From cradle to grave: Deciphering sex-specific disruptions of the nervous and reproductive systems through interactions of 4-methylbenzylidene camphor and nanoplastics in adult zebrafish.

4-methylbenzylidene camphor (4-MBC) and micro/nanoplastics (MNPs) are common in personal care and cosmetic products (PCCPs) and consumer goods; however, they have become pervasive environmental contaminants. MNPs serve as carriers of 4-MBC in both PCCPs and the environment. Our previous study demonstrated that 4-MBC induces estrogenic effects in zebrafish larvae. However, knowledge gaps remain regarding the sex- and tissue-specific accumulation and potential toxicities of chronic coexposure to 4-MBC and MNPs. Herein, adult zebrafish were exposed to environmentally realistic concentrations of 4-MBC (0, 0.4832, and 4832 µg/L), with or without polystyrene nanoplastics (PS-NPs; 50 nm, 1.0 mg/L) for 21 days. Sex-specific accumulation was observed, with higher concentrations in female brains, while males exhibited comparable accumulation in the liver, testes, and brain. Coexposure to PS-NPs intensified the 4-MBC burden in all tested tissues. Dual-omics analysis (transcriptomics and proteomics) revealed dysfunctions in neuronal differentiation, death, and reproduction. 4-MBC-co-PS-NP exposure disrupted the brain histopathology more severely than exposure to 4-MBC alone, inducing sex-specific neurotoxicity and reproductive disruptions. Female zebrafish exhibited autism spectrum disorder-like behavior and disruption of vitellogenesis and oocyte maturation, while male zebrafish showed Parkinson's-like behavior and spermatogenesis disruption. Our findings highlight that PS-NPs enhance tissue accumulation of 4-MBC, leading to sex-specific impairments in the nervous and reproductive systems of zebrafish.

Description of Solvent-Extractable Chemicals in Thermal Receipts and Toxicological Assessment of Bisphenol S and Diphenyl Sulfone.

Research on thermal receipts has previously focused on the toxic effects of dermal exposure from the most publicized developers (e.g., bisphenol A (BPA) and bisphenol S (BPS)), while no studies have reported on the other solvent-extractable compounds therein. Diphenyl sulfone (DPS) is a sensitizer added to thermal receipts, but little is known about DPS concentrations in receipts or potential toxicity. Here, we quantified BPA, BPS, and DPS concentrations and tentatively identified the solvent-extractable compounds of thermal receipts collected from three South Dakota (USA) cities during 2016-2017. An immortalized chicken hepatic cell line, cultured as 3D spheroids, was used to screen effects of DPS, BPS, and 17ß estradiol (E2; 0.1-1000 µM) on cell viability and gene expression changes. These chemicals elicited limited cytotoxicity with LC50 values ranging from 113 to 143 µM, and induced dysregulation in genes associated with lipid and bile acid homeostasis. Taken together, this study generated novel information on solvent-extractable chemicals from thermal receipts and toxicity data for DPS.

Use of All-Male cyp17a1-Deficient Zebrafish (Danio rerio) for Evaluation of Environmental Estrogens.

Natural and synthetic environmental estrogens (EEs) are widespread and have received extensive attention. Our previous studies demonstrated that depletion of the cytochrome P450 17a1 gene (cyp17a1) leads to all-testis differentiation phenotype in zebrafish and common carp. In the present study, cyp17a1-deficient zebrafish with defective estrogen biosynthesis were used for the evaluation of EEs, as assessed by monitoring vitellogenin (vtg) expression. A rapid and sensitive assessment procedure was established with the 3-day administration of estradiol (E2), followed by examination of the transcriptional expression of vtgs in our cyp17a1-deficient fish. Compared with the control fish, a higher E2-mediated vtg upregulation observed in cyp17a1-deficient zebrafish exposed to 0.1 µg/L E2 is known to be estrogen receptor-dependent and likely due to impaired in vivo estrogen biosynthesis. The more responsive vtg expression in cyp17a1-deficient zebrafish was observed when exposed to 200 and 2000 µg/L bisphenol A (BPA) and perfluoro-1-octanesulfonate (PFOS). The estrogenic potentials of E2, BPA, and PFOS were compared and assessed by the feminization effect on ovarian differentiation in cyp17a1-deficient zebrafish from 18 to 50 days postfertilization, based on which a higher sensitivity of E2 in ovarian differentiation than BPA and PFOS was concluded. Collectively, through the higher sensitivity to EEs and the capacity to distinguish chemicals with different estrogenic potentials exhibited by the all-male cyp17a1-deficient zebrafish with impaired estrogen biosynthesis, we demonstrated that they can be used as an excellent in vivo model for the evaluation of EEs. Environ Toxicol Chem 2024;43:1062-1074. © 2024 SETAC.

