Developmental Toxicology Division, System Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Vishvigyan Bhawan, 31, M.G. Marg, Lucknow, 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201 002, Uttar Pradesh, India.
Developmental Toxicology Division, System Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Vishvigyan Bhawan, 31, M.G. Marg, Lucknow, 226001, Uttar Pradesh, India; Plant Molecular Biology Laboratory, CSIR-National Botanical Research Institute, Rana Pratap Marg, Lucknow, 226 001, India.
Neurotoxicology. 2019 Sep;74:184-195. doi: 10.1016/j.neuro.2019.07.004. Epub 2019 Jul 19.
Proteomic analysis was carried out in substantia nigra (SNi) and hippocampus (Hi) isolated from rat offspring born to mothers exposed to lindane (orally; 0.25 mg/kg) from gestation day 5 (GD5) to GD 21 and subsequently rechallenged (orally; 2.5 mg/kg X 21 days) at adulthood (12 weeks). 2D gel electrophoresis revealed no significant differences in the expression of proteins in brain regions isolated from prenatally exposed offspring at adulthood. Significantly greater magnitude of alterations was observed in the expression of proteins related to mitochondrial and energy metabolism, ubiquitin-proteasome pathway, structural and axonal growth leading to increased oxidative stress in Hi and SNi isolated from rechallenged offspring when compared to control offspring treated postnatally with lindane. Western blotting and DNA laddering showed a greater magnitude of increase in apoptosis in the Hi and SNi of rechallenged offspring. Ultrastructural analysis demonstrated disrupted mitochondrial integrity, synaptic disruption and necrotic structures in the brain region of rechallenged offspring. Neurobehavioral studies also demonstrated a greater magnitude of alterations in cognitive and motor functions in rechallenged rats. The data suggest that prenatal exposure of lindane induces persistent molecular changes in the nervous system of offspring which are unmasked leading to neurodegeneration following rechallenge at adulthood.
采用蛋白质组学分析方法，研究了母体在妊娠第 5 天（GD5）至第 21 天（GD21）期间经口摄入林丹（0.25mg/kg），并在成年期（12 周）再次经口摄入林丹（2.5mg/kg×21 天）后，其子代出生大鼠的纹状体（SNi）和海马（Hi）中蛋白质的表达情况。2D 凝胶电泳显示，在成年期，来自于经产前林丹暴露的子鼠的大脑区域中，蛋白质的表达没有明显差异。与经林丹产后处理的对照组子鼠相比，在再次接受林丹暴露的子鼠的海马和纹状体中，与线粒体和能量代谢、泛素蛋白酶体通路、结构和轴突生长相关的蛋白质表达的变化幅度显著更大，从而导致 Hi 和 SNi 中的氧化应激增加。Western 印迹和 DNA 梯带分析显示，再次接受林丹暴露的子鼠的海马和纹状体中，细胞凋亡的增加幅度更大。超微结构分析表明，再次接受林丹暴露的子鼠的大脑区域中，线粒体完整性被破坏、突触中断和出现坏死结构。神经行为学研究还表明，再次接受林丹暴露的大鼠的认知和运动功能发生了更大程度的改变。这些数据表明，林丹的产前暴露会导致子代神经系统中出现持续的分子变化，这些变化在成年期再次接受林丹暴露时会显现出来，导致神经退行性变。
