Effects Of Bisphenol A Research Articles

Exploring aryl hydrocarbon receptor (AhR) as a target for Bisphenol-A (BPA)-induced pancreatic islet toxicity and impaired glucose homeostasis: Protective efficacy of ethanol extract of Centella asiatica

The estrogenic impact of Bisphenol-A (BPA), a widely recognized endocrine disruptor, causes disruption of pancreatic β-cell function through estrogen receptors (ERs). While BPA's binding affinity for ERs is significantly lower than that of its natural counterpart, estrogen, recent observations of BPA's affinity for aryl hydrocarbon receptor (AhR) in specific cellular contexts have sparked a specific question: does AhR play a role in BPA's toxicological effects within the endocrine pancreas? To explore this question, we investigated BPA's (10 and 100 μg/ kg body weight/day for 21 days) potential to activate AhR within pancreatic islets and assessed the protective role of ethanol extract of Centella asiatica (CA) (200 and 400 mg/kg body weight/day for 21 days) against BPA-mediated toxicity in mouse model. Our results indicate that BPA effectively triggers the activation of AhR and modulates its target genes within pancreatic islets. In contrast, CA activates AhR but directs downstream pathways differentially and activates Nrf2. Additionally, CA was observed to counteract the disruption caused by BPA in glucose homeostasis and insulin sensitivity. Furthermore, BPA-induced oxidative stress and exaggerated production of proinflammatory cytokines were effectively counteracted by CA supplementation. In summary, our study suggests that CA influenced AhR signaling to mitigate the disrupted pancreatic endocrine function in BPA exposed mice. By shedding light on how BPA interacts with AhR, our research provides valuable insights into the mechanisms involved in the diabetogenic actions of BPA.

Bisphenol a alternatives suppress human and rat aromatase activity: QSAR structure-activity relationship and in silico docking analysis

The use of alternative substances to replace bisphenol A (BPA) has been encouraged. The objective of this study was to evaluate the effects of BPA and 9 BPA alternatives on human and rat aromatase (CYP19A1) in human and rat placental microsomes. The results revealed that bisphenol A, AP, B, C, E, F, FL, S, and Z, and 4,4′-thiodiphenol (TDP) inhibited human CYP19A1 and bisphenol A, AP, B, C, FL, Z, and TDP inhibited rat CYP19A1. The IC50 values of human CYP19A1 ranged from 3.3 to 172.63 μM and those of rat CYP19A1 ranged from 2.20 to over 100 μM. BPA alternatives were mixed/competitive inhibitors and inhibited estradiol production in BeWo placental cells. Molecular docking analysis showed that BPA alternatives bind to the domain between heme and steroid and form a hydrogen bond with catalytic residue Met374. Pharmacophore analysis showed that there were one hydrogen bond donor, one hydrophobic region, and one ring aromatic hydrophobic region. Bivariate correlation analysis showed that molecular weight, alkyl atom weight, and LogP of BPA alternatives were inversely correlated with their IC50 values. In conclusion, BPA alternatives can inhibit human and rat CYP19A1 and the lipophilicity and the substituted alkyl size determines their inhibitory strength.

Drivers of divergent assessments of bisphenol-A hazards to semen quality by various European agencies, regulators and scientists