Syringin alleviates bisphenol A-induced spermatogenic defects and testicular injury by suppressing oxidative stress and inflammation in male zebrafish.

Syringin (SRG) is a bioactive principle possessing extensive activities including scavenging of free radicals, inhibition of apoptosis, and anti-inflammatory properties. However, its effects on spermatogenic defects and testicular injury as well as the underlying mechanisms are still unclear. This study aims to investigate the protective effect of SRG on testis damage in zebrafish and explore its potential molecular events. Zebrafish testicular injury was induced by exposure to bisphenol A (BPA) (3000 µg/L) for two weeks. Fish were treated with intraperitoneal injection of SRG at different doses (5 and 50 mg/kg bodyweight) for two more weeks under BPA induction. Subsequently, the testis and sperm were collected for morphological, histological, biochemical and gene expression examination. It was found that the administration of SRG resulted in a significant protection from BPA-caused impact on sperm concentration, morphology, motility, fertility rate, testosterone level, spermatogenic dysfunction and resulted in increased apoptotic and reactive oxygen species' levels. Furthermore, testicular transcriptional profiling alterations revealed that the regulation of inflammatory response and oxidative stress were generally enriched in differentially expressed genes (DEGs) after SRG treatment. Additionally, it was identified that SRG prevented BPA-induced zebrafish testis injury through upregulation of fn1a, krt17, fabp10a, serpina1l and ctss2. These results indicate that SRG alleviated spermatogenic defects and testicular injury by suppressing oxidative stress and inflammation in male zebrafish.

Rats' testicular toxicity induced by bisphenol A is lessened by crocin via an antiapoptotic mechanism and bumped P-glycoprotein expression.

Bisphenol A (BPA) engenders testicular toxicity via hydroxyl free radical genesis in rat striatum and depletion of the endogenous antioxidants in the epididymal sperms. The multi-drug resistance efflux carrier; P-glycoprotein (P-gp) expel the BPA from the testis and is responsible for the testicular protection through the deactivation of numerous xenobiotics. In our study, we investigated whether the BPA-induced testicular toxicity could be circumvented through administration of an antioxidant; crocin (Cr). Implication of P-gp expression was also investigated. Rats administered BPA (10 mg/kg b.w. orally for 14 days), dropped the body weight, testes/body weight ratio, total protein content, testosterone, follicle stimulating hormone, luteinizing hormone, and sperm motility & count, total antioxidant status, glutathione content and antioxidant enzymes (superoxide dismutase and catalase), concomitant with the elevation of the percentage abnormal sperm morphology, as well as testicular lipid peroxides and nitrite/nitrate levels. Histopathological examination showed spermatogenesis disorders after the BPA rats exposure. The immunohistochemical study showed up-regulation of the P-gp as evident by increasing immunoreactivity in interstitial cells, with positive localization in some spermatogonia cells. The BPA-treated rats showed positive immunoreactivity against caspase-3. The co-intake of Cr (200 mg/kg b.w./day, i.p. 14 days) along with the BPA, significantly ameliorated all the mentioned parameters, boosted histopathological image, fell the caspase-3 up-regulation, and perched the P-gp expression. We showed that, Cr promotes P-gp as an approach to nurture the testicles against the BPA toxicity. In conclusion; Cr lessens the oxidative stress conditions to safeguard rats from the BPA-induced testicular toxicity and sex hormones abnormalities, reducing apoptosis and up-regulating P-gp.

Deciphering the mechanisms and interactions of the endocrine disruptor bisphenol A and its analogs with the androgen receptor.

