Perinatal bisphenol S exposure exacerbates the oxidative burden and apoptosis in neonatal ovaries by suppressing the mTOR/autophagy axis.

Bisphenol S (BPS) is an emerging environmental endocrine disruptor capable of crossing the placental barrier, resulting in widespread exposure to pregnant women due to its extensive usage. However, the impact of perinatal maternal exposure to BPS on reproductive health in offspring and the underlying molecular mechanism remain underexplored. In this study, gestational ICR mice were provided with drinking water containing 3.33 mg/L BPS to mimic possible human exposure in some countries. Results demonstrated that BPS accelerated the breakdown of germ-cell cysts and the assembly of primordial follicles in neonates, leading to oocyte over-loss. Furthermore, the expression levels of folliculogenesis-related genes (Kit, Nobox, Gdf9, Sohlh2, Kitl, Bmp15, Lhx8, Figla, and Tgfb1) decreased, thus compromising oocyte quality and disrupting early folliculogenesis dynamics. BPS also disrupted other aspects of offspring reproduction, including advancing puberty onset, disrupting the estrus cycle, and impairing fertility. Further investigation found that BPS exposure inhibited the activities and expression levels of antioxidant-related enzymes in neonatal ovaries, leading to the substantial accumulation of MDA and ROS. The increased oxidative burden exacerbated the intracellular apoptotic signaling, manifested by increased expression levels of pro-apoptotic markers (Bax, Caspase 3, and Caspase 9) and decreased expression levels of anti-apoptotic marker (Bcl2). Concurrently, BPS inhibited autophagy by increasing p-mTOR/mTOR and decreasing p-ULK1/ULK1, subsequently down-regulating autophagy flux-related biomarkers (LC3b/LC3a and Beclin-1) and impeding the degradation of autophagy substrate p62. However, the imbalanced crosstalk between autophagy, apoptosis and oxidative stress homeostasis was restored after rapamycin treatment. Collectively, the findings demonstrated that BPS exposure induced reproductive disorders in offspring by perturbing the mTOR/autophagy axis, and such autophagic dysfunction exacerbated redox imbalance and promoted excessive apoptosis. These results provide novel mechanistic insights into the role of autophagy in mitigating BPS-induced intergenerational reproductive dysfunction.

G protein-coupled estrogen receptor activation by bisphenol-A disrupts lipid metabolism and induces ferroptosis in the liver.

As a metabolic disruptor, bisphenol A (BPA) has been widely reported to disrupt lipid balance. Moreover, BPA has gained significant attention due to its estrogenic activity. While both ferroptosis and the G-protein-coupled estrogen receptor (GPER) have been implicated in lipid metabolism, their link to BPA-induced lipid accumulation remains unclear. In this study, chickens were randomly assigned to three groups and housed them for 4 weeks: a control group (0 µg/L BPA), a low dose group (50 µg/L BPA) and a high dose group (5000 µg/L BPA) to investigate the underlying mechanism of BPA-induced hepatotoxicity. Our results showed that BPA exposure significantly increased the contents of TG, TC, and LDL-C while decreasing HDL-C levels. We also found that BPA treatment altered the levels of genes involved in fatty acid ß-oxidation (ampkα, cpt-1, and ppaα), synthesis (acc, fas, scd-1, and srebp-1) and absorption (lpl and cd36). Moreover, the results showed that the BPA group had higher levels of IL-1ß, IL-18 and TNF-α. These results indicated that BPA exposure disrupted lipid metabolism and induced inflammation in the liver. We also demonstrated that BPA caused hepatic ferroptosis by raising iron content and the expression of genes related to lipid peroxidation (lpcat3, acsl4 and alox15), while reducing the expression of antioxidant system-associated genes (gpx4, slc7a11 and slc3a2). Importantly, BPA remarkably activated GPER expression in the liver. Interestingly, inhibition of GPER remarkably ameliorated BPA-induced lipid metabolism disorder, inflammatory response, and ferroptosis, indicating the crucial role of GPER in BPA-induced liver abnormalities. These findings highlight the link between GPER and ferroptosis in BPA-induced hepatotoxicity, providing new insights into the potential hazard of BPA.

The gut microbiota metabolite glycochenodeoxycholate activates TFR-ACSL4-mediated ferroptosis to promote the development of environmental toxin-linked MAFLD.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disorders in the world, and yet has no approved pharmacotherapy due to the etiology is complex. In the last ten years, increasing evidence have identified the environmental pollutants as risk factors for MAFLD. However, the underlying mechanism remains unclear. Our study found that bromoacetic acid (BAA, a typical kind of environmental toxin) increased triglycerides and total cholesterol levels as well as induced obvious hepatic steatosis and inflammation. The lipidomics showed that ferroptosis was implicated in the environmental toxin-linked MAFLD. Besides, the analysis of microbial metabolomics showed significant change of gut microbiome in BAA groups and the content of gut microbiota metabolite (glycochenodeoxycholate, GCDCA) increased sharply. In vitro study, we observed features of ferroptotic cells by transmission electron microscopy after BAA/GCDCA treatment. Besides, we demonstrated that BAA/GCDCA significantly increased iron contents, with upregulating transferrin receptor (TFR) and acyl-CoA synthetase long-chain family 4 (ACSL4) expression levels. By contrast, iron chelator or silencing TFR relieved BAA/GCDCA-induced lipid metabolism disorder and inflammation. What's more, the interaction between TFR and ACSL4 was also identified. Taken together, we found that, in response to environmental toxin, gut microbiota metabolite GCDCA activates TFR-ACSL4-mediated ferroptosis, which triggered subsequent lipid metabolism disorder and inflammation. Moreover, these findings firstly highlighted the functional relevance among ferroptosis, lipid metabolism and gut microbiota metabolite during environmental pollutant exposure, which shed light on the deep mechanism of environmental toxin-related MAFLD, providing potential targets for the prevention of MAFLD.