双酚S(BPS)是一种新兴的环境内分泌干扰物,能够穿过胎盘屏障,由于其广泛使用,导致广泛接触孕妇。然而,围产期母亲暴露于BPS对后代生殖健康的影响及其潜在的分子机制仍未得到充分研究。在这项研究中,在某些国家,为妊娠ICR小鼠提供含有3.33mg/LBPS的饮用水,以模拟可能的人类暴露。结果表明,BPS加速了新生儿生殖细胞囊肿的分解和原始卵泡的组装,导致卵母细胞过度流失。此外,卵泡发育相关基因的表达水平(Kit,Nobox,Gdf9,Sohlh2,Kitl,Bmp15,Lhx8,Figla,和Tgfb1)下降,从而损害卵母细胞质量并破坏早期卵泡发育动力学。BPS还扰乱了后代繁殖的其他方面,包括推进青春期的开始,扰乱发情周期,损害生育能力。进一步调查发现,BPS暴露抑制了新生儿卵巢抗氧化相关酶的活性和表达水平,导致MDA和ROS的大量积累。增加的氧化负荷加剧了细胞内凋亡信号传导,表现为促凋亡标志物的表达水平增加(Bax,Caspase3和Caspase9)和降低抗凋亡标志物(Bcl2)的表达水平。同时,BPS通过增加p-mTOR/mTOR和减少p-ULK1/ULK1来抑制自噬,随后下调自噬通量相关生物标志物(LC3b/LC3a和Beclin-1)并阻止自噬底物p62的降解。然而,自噬之间的不平衡串扰,雷帕霉素治疗后细胞凋亡和氧化应激稳态恢复。总的来说,研究结果表明,BPS暴露通过干扰mTOR/自噬轴引起后代生殖障碍,这种自噬功能障碍加剧了氧化还原失衡,促进了细胞过度凋亡。这些结果为自噬在减轻BPS诱导的代际生殖功能障碍中的作用提供了新的机制见解。
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.