Naffaa Vanessa, Van Steenwinckel Juliette, Magny Romain, Regazzetti Anne, Keime Céline, Gressens Pierre, Laprévote Olivier, Auzeil Nicolas, Schang Anne-Laure
Université Paris Cité, CNRS, CiTCoM, Paris 75006, France.
Université Paris Cité, Inserm, NeuroDiderot, Paris 75019, France.
Toxicology. 2025 Mar;512:154041. doi: 10.1016/j.tox.2024.154041. Epub 2024 Dec 30.
Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor, is suspected of disturbing brain development through largely unknown cellular and molecular mechanisms. In the central nervous system, oligodendrocytes are responsible for forming myelin sheaths, which enhance the propagation of action potentials along axons. Disruption of axon myelination can have lifelong consequences, making oligodendrocyte differentiation and myelination critical stages of brain development. In the present study, mice were exposed to BPA during gestation and lactation through drinking water at concentrations of 25 and 250 μg.L. These doses, corresponding to estimated exposures of 4 μg.kg.d and 40 μg.kg.d, respectively, led to disturbances in lipid remodeling associated with myelination in the offspring. Importantly, changes in myelin lipid composition were selectively observed in female mice and were transient, being visible only at post-natal day P15 but not at later stages (P30 and P60). In females exposed to BPA, myelin exhibited a lower proportion of phosphatidylcholines and higher proportions of other glycerophospholipid subclasses, thus resembling more mature myelin. Conversely, male myelin was not affected, likely due to its already more mature lipid composition. Additionally, transcriptomic analysis of female oligodendrocytes at P15 did not reveal any transcriptional changes in genes related to lipid metabolism, further suggesting post-transcriptional effects of BPA via chaperone-mediated protein folding and RNA splicing. In males, the altered genes were mainly associated with synaptic transmission. Finally, alterations in chromatin accessibility were also largely sex dependent and did not correlate with transcription, with the exception of the Cwc22. At this locus, BPA exposure increased chromatin accessibility in half of mice of both sexes, leading to an "unchanged/open" bimodal profile correlated with "unchanged/upregulated" gene expression. Together, these results open new insights into the sex-dependent mechanisms of BPA's effects on brain development.
双酚A（BPA）是一种普遍存在的环境内分泌干扰物，人们怀疑它通过 largely unknown 的细胞和分子机制干扰大脑发育。在中枢神经系统中，少突胶质细胞负责形成髓鞘，髓鞘可增强动作电位沿轴突的传播。轴突髓鞘形成的破坏可能会产生终身影响，使少突胶质细胞分化和髓鞘形成成为大脑发育的关键阶段。在本研究中，小鼠在妊娠期和哺乳期通过饮用水接触浓度为25和250μg/L的BPA。这些剂量分别对应估计暴露量4μg/kg·d和40μg/kg·d，导致后代中与髓鞘形成相关的脂质重塑受到干扰。重要的是，仅在雌性小鼠中选择性观察到髓鞘脂质组成的变化，且这些变化是短暂的，仅在出生后第15天可见，而在后期阶段（第30天和第60天）则不可见。在接触BPA的雌性小鼠中，髓鞘中磷脂酰胆碱的比例较低，而其他甘油磷脂亚类的比例较高，因此更类似于成熟的髓鞘。相反，雄性髓鞘未受影响，可能是因为其脂质组成已经更成熟。此外，对出生后第15天雌性少突胶质细胞的转录组分析未发现与脂质代谢相关基因的任何转录变化，进一步表明BPA通过伴侣介导的蛋白质折叠和RNA剪接产生转录后效应。在雄性中，改变的基因主要与突触传递相关。最后，染色质可及性的改变在很大程度上也依赖于性别，并且除了Cwc22外，与转录不相关。在这个位点，BPA暴露增加了两性中一半小鼠的染色质可及性，导致与“未改变/上调”基因表达相关的“未改变/开放”双峰模式。总之，这些结果为BPA对大脑发育影响的性别依赖性机制提供了新的见解。