The downward revision of the bisphenol A (BPA) Health-based Guidance Value (HBGV) by the European Food Safety Authority (EFSA) has led to disagreements with other regulatory agencies, among them the German Federal Institute for Risk Assessment (BfR). The BfR has recently published an alternative Tolerable Daily Intake (TDI), 1000-times higher than the EFSA HBGV of 0.2 ng/kg/d. While the EFSA value is defined in relation to immunotoxicity, the BfR alternative TDI is based on declines in sperm counts resulting from exposures in adulthood. Earlier, we had used semen quality deteriorations to estimate a BPA Reference Dose (RfD) of 3 ng/kg/d for use in mixture risk assessments of male reproductive health. We derived this estimate from animal studies of gestational BPA exposures which both EFSA and BfR viewed as irrelevant for human hazard characterisations. Here, we identify factors that drive these diverging views. We find that the fragmented, endpoint-oriented study evaluation system used by EFSA and BfR, with its emphasis on data that can support dose-response analyses, has obscured the overall BPA effect pattern relevant to male reproductive effects. This has led to a disregard for the effects of gestational BPA exposures. We also identify problems with the study evaluation schemes used by EFSA and BfR which leads to the omission of entire streams of evidence from consideration. The main driver of the diverging views of EFSA and BfR is the refusal by BfR to accept immunotoxic effects as the basis for establishing an HBGV. We find that switching from immunotoxicity to declines in semen quality as the basis for deriving a BPA TDI by deterministic or probabilistic approaches produces values in the range of 2.4–6.6 ng/kg/d, closer to the present EFSA HBGV of 0.2 ng/kg/d than the BfR TDI of 200 ng/kg/d. The proposed alternative BfR value is the result of value judgements which erred on the side of disregarding evidence that could have supported a lower TDI. The choices made in terms of selecting key studies and methods for dose-response analyses produced a TDI that comes close to doses shown to produce effects on semen quality in animal studies and in human studies of adult BPA exposures.

BPA and low-Se exacerbate apoptosis and autophagy in the chicken bursa of Fabricius by regulating the ROS/AKT/FOXO1 pathway

Bisphenol A (BPA) is a ubiquitous environmental pollutant that can have harmful effects on human and animal immune systems by inducing oxidative stress. Selenium (Se) deficiency damages immune organ tissues and exhibits synergistic effects on the toxicity of environmental pollutants. However, oxidative stress, cell apoptosis, and autophagy caused by the combination of BPA and low-Se, have not been studied in the bursa of Fabricius of the immune organ of poultry. Therefore, in this study, BPA and/or low-Se broiler models and chicken lymphoma cells (MDCC-MSB-1 cells) models were established to investigate the effects of BPA and/or low-Se on the bursa of Fabricius of poultry. The data showed that BPA and/or low-Se disrupted the normal structure of the bursa of Fabricius, BPA (60 μM) significantly reduced the activity of MDCC-MSB-1 cells and disrupted normal morphology (IC50 = 192.5 ± 1.026 μM). Compared with the Control group, apoptosis and autophagy were increased in the BPA or low-Se groups, and the generation of reactive oxygen species (ROS) was increased. This inhibited the AKT/FOXO1 pathway, leading to mitochondrial fusion/division imbalance (Mfn1, Mfn2, OPA1 were increased, DRP1 was decreased) and dysfunction (CI-NDUFB8, CII-SDHB, CIII-UQCRC2, CIV-MTCO1, CV-ATP5A1, ATP). Furthermore, combined exposure of BPA and low-Se aggravated the above-mentioned changes. Treatment with N-acetylcysteine (NAC) reduced ROS levels and activated the AKT/FOXO1 pathway to further alleviate BPA and low-Se-induced apoptosis and autophagy. Apoptosis induced by low-Se + BPA was exacerbated after 3-Methyladenine (3-MA, autophagy inhibitor) treatment. Together, these results indicated that BPA and low-Se aggravated apoptosis and autophagy of the bursa of Fabricius in chickens by regulating the ROS/AKT/FOXO1 pathway.

Distinct inhibitory strength of bisphenol A analogues on human and rat 11β-hydroxysteroid dehydrogenase 1: 3D quantitative structure-activity relationship and in silico molecular docking analysis

