BPA is extremely hazardous to humans and can persist in tissues. Human reproductive functions are a worry due to human exposure to BPA, especially for occupational workers who are typically exposed to higher doses of BPA. As a result, in order to reduce the health risks, BPA usage must be minimized across a diverse range of industries, and improper plastic container handling must be prohibited. By giving CoQ10 to patients, BPA's harmful effects on reproductive structures and functions may be avoided.

Effects of short-term exposure to low doses of bisphenol A on cellular senescence in the adult rat kidney

Bisphenol A (BPA) is one of the primary chemicals produced by volume worldwide. Extensive literature has raised many concerns about its possible involvement in the pathogenesis of kidney diseases, but its contribution has not been extensively studied. During cellular senescence, the interference of lipofuscin with cellular functions promotes further senescence, causing cellular malfunction. Insulin-like growth factor-1 (IGF-1) plays an important protective role in the setting of kidney injury. The goal of the present work was to evaluate the effects of short-term treatment with low doses of BPA on cellular senescence in adult rat kidneys. Male Wistar rats were injected with vehicle (CONTROL group) or 50 or 500 μg/kg/day of BPA for 1 week (BPA50 and BPA500 groups, respectively). The kidneys were fixed in 4% buffered formaldehyde and embedded in paraffin. Immunohistochemical analyses were performed, and an immunoreactive score (IRS) was calculated. Lipofuscin autofluorescence was used for the study of cellular senescence. The renal cortex showed diffuse autofluorescent lipofuscin signal in the proximal convoluted tubules (PCTs) of males in the BPA50-treated (weak intensity) and BPA500-treated (strong intensity) groups, but not in CONTROL males. Labeling of cortical PCTs with anti-IGF-1 antibodies showed an IRS of 0 in the CONTROL group, but IRSs of 4 and 6 in the BPA50- and BPA500-treated groups, respectively. The present results suggest that low, “safe” doses of BPA induce renal injury, as measured by histological signs of renal changes, increased cellular senescence, and activation of cellular repair systems in PCTs.

Effects of the long-term influence of bisphenol A and bisphenol S on the population of nitrergic neurons in the enteric nervous system of the mouse stomach

Bisphenol A (BPA) is an endocrine disruptor commonly used in the production of plastics. Due to its relatively well-known harmful effects on living organisms, BPA is often replaced by its various analogues. One of them is bisphenol S (BPS), widely used in the plastics industry. Until recently, BPS was considered completely safe, but currently, it is known that it is not safe for various internal organs. However, knowledge about the influence of BPS on the nervous system is scarce. Therefore, the aim of this study was to investigate the influence of two doses of BPA and BPS on the enteric nitrergic neurons in the CD1 strain mouse stomach using the double-immunofluorescence technique. The study found that both substances studied increased the number of nitrergic neurons, although changes under the impact of BPS were less visible than those induced by BPA. Therefore, the obtained results, for the first time, clearly indicate that BPS is not safe for the innervation of the gastrointestinal tract.

EFFECTS OF BISPHENOL A AND NICOTINE ON CYTOCHROME P450S IN BRAIN AND LIVER OF PREGNANT RATS

Bisphenol A (BPA), a widely used chemical, is associated with endocrine disruption through its interactions with the aryl hydrocarbon receptor (AhR). BPA crosses into the human body mostly through migration from plastic packaging into the daily diet. AhR regulates the expression of drug-metabolizing enzymes (DMEs), including numerous CYP450s, and mediates xenobiotic reactions. This study aims at examining how the expression of CYP450s expression is affected, in the brain and liver of pregnant rats, by exposure to BPA and nicotine. Pregnant female Sprague-Dawley dams were exposed to increasing doses of BPA; 0 (control), 50, 500, and 5000 g/kg/day , or in combination with nicotine; 3000 µg/kg/day, through drinking water. Brain and liver tissues were isolated after 2 weeks of exposure, and western blotting was used to assess the expression of selected protein targets. The results showed that BPA exposure decreased the expression levels of CYP1A1 and CYP1B1 in the brain (by 55% and 79% respectively). It also decreased CYP2E1 levels in the brain (by 42%), but increased its levels in the liver (by 126%). Moreover, BPA exposure decreased levels of CYP19A1 and ARNT in the liver (by 51% and 44% respectively), and decreased those of AhRR (AhR repressor) in the brain (by 28%). On the other hand, nicotine treatment exhibited an inhibitory effect with CYP1A1, CYP1B1, and AhRR in the brain (by 67%, 78%, and 13% respectively), whereas, it inhibited CYP1A1, CYP19A1, and ARNT (AhR Nuclear Translocator) in the liver (47%, 54%, and 63% respectively). In conclusion, adult brain and liver tissues showed BPA sensitivity, which disrupts CYP450s expression, and is modulated by nicotine. The observed effects could be mediated by AhR-ARNT-dependent or independent pathways, which need to be investigated further.

Low Doses of Bisphenol A Disrupt Neuronal Differentiation of Human Neuronal Stem/Progenitor Cells.

