Department of Biological Sciences, Institute of Environmental Health Sciences, Integrative Biosciences Center (IBio), Wayne State University, Detroit, MI, USA.
Van Andel Research Institute, Grand Rapids, MI, USA.
Chemosphere. 2023 Jul;330:138738. doi: 10.1016/j.chemosphere.2023.138738. Epub 2023 Apr 19.
Maternal exposure to environmental contaminants during pregnancy poses a significant threat to a developing fetus, as these substances can easily cross the placenta and disrupt the neurodevelopment of offspring. Specifically, the hypothalamus is essential in the regulation of metabolism, notably during critical windows of development. An abnormal hormonal and inflammatory milieu during development can trigger persistent changes in the function of hypothalamic circuits, leading to long-lasting effects on the body's energy homeostasis and metabolism. We recently demonstrated that gestational exposure to clinically relevant levels of benzene induces severe metabolic dysregulation in the offspring. Given the central role of the hypothalamus in metabolic control, we hypothesized that prenatal exposure to benzene impacts hypothalamic development, contributing to the adverse metabolic effects in the offspring. C57BL/6JB dams were exposed to benzene at 50 ppm in the inhalation chambers exclusively during pregnancy (from E0.5 to E19). Transcriptomic analysis of the exposed offspring at postnatal day 21 (P21) revealed hypothalamic changes in genes related to metabolic regulation, inflammation, and neurodevelopment exclusively in males. Moreover, the hypothalamus of prenatally benzene-exposed male offspring displayed alterations in orexigenic and anorexigenic projections, impairments in leptin signaling, and increased microgliosis. Additional exposure to benzene during lactation did not promote further microgliosis or astrogliosis in the offspring, while the high-fat diet (HFD) challenge in adulthood exacerbated glucose metabolism and hypothalamic inflammation in benzene-exposed offspring of both sexes. These findings reveal the persistent adverse effects of prenatal benzene exposure on hypothalamic circuits and neuroinflammation, predisposing the offspring to long-lasting metabolic health conditions.
母体在怀孕期间暴露于环境污染物会对发育中的胎儿构成重大威胁，因为这些物质很容易穿过胎盘并干扰后代的神经发育。具体来说，下丘脑在代谢调节中起着至关重要的作用，尤其是在发育的关键窗口期。发育过程中异常的激素和炎症环境会引发下丘脑回路功能的持久变化，从而对身体的能量稳态和代谢产生持久影响。我们最近表明，妊娠期间暴露于临床相关水平的苯会导致后代严重的代谢失调。鉴于下丘脑在代谢控制中的核心作用，我们假设产前暴露于苯会影响下丘脑的发育，从而导致后代的不良代谢影响。C57BL/6JB 孕鼠在妊娠期间（从 E0.5 到 E19）仅在吸入室中以 50ppm 的浓度暴露于苯。对暴露于苯的后代在出生后第 21 天（P21）的转录组分析显示，与代谢调节、炎症和神经发育相关的基因在雄性后代的下丘脑发生了变化。此外，产前苯暴露雄性后代的下丘脑显示出摄食和厌食投射的改变、瘦素信号的损伤以及小胶质细胞增生的增加。哺乳期内进一步暴露于苯并未促进后代小胶质细胞或星形胶质细胞的进一步增生，而成年期的高脂肪饮食（HFD）挑战则加剧了暴露于苯的后代的葡萄糖代谢和下丘脑炎症。这些发现揭示了产前苯暴露对下丘脑回路和神经炎症的持久不良影响，使后代容易出现长期的代谢健康状况。