Bisphenol A (BPA) analogues are developed to replace BPA usage. However, their effects on 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) are largely unknown. The inhibitory effects of BPA and 10 BPA analogues with the substituents on the bridge moiety on human and rat 11β-HSD1 were explored in human and rat liver microsomes. The strength of inhibiting human 11β-HSD1 was bisphenol FL (IC50, 3.87 μM) > bisphenol Z (6.86 μM) > bisphenol AF (9.42 μM) > bisphenol C (16.14 μM) > bisphenol AP (32.14 μM) = bisphenol B (32.34 μM) > 4,4′-thiodiphenol (67.35 μM) > BPA (297.35 μM) > other BPA analogues (ineffective at 100 μM). The strength of inhibiting rat 11β-HSD1 was bisphenol Z (IC50, 14.44 μM) > 4,4′-thiodiphenol (19.01 μM) > bisphenol B (20.13 μM) > bisphenol F (22.10 μM) > bisphenol E (33.04 μM) > bisphenol AF (49.67 μM) > bisphenol C > (56.97 μM) > bisphenol AP (62.71 μM) >bisphenol FL (96.31 μM) > other BPA analogues (ineffective at 100 μM). Bisphenol A, AF, AP, B, C, F, FL, Z, and 4,4′-thiodiphenol bind to the active sites of human and rat 11β-HSD1. Regression of LogP and molecular weight with IC50 values revealed distinct inhibitory pattern (negative correlation for human 11β-HSD1 vs. positive correlation for rat enzyme). Regression of the lowest binding energy with IC50 values revealed a significant positive regression. 3D QSAR pharmacophore analysis showed one hydrogen bond acceptor and two hydrogen bond donors for human 11β-HSD1. In conclusion, most BPA analogues are more potent inhibitors of human and rat 11β-HSD1 enzymes and there is structure-dependent and species-dependent inhibition.

A new non-enzymatic biosensor for the determination of bisphenol-A.

In this study, a new non-enzymatic carbon paste biosensor was developed for the determination of Bisphenol-A (BPA) based on Multiwalled Carbon Nanotube (MWCNT) modified Myoglobin (Mb). The measurement principle of the biosensor was developed based on the inhibition effect of BPA on the heme group of myoglobin in the presence of hydrogen peroxide. With the designed biosensor, measurements were taken in the potential range of (-0.15V & +0.65V) using the differential pulse voltammetry (DPV) method in the medium containing K4[Fe(CN)6]. The linear range for BPA was determined to be 100-1000µM. Response time was calculated as 16s. The limit of detection was set at 89μM. As a result, it has been proven that MWCNT modified myoglobin based biosensor is an alternative method that can be used for BPA determination, giving very sensitive and fast results.

IVIVE-PBPK based new approach methodology for addressing early life toxicity induced by Bisphenol A

Bisphenol A (BPA) is a known endocrine disruptor mimicking natural estrogens with the potential to affect human health, especially during prenatal and postnatal exposure at or below current acceptable daily intake levels. Different adverse effects of BPA are still under investigation, and multiple mechanisms of action remain unexplored. This may be one of the reasons for the continuously changing tolerable daily intake (TDI) of BPA with the emergence of new adverse health effects over time. In addition, translational modelling through in vitro-in vivo extrapolation (IVIVE) can act as prerequisite bridge for translating in-vitro finding into human risk assessment. The objective of this study was to conduct in-vitro experiments and utilize an IVIVE-pregnancy physiologically based pharmacokinetic (P-PBPK) modeling to investigate developmental neurotoxicity and embryotoxicity in humans. The data obtained from human embryonic stem cells-based assays (study conducted between October 2020–2021) were used for the IVIVE-P-PBPK models to obtain the human equivalent doses (HEDs) which were further extrapolated to reference doses (RfDs). The results showed that simulated mean RfDs (μg/kg/day) derived from the HSD3B1 and NFATC2 gene of embryotoxicity and neurodevelopmental toxicity tests, respectively, were 4.94 and 5.18. The simulated RfDs were close to the temporary-tolerable daily intake (t-TDI) recommended by European Food Safety Authority (EFSA) in 2015 (t-TDI: 4 μg/kg·bw) and higher than the TDI of 2023 (0.2 ng/kg·bw). In conclusion, in-vitro toxicogenomics dose-response data combined with PBPK modeling can become a promising alternative new approach methodology (NAM) to support decision-making in chemical risk assessment. Based on the simulated RfDs derived from this NAM, the t-TDI set by EFSA in 2015 may be considered a safe exposure limit for mothers and fetuses at the current BPA intake levels in Chinese mothers. This study provided an animal-free new strategy for NAMs based risk assessment by combining toxicogenomics and computational toxicology.