Bisphenol A (BPA) and its various forms used as BPA alternatives in industries are recognized toxic compounds and antiandrogenic endocrine disruptors. These chemicals are widespread in the environment and frequently detected in biological samples. Concerns exist about their impact on hormones, disrupting natural biological processes in humans, together with their negative impacts on the environment and biotic life. This study aims to characterize the interaction between BPA analogs and the androgen receptor (AR) and the effect on the receptor's normal activity. To achieve this goal, molecular docking was conducted with BPA and its analogs and dihydrotestosterone (DHT) as a reference ligand. Four BPA analogs exhibited higher affinity (-10.2 to -8.7 kcal/mol) for AR compared to BPA (-8.6 kcal/mol), displaying distinct interaction patterns. Interestingly, DHT (-11.0 kcal/mol) shared a binding pattern with BPA. ADMET analysis of the top 10 compounds, followed by molecular dynamics simulations, revealed toxicity and dynamic behavior. Experimental studies demonstrated that only BPA disrupts DHT-induced AR dimerization, thereby affecting AR's function due to its binding nature. This similarity to DHT was observed during computational analysis. These findings emphasize the importance of targeted strategies to mitigate BPA toxicity, offering crucial insights for interventions in human health and environmental well-being.

Mechanistic interplay of dual environmental stressors: Bisphenol-A and cadmium-induced ovarian follicular damage and hepatocyte dysfunction in vivo.

This study investigates the individual and combined toxic effects of Bisphenol A (BPA) and Cadmium (Cd) in zebrafish, recognizing the complex mixture of pollutants organisms encounter in their natural environment. Examining developmental, neurobehavioral, reproductive, and physiological aspects, the study reveals significant adverse effects, particularly in combined exposures. Zebrafish embryos exposed to BPA + Cd exhibit synergistically increased mortality, delayed hatching, and morphological abnormalities, emphasizing the heightened toxicity of the combination. Prolonged exposure until 10 days post-fertilization underscores enduring effects on embryonic development. BPA and Cd induce oxidative stress, as evidenced by increased production of reactive oxygen species and lipid peroxidation. This oxidative stress disrupts cellular functions, affecting lipid metabolism and immune response. Adult zebrafish exposed to BPA and Cd for 40 days display compromised neurobehavioral functions, altered antioxidant defenses, and increased oxidative stress, suggesting potential neurotoxicity. Additionally, disruptions in ovarian follicle maturation and skeletal abnormalities indicate reproductive and skeletal impacts. Histological analysis reveals significant liver damage, emphasizing the synergistic hepatotoxicity of BPA and Cd. Molecular assessments further demonstrate compromised cellular defense mechanisms, synaptic function, and elevated cellular stress and inflammation-related gene expression in response to combined exposures. Bioaccumulation analysis highlights differential tissue accumulation patterns. In conclusion, this study provides comprehensive insights into the multifaceted toxicological effects of BPA and Cd in zebrafish, raising concerns about potential adverse impacts on environmental ecosystems and human health.

Bisphenols can promote antibiotic resistance by inducing metabolic adaptations and natural transformation.

Whether bisphenols, as plasticizers, can influence bacterial uptake of antibiotic resistance genes (ARGs) in natural environment, as well as the underlying mechanism remains largely unknown. Our results showed that four commonly used bisphenols (bisphenol A, S, F, and AF) at their environmental relative concentrations can significantly promote transmission of ARGs by 2.97-3.56 times in Acinetobacter baylyi ADP1. Intriguingly, we observed ADP1 acquired resistance by integrating plasmids uptake and cellular metabolic adaptations other than through reactive oxygen species mediated pathway. Metabolic adaptations including upregulation of capsules polysaccharide biosynthesis and intracellularly metabolic enzymes, which enabled formation of thicker capsules for capturing free plasmids, and degradation of accumulated compounds. Simultaneously, genes encoding DNA uptake and translocation machinery were incorporated to enhance natural transformation of antibiotic resistance carrying plasmids. We further exposed aquatic fish to bisphenols for 120 days to monitor their long-term effects in aquatic environment, which showed that intestinal bacteria communities were dominated by a drug resistant microbiome. Our study provides new insight into the mechanism of enhanced natural transformation of ARGs by bisphenols, and highlights the investigations for unexpectedly-elevated antibiotic-resistant risks by structurally related environmental chemicals.

