Integrated transcriptome analysis of rats exposed to bisphenol mixtures from fetus to developmental stage

Bisphenol A (BPA), widely used in plastics and resins, raised health concerns for its endocrine-disrupting effects. BPA analogues like bisphenol S (BPS) and bisphenol F (BPF) emerged as alternatives but were found to exhibit similar risks. Despite many countries have implemented BPA regulations, alternatives remain insufficiently regulated Although the safety of BPS and BPF has not been sufficiently verified, they have already been detected in various surrounding environments and human urine, raising serious concerns Bisphenols are expected to have various adverse effects, but research on this is lacking. This study explores the adverse effects of bisphenol mixtures on rats from fetus to young adulthood, analyzing transcriptomes by tissue and gender to identify key genes impacted by bisphenol exposure. Dams were orally administered test substances from gestational day 6 to lactation day 6. F1 pups received the same substances at half the concentration from postnatal day 7 to day 63. The tissues collected from the pups were subjected to transcriptome analysis, and core genes were identified through integrated analysis. The study identifies core genes associated with high-density lipoprotein and hormone secretion. These genes provide insights into the mechanisms through which BPA may cause hormonal imbalances. Furthermore, the study suggests that a complex exposure of BPA, BPS, and BPF can exerts different effects than BPA alone, pronounced effects on the thyroid and reproductive organs, even though individual concentrations were below the no-observed-adverse-effect-level. It highlights the potential cumulative impact of endocrine disrupting chemicals in the body.双酚A（Bisphenol A, BPA）广泛应用于塑料与树脂制造领域，因其具有内分泌干扰效应（endocrine-disrupting effects）而引发健康安全担忧。双酚A类似物如双酚S（Bisphenol S, BPS）与双酚F（Bisphenol F, BPF）作为替代产品被开发出来，但后续研究发现它们同样存在类似的健康风险。尽管诸多国家已针对双酚A出台监管法规，但相关替代产品的监管仍存在明显不足。尽管双酚S与双酚F的安全性尚未得到充分验证，但它们已在多种环境介质与人类尿液样本中被检出，这一现象引发了严重的安全关切。双酚类化合物被认为可能引发多种不良健康效应，但相关研究仍较为匮乏。本研究聚焦双酚类混合物对大鼠从胎儿期至青年期的不良健康效应，通过按组织与性别分层分析转录组（transcriptome），以筛选双酚暴露所影响的关键基因。研究中，受孕母鼠自妊娠第6天至泌乳第6天期间经口给予受试物质；其子一代（F1）幼鼠则自出生后第7天至第63天，以减半浓度经口给予相同受试物质。研究人员收集幼鼠的组织样本进行转录组分析，并通过整合分析鉴定得到核心基因。本研究鉴定出与高密度脂蛋白（high-density lipoprotein, HDL）代谢及激素分泌相关的核心基因，这些基因为解析双酚A引发激素失衡的分子机制提供了重要线索。此外，本研究表明，相较于单一暴露于双酚A，BPA、BPS与BPF的复合暴露可产生不同的生物学效应，对甲状腺与生殖器官具有显著影响——即便各物质的单独浓度均未达到未观察到有害作用水平（no-observed-adverse-effect-level, NOAEL）。该研究凸显了内分泌干扰化学物（endocrine disrupting chemicals, EDCs）在体内潜在的累积效应。