Potential neuroprotective effect of nanomicellar curcumin on learning and memory functions following subacute exposure to bisphenol A in adult male rats.

Bisphenol A (BPA) is an endocrine-disrupting chemical commonly utilized in the manufacture of plastics, which may cause damage to brain tissue. Curcumin is a phytochemical with protective effects against neurological and mental diseases. The purpose of this research was to evaluate whether nanomicellar curcumin (NmCur) might protect rats against BPA-induced learning and memory deficits. After determining the proper dose of BPA, the animals were randomly divided into 8 groups (8 rats in each group) receiving dextrose 5% (as vehicle of NmCur) (Dex), sesame oil (as vehicle of BPA) (Sea), Sea plus Dex, NmCur (50mg/kg), BPA (50mg/kg), and 50mg/kg BPA plus 10, 25, and 50mg/kg NmCur groups, respectively. Behavioral tests performed using passive avoidance training (PAT), open-field (OF), and Morris water maze (MWM) tests. The expression of oxidative stress markers, proinflammatory cytokines, oxidative stress-scavenging enzymes, glutamate receptors, and MAPK and memory-related proteins was measured in rat hippocampus and cortical tissues. BPA up-regulated ROS, MDA, TNF-α, IL-6, IL-1β, SOD, GST, p-P38, and p-JNK levels; however, it down-regulated GSH, GPx, GR, CAT, p-AKT, p-ERK1/2, p-NR1, p-NR2A, p-NR2B, p-GluA1, p-CREB, and BDNF levels. BPA decreased step-through latency (STL) and peripheral and total, but not central, locomotor activity. It increased the time to find the hidden platform, the mean of escape latency time,and the traveled distance in the target quadrant, but decreased the time spent in the target quadrant. The combination of BPA (50mg/kg) and NmCur (25 and 50mg/kg) reversed all of BPA's adverse effects. Therefore, NmCur exhibited neuroprotective effects against subacute BPA-caused learning and memory impairment.

Association of urinary bisphenols with oxidative stress and inflammatory markers and their role in obesity

Bisphenol A (BPA) and its substitutes are widely used in daily life. Animal and cell line experiments have confirmed the effects of bisphenols on oxidative stress and inflammation. However, current population evidence for the effects of BPA alternatives, such as bisphenol F (BPF) and bisphenol S (BPS), on oxidative stress and inflammation is still sparse. Based on the National Health and Nutrition Examination Survey 2013–2016 data, our study used linear regression, weighted quantile sum model, and Bayesian kernel machine regression model to evaluate the effects of BPA, BPS, and BPF alone and in combination on oxidative stress (serum total bilirubin, and iron) and inflammation (alkaline phosphatase, C-reactive protein, γ-glutamyl transferase ferritin, neutrophil count, lymphocyte count, and neutrophil-to-lymphocyte ratio) markers. On this basis, the possible roles of oxidative stress and inflammation in obesity, which is associated with exposure to bisphenols (BPs), were initially explored. Based on the different covariates selected, a total of 3039 and 2258 participants were included in our study for models 1 and 2, respectively; the median age of participants was 48 years, and 48.7 % were male. Based on all models, our results showed that exposure to BPs alone or in combination was associated with downregulation of serum total bilirubin. Urinary BPF concentration was specifically associated with the neutrophil-to-lymphocyte ratio. Serum total bilirubin may play a role in the association between obesity and BP mixture exposure. Upregulation of the neutrophil-to-lymphocyte ratio was not associated with obesity. In conclusion, our study found that single or combined exposure to BPs, as measured in urine, may be associated with changes in oxidative stress and inflammatory markers, and a decrease in serum total bilirubin may play a mediating role in BP-induced obesity.