Molecular insights into the antioxidative and anti-inflammatory effects of P-coumaric acid against bisphenol A-induced testicular injury: In vivo and in silico studies.

This study investigated the protective effects of p-coumaric acid (PCA) against bisphenol A (BPA)-induced testicular toxicity in male rats. The rats were divided into control, BPA, BPA+PCA50, BPA+PCA100, and PCA100 groups. Following a 14-day treatment period, various analyses were conducted on epididymal sperm quality and testicular tissues. PCA exhibited dose-dependent cytoprotective, antioxidant, and anti-inflammatory effects, ameliorating the decline in sperm quality induced by BPA. The treatment elevated antioxidant enzyme activities (SOD, GPx, CAT) and restored redox homeostasis by increasing cellular glutathione (GSH) and reducing malondialdehyde (MDA) levels. PCA also mitigated BPA-induced proinflammatory responses while reinstating anti-inflammatory IL-10 levels. Apoptotic parameters (p53 and p38-MAPK) were normalized by PCA in BPA-treated testicular tissue. Immunohistochemical and immunofluorescent analyses confirmed the cytoprotective and anti-inflammatory effects of PCA, evidenced by the upregulation of HO-1, Bcl-2, and Nrf-2 and the downregulation of the proapoptotic gene Bax in BPA-induced testicular intoxication. PCA corrected the disturbance in male reproductive hormone levels and reinstated testosterone biosynthetic capacity after BPA-induced testicular insult. In silico analyses suggested PCA's potential modulation of the oxidative stress KEAP1/NRF2/ARE pathway, affirming BPA's inhibitory impact on P450scc. This study elucidates BPA's molecular disruption of testosterone biosynthesis and highlights PCA's therapeutic potential in mitigating BPA's adverse effects on testicular function, showcasing its cytoprotective, anti-inflammatory, and hormone-regulating properties. The integrated in vivo and in silico approach offers a comprehensive understanding of complex mechanisms, paving the way for future research in reproductive health and toxicology, and underscores the importance of employing BPA-free plastic wares in semen handling.

Toxic effects of environmental concentration Bisphenol AF exposure on the survival, growth and reproduction of adult male Oryzias curvinotus.

Bisphenol AF (BPAF) is a novel environmental endocrine disruptor, and is widely detected in the aquatic environment, which is a potential threat to the health of fish. In this study, male Oryzias curvinotus were exposed to environmental concentrations (0.93 and 9.33 µg/L) of BPAF for 21 days. The effects of BPAF on survival, growth, reproduction, liver and testis histology, and gene transcriptional profiles of O. curvinotus were investigated. The results showed that the survival rate of male O. curvinotus slight decrease with increasing BPAF concentration, and there was no significant effect on body length, body weight, and K-factor. BPAF (9.33 µg/L) caused significant changes in testicular structure and reduced spermatid count in O. curvinotus. Changes in transcript levels of some antioxidant-related genes in gills and liver following BPAF exposure, imply an effect of BPAF on the immune system. After BPAF exposure, chgs and vtgs were up-regulated, validating the estrogenic effect of BPAF. In the hypothalamic - pituitary - gonadal axis (HPG) results, erα, erγ and cyp19a1b were all up-regulated in the brain, and the 0.93 µg/L BPAF group was more up-regulated than the 9.33 µg/L BPAF group. In testis, BPAF significantly up-regulated the mRNA expression level of cyp17a1 and cyp11b, while significantly down-regulated mRNA expression level of cyp11a, and cyp19a1 was significantly down-regulated only in the 0.93 µg/L BPAF group. In conclusion, environmental levels of BPAF have adverse effects on the survival and reproduction of O. curvinotus, and the potential toxic effects of environmental levels of BPAF cannot be ignored.

Cuscuta chinensis flavonoids alleviate ovarian damage in offspring female mice induced by BPA exposure during pregnancy by regulating the central carbon metabolism pathway.

