Department of Pharmacology, School of Medicine, Eulji University, Daejeon 34824, Korea.
Center for Sport Science in Seoul, Seoul Sports Council, Seoul 02119, Korea.
Int J Mol Sci. 2021 Jul 27;22(15):8009. doi: 10.3390/ijms22158009.
Trimethyltin (TMT) is an irreversible neurotoxicant. Because prenatal TMT exposure has been reported to induce behavioral changes, this study was conducted to observe gender differences and epigenetic changes using a mouse model. In behavioral testing of offspring at 5 weeks of age, the total times spent in the center, corner, or border zones in the male prenatal TMT-exposed mice were less than those of control unexposed mice in the open-field test. Female TMT-exposed mice scored lower on total numbers of arm entries and percentages of alternations than controls in the Y-maze test with lower body weight. We found that only TMT-exposed males had fewer copies of mtDNA in the hippocampus and prefrontal cortex region than controls. Additional epigenetic changes, including increased 5-methyl cytosine/5-hydroxymethyl cytosine levels in the male TMT hippocampus, were observed. After methylation binding domain (MBD) sequencing, multiple signaling pathways related to metabolism and neurodevelopment, including FoxO signaling, were identified by pathway analysis for differentially methylated regions (DMRs). Increased FOXO3 and decreased ASCL1 expression were also observed in male TMT hippocampi. This study suggests that sex differences and epigenetics should be more carefully considered in prenatal toxicology studies.
三甲基锡（TMT）是一种不可逆的神经毒素。由于有报道称产前 TMT 暴露会引起行为变化，因此本研究通过小鼠模型观察性别差异和表观遗传变化。在 5 周龄后代的行为测试中，与对照组未暴露的小鼠相比，雄性产前 TMT 暴露的小鼠在旷场测试中处于中央、角落或边界区域的总时间较少。在 Y 迷宫测试中，与对照组相比，体重较低的雌性 TMT 暴露的小鼠的臂进入总数和交替百分比较低。我们发现只有 TMT 暴露的雄性海马体和前额叶皮质区域的 mtDNA 拷贝数少于对照组。还观察到其他表观遗传变化，包括雄性 TMT 海马体中 5-甲基胞嘧啶/5-羟甲基胞嘧啶水平升高。通过对差异甲基化区域（DMR）的通路分析，在甲基化结合域（MBD）测序后，鉴定出与代谢和神经发育相关的多个信号通路，包括 FoxO 信号通路。还观察到雄性 TMT 海马体中 FOXO3 表达增加和 ASCL1 表达减少。本研究表明，在产前毒理学研究中应更仔细地考虑性别差异和表观遗传学。