Effects of Endocrine Disrupting Chemicals (EDCs) on Skeletal System Development: A Review.

Endocrine-disrupting chemicals (EDCs) are exogenous substances that alter endocrine function and cause adverse effects on an organism. EDC interference with the endocrine system leads to chronic autoimmune disorders, abnormal osteogenesis, infertility, and reproductive, neurological, cardiovascular, and metabolic disorders. Among the adverse effects of EDCs are their impact on developing fetuses and neonates. EDCs like bisphenol A (BPA), pesticides, and lead interfere with or alter sex steroid hormone synthesis and metabolism, leading to developmental delay, infertility, and urogenital carcinoma in both sexes. This review article examines the most harmful EDC, BPA, which affects the skeletal system during the embryonic period. The literature investigates the effects of BPA on various systems in our body, but the mechanism behind skeletal system development during the embryonic period is still unknown. In the present review, 25 articles were reviewed through multiple windows like PubMed, Scopus, and Web of Science. Many articles mention the effects of BPA on the skeletal system after birth and also examine reproductive system abnormalities, hereditary characteristics, excretory system malfunctions, and physical and mental illness in various mechanisms. The impact of BPA on the skeletal system causes morphological and physiological changes in developing embryos. The general ideology regarding skeletal system development and its mechanism is as follows: the formation of bone (osteocytes) is reduced by the apoptosis of precursor bone cells (osteoblasts) by the effect of BPA. EDC exposure induces the apoptosis of bone cells and inhibits the formation of osteoblasts, and long-term exposure to these chemicals will also impact immune system development.

Chronic exposure to bisphenol A induces behavioural, neurochemical, histological, and ultrastructural alterations in the ganglia tissue of the date mussels Lithophaga lithophaga.

Bisphenol A (BPA), a common plastic additive, has been demonstrated mechanistically to be a potential endocrine disruptor and to affect a variety of body functions in organisms. Although previous research has shown that BPA is toxic to aquatic organisms, the mechanism of neurotoxic effects in marine bivalves remains unknown. The current study aimed to elucidate the neurotoxic effects of BPA when administered at different concentrations (0.25, 1, 2, and 5 µg/L) for twenty-eight days in the ganglia of a bivalve model, the Mediterranean mussel (Lithophaga lithophaga), which is an ecologically and economically important human food source of bivalve species in the Mediterranean Sea. Our findings revealed an increase in behavioural disturbances and malondialdehyde levels in treated mussel ganglia compared to the control group. Furthermore, superoxide dismutase activity increased in the ganglia of L. lithophaga treated with 0.25 and 2 µg/L. However, at BPA concentrations of 1 and 5 µg/L, SOD activity was significantly reduced, as was total glutathione concentration. BPA causes neurotoxicity, as evidenced by concentration-dependent inhibition of acetylcholinesterase, dopamine, and serotonin. After chronic exposure to BPA, neurons showed distortion of the neuronal cell body and varying degrees of pyknosis. The ultrastructure changes in BPA-treated groups revealed the lightening of the nucleoplasm and a shrunken nuclear envelope. Overall, our findings suggest that BPA exposure altered antioxidation, neurochemical biomarkers, histopathological, and ultrastructural properties, resulting in behavioural changes. As a result, our findings provide a basis for further study into the toxicity of BPA in marine bivalves.

Bisphenol AF Induces Alterations in the Plasma Lipidome of Rats: An Untargeted Lipidomics Approach.

