Agrochemicals became a public health concern due to increased human exposure and possible endocrine disruption effects in several organs, including the brain. Thyroid hormones controls neurodevelopment, which turn them sensitive to endocrine disruptors (EDs). In this work, we evaluated the effect of glyphosate‐based herbicides (GBH) as an intergenerational endocrine disrupter on thyroid homeostasis in cerebellar cells. Female pregnant Wistar rats were exposed to Roundup Transorb® solution at 5 and 50 mg/kg/day, from gestation day 18 to post‐natal day 5 (P5). Cerebellum of male offspring was used to evaluate gene expression. The mRNA levels of thyroid hormone receptors, hormonal conversion enzymes, hormone transporters, as well as, de novo epigenetic regulators were altered, with some of these genes presenting a non‐monotonic dose response. Furthermore, metabolomic profile correlation with tested dose demonstrated altered metabolic profile, in agreement with cerebellar gene alterations. Moreover, cerebellar primary cultures exposed to non‐toxic GBH concentration presented a decrease level in glial fibrillary acidic protein, a protein regulated by endocrine signals. In conclusion, our results indicate that animals exposed to non‐toxic GBH doses during perinatal phase carry intergenerational alterations in key regulators of cellular thyroid hormone homeostasis and epigenetic controllers in adulthood, indicating the possible ED effect of GBH based on epigenetic alterations.

中文翻译：

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草甘膦除草剂围产期大鼠小脑代际甲状腺激素稳态失衡


由于人类接触农用化学品的增加以及可能对包括大脑在内的多个器官的内分泌干扰影响，农用化学品已成为一个公共健康问题。甲状腺激素控制神经发育，使神经发育对内分泌干扰物 (ED) 敏感。在这项工作中，我们评估了草甘膦除草剂（GBH）作为代际内分泌干扰物对小脑细胞甲状腺稳态的影响。从妊娠第 18 天到产后第 5 天（P5），雌性怀孕 Wistar 大鼠以 5 和 50 毫克/公斤/天的剂量接触农达 Transorb® 溶液。使用雄性后代的小脑来评估基因表达。甲状腺激素受体、激素转化酶、激素转运蛋白以及从头表观遗传调节因子的 mRNA 水平发生了改变，其中一些基因呈现出非单调的剂量反应。此外，代谢组学谱与测试剂量的相关性表明代谢谱发生了改变，与小脑基因的改变一致。此外，暴露于无毒 GBH 浓度的小脑原代培养物中胶质纤维酸性蛋白（一种受内分泌信号调节的蛋白质）水平降低。总之，我们的结果表明，在围产期接触无毒 GBH 剂量的动物在成年期细胞甲状腺激素稳态的关键调节因子和表观遗传控制器中发生代际改变，表明 GBH 可能基于表观遗传改变产生 ED 效应。