Bisphenol A (BPA) is an endocrine disrupting chemical. Human epidemiological studies have suggested that adverse neurobehavioral outcomes are induced by fetal exposure to BPA. The remarkable differences in the corticogenesis between human and agyrencephalic mammals are an increase in the intermediate progenitor cells (IPCs) and a following increase in the subplate thickness. It is uncertain whether low doses of BPA (low-BPA) affect human early corticogenesis when basal progenitor cells (BPs) produce IPCs resulting in amplified neurogenesis. In this study, human-derived neuronal stem/progenitor cells were exposed to low-BPA or the vehicle only, and the resultant cell type-specific molecular changes and morphology were analyzed. We focused on stem cells immunoreactive for SOX2, BPs for NHLH1, and immature neurons for DCX. SOX2-positive cells significantly decreased at day in vitro (DIV) 4 and 7, whereas NHLH1-positive cells tended to be higher, while DCX-positive cells significantly increased at DIV7 when exposed to 100 nM of BPA compared with the vehicle. Morphologically DCX-positive cells showed a decrease in unipolar cells and an increase in multipolar cells when exposed to 100 nM of BPA compared with the vehicle. These results provide insights into the in vivo effect of low-BPA on neuronal differentiation in the human fetal corticogenesis.

Changes in the Enteric Neurons Containing Selected Active Substances in the Porcine Descending Colon after the Administration of Bisphenol A (BPA)

Bisphenol A (BPA) is an endocrine disruptor widely distributed in the environment due to its common use in the plastics industry. It is known that it has a strong negative effect on human and animal organisms, but a lot of aspects of this impact are still unexplored. This includes the impact of BPA on the enteric nervous system (ENS) in the large intestine. Therefore, the aim of the study was to investigate the influence of various doses of BPA on the neurons located in the descending colon of the domestic pig, which due to similarities in the organization of intestinal innervation to the human gastrointestinal tract is a good animal model to study processes occurring in human ENS. During this study, the double immunofluorescence technique was used. The obtained results have shown that BPA clearly affects the neurochemical characterization of the enteric neurons located in the descending colon. The administration of BPA caused an increase in the number of enteric neurons containing substance P (SP) and vasoactive intestinal polypeptide (VIP) with a simultaneously decrease in the number of neurons positive for galanin (GAL) and vesicular acetylcholine transporter (VAChT used as a marker of cholinergic neurons). Changes were noted in all types of the enteric plexuses, i.e., the myenteric plexus, outer submucous plexus and inner submucous plexus. The intensity of changes depended on the dose of BPA and the type of enteric plexus studied. The results have shown that BPA may affect the descending colon through the changes in neurochemical characterization of the enteric neurons located in this segment of the gastrointestinal tract.

LBSUN310 Developmental Programming: Gestational Bpa Treatment Leads To Pancreatic Beta Cell Compromise

Abstract Developmental exposure to endocrine disrupting chemicals (EDC) such as bisphenol A (BPA) have been shown to be associated with many metabolic defects in humans. Studies in animals have documented detrimental effects of fetal exposure to BPA on metabolic variables such as insulin resistance, adiposity, and cardiac function. For instance, developmental exposure of sheep to bisphenol A (BPA), a ubiquitously present EDC, causes insulin resistance and compensatory hyperinsulinemia but the underlying mechanism of it is not fully understood. To determine if pancreatic hyperplasia or hypertrophy contributes to the hyperinsulinemic status and the ontogeny of these effects, pregnant Suffolk sheep were administered daily subcutaneous injections of BPA (0. 05, 0 .5 or 5 mg/Kg BW) in corn oil from days (D) 30-90 of gestation (term 147 days). Controls received corn oil during the same period. Pancreas were taken at Day 65 and 90 of gestation from control and 0.5mg/kg BPA (environmental exposure level)-treated female fetuses, and control and prenatal BPA-treated female offspring at 2 years of age (all 3 doses) during synchronized follicular phase of the cycle. Immunohistochemistry was used to determine beta cell number, size, and islet insulin content. In addition, to determine if the pancreas was fibrotic, islet collagen content was determined by Picro Sirius red staining and whole pancreas collagen content was measured with scroll collagen assay. Data were analyzed by ANOVA (Y2) and Students's t-test (D65 and D90), and magnitude of response by Cohen's Effect Size analysis. Findings showed large magnitude reduction of islet insulin content at day 65, significant decrease in islet insulin and beta cell count at D90 along with large magnitude decrease in pancreas/fetal weight. In contrast, in the Y2 sheep prenatal BPA treatment induced a large magnitude decrease in beta cell count (0. 05mg/kg dose group), a large magnitude increase in islet insulin content (5mg/kg dose group) and large magnitude increase in islet collagen content (all 3 BPA doses). The decrease in insulin in the D65 and D90 sheep along with the decrease in beta cells and pancreas/fetal weight at D90 indicates adverse developmental impact of BPA exposure on pancreatic beta cell differentiation. Increase in collagen accumulation in Y2 sheep likely contributes to the beta cell loss reflected as decrease in beta cell number seen in 0. 05 mg/kg dose of BPA. Absence of beta cell loss in 0.5 and 5mg/kg dose in the face of increased collagen is consistent with the nonmonotonic responses these EDCs manifest. Taken together, these results highlight the risks posed by developmental exposure to BPA on beta cell function and the corresponding risk for beta cell loss as animals age. Supported by NIH R01 grants ES016541 and ES030374 Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.