Pregnancy is a sensitive window period for bisphenol A (BPA) exposure. BPA can pass through the placenta and cause reproductive damage in offspring female mice. Even BPA that is not metabolized during lactation can be passed through milk. Cuscuta chinensis flavonoids (CCFs) can alleviate reproductive damage caused by BPA, but the mechanism of action is unclear. To investigate the potential mitigating impact of CCFs on ovarian damage resulting from BPA exposure during pregnancy, we administered BPA and CCFs to pregnant mice during the gestational period spanning from 0.5 to 17.5 days. Aseptic collection of serum and ovaries from female mice was conducted on postnatal day 21 (PND21). Serum hormone levels and tissue receptor levels were quantified utilizing ELISA and PCR, while ovaries underwent sequencing and analysis through transcriptomics and metabolomics techniques. Additionally, the assessment of ovarian oxidative stress levels was carried out as part of the comprehensive analysis. The results showed that CCFs administration mitigated the adverse effects induced by BPA exposure on ovarian index, hormone levels, receptor expression, and mRNA expression levels in female offspring mice. The joint analysis of transcriptome and metabolome revealed 48 enriched pathways in positive ion mode and 44 enriched pathways in negative ion mode. Among them, the central carbon metabolism pathway is significantly regulated by BPA and CCFs. The screened sequencing results were verified through qPCR and biochemical kits. In this study, CCFs may participate in the central carbon metabolism pathway by reducing the expression of Kit proto-oncogene (Kit), hexokinase 1 gene (Hk1) and pyruvate kinase M (Pkm) mRNA and increasing the expression of h-ras proto-oncogene (Hras), sirtuin 3 (Sirt3), sirtuin 6 (Sirt6) and TP53 induced glycolysis regulatory phosphatase gene (Tigar) mRNA, thereby resisting the effects of BPA on the body. At the same time, the metabolic levels of D-Fructose 1,6-bisphosphate and L-Asparagine tend to be stable. Moreover, CCFs demonstrated a capacity to diminish the BPA-induced escalation in reactive oxygen species (ROS) and malondialdehyde (MDA). Simultaneously, it exhibited the ability to elevate levels of glutathione (GSH) and catalase (CAT), thereby effectively preventing peroxidation. In summary, CCFs alleviate BPA-induced ovarian damage in offspring female mice by regulating the central carbon metabolism pathway. This study will improve the information on BPA reproductive damage antagonist drugs and provide a theoretical basis for protecting animal reproductive health.

Bisphenol A promotes cell death in healthy respiratory system cells through inhibition of cell proliferation and induction of G2/M cell cycle arrest.

Bisphenol A (BPA) is a substance that can harm the environment and human health by interfering with the normal functioning of the body's hormonal system. It is commonly found in various plastic-based products such as cosmetics, canned foods, beverage containers, and medical equipment and as well as it can also be absorbed by inhalation. There have been limited studies on the effects of BPA on lung fibroblasts, and it is still unclear how high levels of BPA can impact respiratory system cells, particularly the lungs and trachea. In this research, we aimed to investigate the cell cycle disruption potential of BPA on respiratory system cells by examining healthy trachea and lung cells together for the first time. The findings indicated that BPA exposure can alter the healthy cells' morphology, leading to reduced cellular viability that has been assessed by MTT and SRB assays. BPA treatment was able to activate caspase3 as expected, which could cause apoptosis in treated cells. Although the highest dose of BPA did not increase the apoptotic rate of rat trachea cells, it remarkably caused them to become necrotic (52.12%). In addition to quantifying the induction of apoptosis and necrosis by BPA, cell cycle profiles were also determined using flow cytometry. Thereby, BPA treatment unexpectedly inhibited the cell cycle's progression by causing G2/M cell cycle arrest in both lung and tracheal cells, which hindered cell proliferation. The findings of the study suggested that exposure to BPA could lead to serious respiratory problems, even respiratory tract cancers via alterations in the cell cycle.

Associations of Bisphenols Exposure and Hyperuricemia Based on Human Investigation and Animal Experiments.