Bisphenol AF has gained popularity as a substitute for bisphenol A in industrial applications, leading to its detection in various biological fluids and raising concerns for public health. While the effects of bisphenol A on lipid metabolism are known, the impact of bisphenol AF on different lipid classes remains understudied. This study aimed to address this gap by conducting an untargeted lipidomics analysis in rats to assess the influence of bisphenol AF on lipid homeostasis. The results of the study revealed significant alterations in lipid profiles in plasma with various lipid classes being affected by bisphenol AF exposure. High-dose exposure to bisphenol AF resulted in specific changes within lipid clusters, including a decrease in the fatty acyl lipid cluster, except for 3,6,9,12,15-octadecapentaenoic acid. Additionally, the compound 9-0-acetyl GTb1(d18:1/18:0) within the gangliosides subclass of the sphingolipids and the sterol lipid clusters was also affected. These findings contribute to a better understanding of how bisphenol AF disrupts lipid metabolism and its associated health effects. This study provides valuable insights into the potential risks posed by bisphenol AF. Further research in this area is warranted to explore the mechanisms underlying the bisphenol AF-induced dysregulation of lipid metabolism and its implications for human health.

Multilevel meta-analysis and dose-response analysis for bisphenol A (BPA) exposure on metabolic and neurobehavioral effects

Evidence suggests that oral exposure to bisphenol A (BPA) may result in adverse metabolic and neurobehavioral effects. The aim of the present meta-analysis is to examine this association based on systematically selected laboratory rodent studies published from 2012 to 2021 and sourced from Scopus, Web of Science, EmBase, and PubMed. Articles satisfying eligibility and inclusion criteria were included for the calculation of the summary standardised mean difference (SMD). Subgroup analysis and subsequent dose-response analysis were conducted if applicable. In total, 32 studies were analysed for 6 metabolic endpoints (cholesterol, triglycerides, insulin, glucose, leptin, and adiponectin) and 6 neurobehavioral endpoints (locomotor activity, exploratory, anxiety, depression, spatial learning and memory, non-spatial learning and memory). Summary SMDs implied that no significant effects were observed in endpoints considered. The dose was not determined as a significant moderator with regards to medium or high heterogeneity; however, there was significant impairment of spatial learning and memory at health-based guidance value (‘HBGV’) (0.05–9 mg (kg bw)−1 day−1) and ‘High’ (>9 mg (kg bw)−1 day−1) dose group. As a result, an indicative toxicological reference dose value of 0.034 mg (kg bw)−1 day−1 was proposed due to large variability. Potential harm to spatial learning and memory from BPA exposure requires further investigation. This study has provided some additional information on potential adverse metabolic and neurobehavioral effects of BPA from the perspective of meta-analysis which can inform the public, regulatory authorities, and policymakers.

Toxicity of bisphenol A (BPA) and its analogues BPF and BPS on the free-floating macrophyte Salvinia biloba

Evidence linking the toxicity of bisphenol A (BPA) to environmental and public-health issues has led to restrictions on its use. This compound has been gradually replaced with analogues proposed as a safer alternative, normally bisphenol F (BPF) and bisphenol S (BPS), but these substitutes are structurally almost identical to BPA, suggesting they may pose similar risks. The effects of BPA and these analogues were compared for antioxidant activity, lipid peroxidation, free-radical generation, photosynthetic pigments, and chlorophyll fluorescence in Salvinia biloba Raddi (S. biloba) plants exposed to environmentally relevant and sublethal concentrations (1, 10, 50, 100 and 150 μM). Bisphenol exposure promoted alterations in most of the physiological parameters investigated, with BPS toxicity differing slightly from that of the analogues. Furthermore, S. biloba removed similar levels of BPA and BPF from aqueous solutions with ≈70% removed at the 150 μM concentration, while BPS was less effectively removed, with only 23% removed at 150 μM. These findings show that high concentrations of bisphenols (10≥) are toxic to S. biloba, and even typical environmental levels (≤1 μM) can induce metabolic changes in plants, bringing to light that both BPA and its substitutes BPF and BPS pose risks to aquatic ecosystems.

Exposure to low dose of Bisphenol A (BPA) intensifies kidney oxidative stress, inflammatory factors expression and modulates Angiotensin II signaling under hypertensive milieu.

