Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Horm Behav. 2018 Jun;102:93-104. doi: 10.1016/j.yhbeh.2018.05.010. Epub 2018 May 18.
Fetal exposure to endocrine disrupting chemicals (EDCs) has been associated with adverse neurobehavioral outcomes across the lifespan and can persist across multiple generations of offspring. However, the underlying mechanisms driving these changes are not well understood. We investigated the molecular perturbations associated with EDC-induced behavioral changes in first (F1) and second (F2) filial generations, using the model EDC bisphenol A (BPA). C57BL/6J dams were exposed to BPA from preconception until lactation through the diet at doses (10 μg/kg bw/d-lower dose or 10 mg/kg bw/d-upper dose) representative of human exposure levels. As adults, F1 male offspring exhibited increased depressive-like behavior, measured by the forced swim test, while females were unaffected. These behavioral changes were limited to the F1 generation and were not associated with altered maternal care. Transcriptome analysis by RNA-sequencing in F1 control and upper dose BPA-exposed adult male hippocampus revealed neurotransmitter systems as major pathways disrupted by developmental BPA exposure. High performance liquid chromatography demonstrated a male-specific reduction in hippocampal serotonin. Administration of the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg bw) rescued the depressive-like phenotype in males exposed to lower, but not upper, dose BPA, suggesting distinct mechanisms of action for each exposure dose. Finally, high resolution mass spectrometry revealed reduced circulating levels of the neuroactive steroid dehydroepiandrosterone in BPA-exposed males, suggesting another potential mechanism underlying the depressive-like phenotype. Thus, behavioral changes associated with early life BPA exposure may be mediated by sex-specific disruptions in the serotonergic system and/or sex steroid biogenesis in male offspring.
胎儿暴露于内分泌干扰化学物质（EDCs）与整个生命周期的不良神经行为结果有关，并可在后代的多个世代中持续存在。然而，导致这些变化的潜在机制尚不清楚。我们使用模型内分泌干扰物双酚 A（BPA）研究了与 EDC 诱导的第一代（F1）和第二代（F2）后代行为变化相关的分子扰动。C57BL/6J 孕鼠通过饮食从受孕前到哺乳期暴露于 BPA，剂量分别为（10μg/kg bw/d-低剂量或 10mg/kg bw/d-高剂量），代表人类暴露水平。作为成年人，F1 雄性后代表现出增加的抑郁样行为，通过强迫游泳试验测量，而雌性则不受影响。这些行为变化仅限于 F1 代，与改变的母婴护理无关。F1 对照组和高剂量 BPA 暴露的成年雄性海马体的 RNA-seq 转录组分析显示，神经递质系统是发育性 BPA 暴露破坏的主要途径。高效液相色谱法显示海马体 5-羟色胺的雄性特异性减少。选择性 5-羟色胺再摄取抑制剂氟西汀（20mg/kg bw）的给药挽救了暴露于低剂量但不暴露于高剂量 BPA 的雄性的抑郁样表型，表明每种暴露剂量的作用机制不同。最后，高分辨率质谱法显示 BPA 暴露雄性的循环神经活性甾体脱氢表雄酮水平降低，表明抑郁样表型的另一个潜在机制。因此，与生命早期 BPA 暴露相关的行为变化可能是由雄性后代中特定于性别的 5-羟色胺能系统和/或性激素生物合成的破坏介导的。