Hyperuricemia is characterized by elevated blood uric acid (UA) levels, which can lead to certain diseases. Epidemiological studies have explored the association between environmental contaminant exposure and hyperuricemia. However, few studies have investigated the role of chemical exposure in the development of hyperuricemia. Here, we sought to investigate the effects of bisphenol exposure on the occurrence of hyperuricemia. Fifteen bisphenol chemicals (BPs) were detected in human serum and urine samples collected from an area with a high incidence of hyperuricemia in China. Serum UA levels positively correlated with urinary bisphenol S (BPS), urinary bisphenol P (BPP), and serum bisphenol F (BPF). The effects of these three chemicals on UA levels in mice were explored at various exposure concentrations. An increase in serum UA levels was observed in BPS- and BPP-exposed mice. The results showed that BPS exposure increased serum UA levels by damaging the structure of the kidneys, whereas BPP exposure increased serum UA levels by disturbing purine metabolism in the liver. Moreover, BPF did not induce an increase in serum UA levels owing to the inhibition of guanine conversion to UA. In summary, we provide evidence of the mechanisms whereby exposure to three BPs disturbs UA homeostasis. These findings provide new insights into the risks of exposure to bisphenol chemicals.

Single and combined exposures to bisphenol A and benzophenone-3 during early mouse pregnancy have differential effects on fetal and placental development.

Endocrine disrupting chemicals (EDCs) possess the capability to interfere with the endocrine system by binding to hormone receptors, for example on immune cells. Specific effects have already been described for individual substances, but the impact of exposure to chemical mixtures during pregnancy on maternal immune regulation, placentation and fetal development is not known. In this study, we aimed to investigate the combined effects of two widespread EDCs, bisphenol A (BPA) and benzophenone-3 (BP-3), at allowed concentrations on crucial pregnancy processes such as implantation, placentation, uterine immune cell populations and fetal growth. From gestation day (gd) 0 to gd10, female mice were exposed to 4 µg/kg/d BPA, 50 mg/kg/d BP-3 or a BPA/BP-3 mixture. High frequency ultrasound and Doppler measurements were used to determine intrauterine fetal development and hemodynamic parameters. Furthermore, uterine spiral artery remodeling and placental mRNA expression were studied via histology and CHIP-RT-PCR, respectively. Effects of EDC exposure on multiple uterine immune cell populations were investigated using flow cytometry. We found that exposure to BP-3 caused intrauterine growth restriction in offspring at gd14, while BPA and BPA/BP-3 mixture caused varying effects. Moreover, placental morphology at gd12 and placental efficiency at gd14 were altered upon BP-3 exposure. Placental gene transcription was altered particularly in female offspring after in utero exposure to BP-3. Flow cytometry analyses revealed an increase in uterine T cells and NK cells in BPA and BPA/BP-3-treated dams at gd14. Doppler measurements revealed no effect on uterine hemodynamic parameters and spiral artery remodeling was not affected following EDC exposure. Our results provide evidence that exposure to BPA and BP-3 during early gestation affects fetal development in a sex-dependent manner, placental function and immune cell frequencies at the feto-maternal interface. These results call for inclusion of studies addressing pregnancy in the risk assessment of environmental chemicals.

Cross sectional study on exposure to BPA and its analogues and semen parameters in Czech men.

Exposure to bisphenols has been found to have adverse effects on male reproductive function in animals. Human exposure to bisphenols is widespread. Bisphenol A (BPA) and its analogues, including bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF) are utilized in various consumer products such as food contact materials and dental resins. The effects of these compounds on male fertility and spermatogenesis are unclear and findings from human studies are inconsistent. In this cross-sectional study, we evaluated the influence of BPA, BPS, BPF, BPAF (BPs) measured in semen on number of spermatozoa, total motility, progressive motility, morphology, and DNA fragmentation. We also examined the association of bisphenols (BPs) exposure with patients' occupation. A total of 358 patients aged 17-62 years with BMI 18-42 were included in the study from 2019 to 2021. BPs were extracted using solvent extraction followed by preconcentration step and determined by high-performance liquid chromatography and tandem mass spectrometry (LC/MSMS). Bisphenols were detected in 343 from 349 analysed samples (98.3% of all the samples). In 6 samples, the concentration of all BPs was under the limit of detection and in 20 samples under the limit of quantification. We did not find a statistically significant relationship between occupation and BPs. However, we observed significant correlations between the concentration of BPA and a lower motility and normal morphology. For BPS, a significant correlation with a lower ejaculate volume and a lower total sperm count was found. BPF and BPAF were detected only in 14.3% and 23.9% of samples, respectively. For BPF and BPAF, no significant correlations with spermiogram parameters were observed. Our results show that BPs are widespread in the male population (more than 90% of analysed samples), independently of an occupation and in case of BPA and BPS having a negative impact on spermiogram parameters.