Humans are constantly exposed to low concentrations of ubiquitous environmental pollutant, Bisphenol A (BPA). Due to the prevalence of hypertension (one of the major risk factors of cardiovascular disease [CVD]) in the population, it is necessary to explore the adverse effect of BPA under hypertension associated pathogenic milieu. The current study exposed the Nω-nitro-l-arginine methyl ester (L-NAME) induced hypertensive Wistar rats to low dose BPA (50 μg/kg) for 30 days period. In tissue samples immunohistochemistry, real-time quantitative polymerase chain reaction and enzymatic assays were conducted. Moreover, studies on primary kidney cell culture were employed to explore the impact of low dose of BPA exposure at nanomolar level (20-80 nM range) on renal cells through various fluorescence assays. The observed results illustrate that BPA exposure potentiates/aggravates hypertension induced tissue abnormalities (renal fibrosis), oxidative stress (ROS generation), elevated angiotensin-converting enzyme activity, malfunction of the antioxidant and tricarboxylic acid cycle enzymes, tissue lipid abnormalities and inflammatory factor expression (both messenger RNA and protein level of TNF-α and IL-6). Further, in vitro exposure of nM levels of BPA to primary kidney cells modulates oxidative stress (both superoxide and total ROS), mitochondrial physiology (reduced mitochondrial transmembrane potential-∆ψm) and lipid peroxidation in a dose dependent manner. In addition, angiotensin II induced ROS generation was aggravated further by BPA during coexposure in kidney cells. Therefore, during risk assessment, a precise investigation on BPA exposure in hypertensive (CVD vulnerable) populations is highly suggested.

Effects of bisphenol A on murine salivary glands and human tumor cell lines

Bisphenol A (BPA) is an endocrine-disrupting chemical with a potential role in endocrine cancers. However, the effects of BPA on the salivary glands have been barely explored. We investigated the impact of in vivo sub-chronic exposure to BPA and its in vitro effects on human salivary gland mucoepidermoid carcinoma cell lines. Male and female mice were exposed to BPA (30 mg/kg/day). Sublingual and submandibular salivary glands from an estrogen-deficiency model were also analyzed. BPA concentration in salivary glands was evaluated by gas chromatography coupled to ion trap mass spectrometry. Immunohistochemical analysis using anti-p63 and anti-α-SMA antibodies was performed on mouse salivary gland tissues. Gene expression of estrogen receptors alpha and beta, P63 and α-SMA was quantified in mouse salivary gland and/or mucoepidermoid (UM-HMC-1 and UM-HMC-3A) cell lines. Cell viability, p63 and Ki-67 immunostaining were evaluated in vitro. BPA disrupted the tissue architecture of the submandibular and sublingual glands, particularly in female mice, and increased the expression of estrogen receptors and p63, effects that were accompanied by significant BPA accumulation in these tissues. Conversely, ovariectomy slightly impacted BPA-induced morphological changes. In vitro, BPA did not affect the proliferation of neoplastic cells, but augmented the expression of p63 and estrogen receptors. The present data highlight a potential harmful effect of BPA on salivary gland tissues, particularly in female mice, and salivary gland tumor cells. Our findings suggest that estrogen-dependent pathways may orchestrate the effects of BPA in salivary glands.

Effects of BPA Exposure and Recovery on the Expression of Genes Involved in the Hepatic Lipid Metabolism in Male Mice.

Exposure to Bisphenol A (BPA) has led to an increased risk of obesity and nonalcoholic fatty liver diseases (NAFLDs). However, it is as yet unclear if the damage caused by BPA is able to be repaired sufficiently after exposure has ceased. Therefore, this project aims to investigate the effects of BPA on the hepatic lipid metabolism function and its potential mechanisms in mice by comparing the BPA exposure model and the BPA exposure + cessation of drug treatment model. Herein, the male C57BL/6 mice were exposed in the dose of 50 μg/kg/day and 500 μg/kg/day BPA for 8 weeks, and then transferred to a standard chow diet for another 8 weeks to recover. Based on our previous RNA-seq study, we examined the expression patterns of some key genes. The results showed that the mice exposed to BPA manifested NAFLD features. Importantly, we also found that there was a significant expression reversion for SCD1, APOD, ANGPT4, PPARβ, LPL and G0S2 between the exposure and recovery groups, especially for SCD1 and APOD (p < 0.01). Notably, BPA could significantly decrease the level of APOD protein (p < 0.01) whereas there was an extremely significant increase after the exposure ceased. Meanwhile, APOD over-expression suppressed TG accumulation in the AML12 cells. In conclusion, the damage caused by BPA is able to be repaired by the upregulation of APOD and exposure to BPA should be carefully examined in chronic liver metabolic disorders or diseases.

