Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China.
Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China; Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China.
Food Chem Toxicol. 2022 May;163:112967. doi: 10.1016/j.fct.2022.112967. Epub 2022 Mar 27.
Prenatal DEHP exposure can cause offspring neurodevelopmental toxicity, but the persistent effects of such exposure window are unclear. This study aimed to investigate the lasting neurobehavioral impact of DEHP on offspring following early exposure from GD9.5 (fetal neural tube closure) to GD16.5 (fetal thyroxin, TH, synthesis). Data showed maternal exposure to DEHP during the thyroid hormone-dependent stage induced a range of neurobehavioral phenotypic changes in adult and middle-aged mice, including anxiety, depression and cognitive impairment. Significant reductions in free TH, TH transporters, and TH metabolic enzyme deiodinase II (D2) were observed in the fetal brain, whereas D3 was elevated, indicating that TH signaling disruption was caused by in utero exposure. Gene expression analyses suggested the expression levels of the TH receptors Trα1, Trβ1 and their downstream target, brain-derived neurotrophic factor, were significantly attenuated, which may partially explain the mechanisms of neurodevelopmental impairment. This study provides new evidence of the persistent effects of sex-specific neurodevelopmental impairment due to in utero DEHP exposure, possibly through damage to the fetal brain TH signaling systems that causes lifelong brain damage. These results further suggest a profound neurobehavioral toxicity of DEHP that may be programmed during early developmental stage exposure and manifested later in life.
产前 DEHP 暴露可导致后代神经发育毒性，但这种暴露窗口的持续影响尚不清楚。本研究旨在探讨早期暴露于 GD9.5（胎儿神经管闭合）至 GD16.5（胎儿甲状腺素，TH，合成）期间 DEHP 对后代的持久神经行为影响。数据显示，母体在甲状腺素依赖性阶段暴露于 DEHP 会导致成年和中年小鼠出现一系列神经行为表型变化，包括焦虑、抑郁和认知障碍。在胎儿大脑中观察到游离 TH、TH 转运蛋白和 TH 代谢酶脱碘酶 II（D2）显著减少，而 D3 升高，表明 TH 信号转导受到干扰。基因表达分析表明，TH 受体 Trα1、Trβ1 及其下游靶基因脑源性神经营养因子的表达水平显著降低，这可能部分解释了神经发育障碍的机制。本研究提供了新的证据，证明宫内 DEHP 暴露会导致性别特异性神经发育损伤的持续影响，可能是通过破坏胎儿大脑 TH 信号系统导致终生脑损伤。这些结果进一步表明，DEHP 具有深刻的神经行为毒性，可能在早期发育阶段暴露时被编程，并在以后的生活中表现出来。