Bombesin-like receptor 3 expression induced by bisphenol A is likely associated with reduced cell proliferation by inhibiting DNA synthesis and inducing inflammation in liver cells.

BACKGROUND: Bisphenol A (BPA) is an exogenous endocrine disruptor mimicking hormones closely associated with health complications, such as cancer progression. BPA is also related to an increase in the prevalence of obesity-related diseases due to its obesogenic action. Bombesin-like receptor 3 (BRS3) is an important factor that should be considered in the adipogenic gene network, as depletion of this gene alters adiposity. METHODS: Therefore, the present study aimed to investigate the messenger ribonucleic acid (mRNA) expression of BRS3 in human liver THLE-2 cells post-BPA treatment by real-time polymerase chain reaction. The effects of BPA on the levels of pro-inflammatory proteins, interleukin 6 (IL6) and CC motif chemokine ligand 2 (CCL2), in conditioned media of BPA-treated THLE-2 cells and deoxyribonucleic acid (DNA) synthesis in replicating BPA-treated THLE-2 cells during the cell cycle were also examined by enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. RESULTS: The study found that the mRNA expression of BRS3 was increased in THLE-2 cells treated with BPA. The study also showed that the expression levels of IL6 and CCL2 reached an optimum level in the conditioned media of BPA-treated THLE-2 cells after 48 h of treatment. Subsequently, the DNA synthesis analysis showed that bromodeoxyuridine/propidium iodide (BrdU/PI) stained positive cells were decreased in BPA-treated THLE-2 cells at 72 h of treatment. CONCLUSION: The study demonstrates that BRS3 expression induced by BPA is likely associated with reduced cell proliferation by inhibiting DNA synthesis and inducing cellular inflammation in liver cells.

Bisphenol F affects neurodevelopmental gene expression, mushroom body development, and behavior in Drosophila melanogaster.

Bisphenol F (BPF) is a potential neurotoxicant used as a replacement for bisphenol A (BPA) in polycarbonate plastics and epoxy resins. We investigated the neurodevelopmental impacts of BPF exposure using Drosophila melanogaster as a model. Our transcriptomic analysis indicated that developmental exposure to BPF caused the downregulation of neurodevelopmentally relevant genes, including those associated with synapse formation and neuronal projection. To investigate the functional outcome of BPF exposure, we evaluated neurodevelopmental impacts across two genetic strains of Drosophila- w1118 (control) and the Fragile X Syndrome (FXS) model-by examining both behavioral and neuronal phenotypes. We found that BPF exposure in w1118 Drosophila caused hypoactive larval locomotor activity, decreased time spent grooming by adults, reduced courtship activity, and increased the severity but not frequency of ß-lobe midline crossing defects by axons in the mushroom body. In contrast, although BPF reduced peristaltic contractions in FXS larvae, it had no impact on other larval locomotor phenotypes, grooming activity, or courtship activity. Strikingly, BPF exposure reduced both the severity and frequency of ß-lobe midline crossing defects in the mushroom body of FXS flies, a phenotype previously observed in FXS flies exposed to BPA. This data indicates that BPF can affect neurodevelopment and its impacts vary depending on genetic background. Further, BPF may elicit a gene-environment interaction with Drosophila fragile X messenger ribonucleoprotein 1 (dFmr1)-the ortholog of human FMR1, which causes fragile X syndrome and is the most common monogenetic cause of intellectual disability and autism spectrum disorder.

Comparative cardiotoxicity assessment of bisphenol chemicals and estradiol using human induced pluripotent stem cell-derived cardiomyocytes.