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.

Ameliorative Effects of Zinc Oxide, in Either Conventional or Nanoformulation, Against Bisphenol A Toxicity on Reproductive Performance, Oxidative Status, Gene Expression and Histopathology in Adult Male Rats

Bisphenol A (BPA) is a widely used endocrine disruptor that represents a significant risk to male reproductive function. Zinc (Zn) is vital for appropriate development of testes and to guarantee optimal testicular function and spermatogenesis. Our goal was to investigate if zinc oxide (ZnO), either in conventional or nanoformulation, could safeguard adult male rats’ reproductive performance against the damaging effects of BPA. Signaling expression of CYP11A1 and Nrf-2 in the testis, testicular oxidant-antioxidant status, Bax/Bcl-2 apoptotic ratio, and histological examination of various reproductive organs were all evaluated. Twenty-eight adult male albino rats were divided randomly into 4 groups (7 animals each) including the control, BPA, conventional zinc oxide (cZnO) + BPA, and zinc oxide nanoparticles (ZnO-NPs) + BPA groups. The study was extended for 2 successive months. Our findings revealed strong negative effects of BPA on sperm cell characteristics such as sperm motility, viability, concentration and abnormalities. Additionally, BPA reduced serum levels of testosterone, triiodothyronine (T3), and thyroxine (T4). Also, it evoked marked oxidative stress in the testes; elevating malondialdehyde (MDA) and reducing total antioxidant capacity (TAC). BPA significantly downregulated testicular mRNA relative expression levels of CYP11A1 and Nrf-2, compared to control. Testicular apoptosis was also prompted by increasing Bax/ Bcl-2 ratio in testicular tissue. Histopathological findings in the testes, epididymis, prostate gland, and seminal vesicle confirmed the detrimental effects of BPA. Interestingly, cZnO and ZnO-NPs significantly alleviated all negative effects of BPA, but ZnO-NPs performed better. In conclusion, our findings point to ZnO, specifically ZnO-NPs, as a viable treatment for BPA-induced testicular dysfunction.

Exposure to Bisphenol A and Its Analogs among Thai School-Age Children.

Bisphenol F (BPF) and bisphenol S (BPS) have become popular substitutes for bisphenol A (BPA) in the plastic industry due to concerns over BPA's adverse effects. However, there is limited information on children's exposure to these chemicals. This study aims to assess the extent of BPA, BPF, and BPS exposure and determine factors that influence such exposure. A group of Thai children (age 6-13 years, N = 358) were recruited between October 2019 and 2020. Two first-morning voids were collected one week apart. Demographic and exposure-related information was gathered. Urinary concentrations of bisphenols were analyzed by liquid chromatography and tandem mass spectrometry. Correlation between bisphenol concentrations with age, body weight, and sources of bisphenol exposure, was determined using generalized estimating equations with linear model. BPA, BPF, and BPS were detected at 79.6%, 31.0%, and 16.8%, with geometric mean (GM) concentrations of 1.41, 0.013, and 0.014 ng/mL, respectively. Younger children aged <10 years exhibited 1.3-1.6 times higher GM levels of all bisphenols compared to older children. Exposure to food stored in plastic containers was associated with higher levels of BPF and BPS. In conclusion, BPA was the most frequently detected bisphenol in urine samples from Thai children, followed by BPF and BPS.