Bisphenol A (BPA) is commonly used to manufacture consumer and medical-grade plastics. Due to health concerns, BPA substitutes are being incorporated-including bisphenol S (BPS) and bisphenol F (BPF)-without a comprehensive understanding of their toxicological profile. Previous studies suggest that bisphenol chemicals perturb cardiac electrophysiology in a manner that is similar to 17ß-estradiol (E2). We aimed to compare the effects of E2 with BPA, BPF, and BPS using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Cardiac parameters were evaluated using microelectrode array (MEA) technology and live-cell fluorescent imaging. Cardiac metrics remained relatively stable after exposure to nanomolar concentrations (1-1000 nM) of E2, BPA, BPF, or BPS. At higher micromolar concentrations, chemical exposures decreased the depolarization spike amplitude, and shortened the field potential, action potential duration, and calcium transient duration (E2 ≥ BPA ≥ BPF ≫ BPS). Cardiomyocyte physiology was largely undisturbed by BPS. BPA-induced effects were exaggerated when coadministered with an L-type calcium channel (LTCC) antagonist or E2, and reduced when coadministered with an LTCC agonist or an estrogen receptor alpha antagonist. E2-induced effects were not exaggerated by coadministration with an LTCC antagonist. Although the observed cardiac effects of E2 and BPA were similar, a few distinct differences suggest that these chemicals may act (in part) through different mechanisms. hiPSC-CM are a useful model for screening cardiotoxic chemicals, nevertheless, the described findings should be validated using a more complex ex vivo and/or in vivo model.

Effects of Bisphenol A and Its Substitute, Bisphenol F, on the Gut Microbiota in Mice.

Objective: The aim of this study was to assess the impact of bisphenol A (BPA) and its substitute, bisphenol F (BPF), on the colonic fecal community structure and function of mice. Methods: We exposed 6-8-week-old male C57BL/6 mice to 5 mg/(kg∙day) and 50 µg/(kg∙day) of BPA or BPF for 14 days. Fecal samples from the colon were analyzed using 16S rRNA sequencing. Results: Gut microbiome community richness and diversity, species composition, and function were significantly altered in mice exposed to BPA or BPF. This change was characterized by elevated levels of Ruminococcaceae UCG-010 and Oscillibacter and decreased levels of Prevotella 9 and Streptococcus. Additionally, pathways related to carbohydrate and amino acid metabolism showed substantial enrichment. Conclusion: Mice exposed to different BP analogs exhibited distinct gut bacterial community richness, composition, and related metabolic pathways. Considering the essential role of gut bacteria in maintaining intestinal homeostasis, our study highlights the intestinal toxicity of BPs in vertebrates.

Biochemical responses and antioxidant defense mechanisms in Channa Striatus exposed to Bisphenol S.

Bisphenol S (BPS), a BPA analog and a safer alternative, is utilized in a diverse range of industrial applications, such as making polycarbonate plastics, epoxy resins, thermal receipt papers, and currency bills. Recently, the increased use of BPS in containers and packages for daily life has been interrogated due to its identical chemical structure and probable endocrine-disrupting actions as BPA has. The present study aimed to evaluate the alterations in biochemical indices and antioxidant enzymes as certain indicators of the endocrine-disrupting effect of BPS in Channa striatus, a freshwater fish. BPS-exposed fish species were subjected to three sub-lethal concentrations of BPS (1, 4, and 12 ppm) and observed after an interval of 7 and 21 days. Exposure to BPS caused a reduction in the level of protein in muscle, gonads and the liver due to an impairment of protein synthesis. Levels of cholesterol in the muscle, gonads, and liver of BPS-exposed fish were found to be decreased after treatment, indicating either an inhibition of cholesterol biosynthesis in the liver or reduced absorption of dietary cholesterol. The levels of antioxidant enzymes such as superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase showed remarkable increases, while the activity of glutathione S-transferase decreased considerably, indicating the antioxidant defense mechanism to counteract the oxidative stress induced by BPS. Moreover, a significant increase was noted in the level of lipid peroxidation products, like malondialdehyde and conjugate diene, which represent biomarkers of oxidative stress. The histoarchitecture changes were also observed in the liver, muscle and gonads of BPS-treated fish species. The present study showed that sub-lethal exposure to BPS significantly influenced the activities of these enzymes and peroxidation byproducts. From this study, it is concluded that BPS-caused toxic effects in fish species lead to an imbalance in the antioxidant defense system. It is clearly indicated that BPS toxicity could lead to susceptible oxidative stress in various tissues and could damage vital organs.