Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Lucknow Campus, Lucknow, 226001, Uttar Pradesh, India.
Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; School of Dental Sciences, Department of Biochemistry, Babu Banarasi Das University, BBD City, Faizabad Road, Lucknow, 226028, India.
Neurotoxicology. 2019 Jan;70:161-179. doi: 10.1016/j.neuro.2018.11.007. Epub 2018 Nov 22.
During the mammalian brain development, oligodendrocyte progenitor cells (OPCs) are generated from neuroepithelium and migrate throughout the brain. Myelination is a tightly regulated process which involves time framed sequential events of OPCs proliferation, migration, differentiation and interaction with axons for functional insulated sheath formation. Myelin is essential for efficient and rapid conduction of electric impulses and its loss in the hippocampus of the brain may result in impaired memory and long-term neurological deficits. Carbofuran, a carbamate pesticide is known to cause inhibition of hippocampal neurogenesis and memory dysfunctions in rats. Nonetheless, the effects of carbofuran on OPCs proliferation, fate determination, maturation/differentiation and myelination potential in the hippocampus of the rat brain are still completely elusive. Herein, we investigated the effects of sub-chronic exposure of carbofuran during two different time periods including prenatal and adult brain development in rats. We observed carbofuran hampers OPCs proliferation (BrdU incorporation) and oligodendroglial differentiation in vitro. Similar effects of carbofuran were also observed in the hippocampus region of the brain at both the time points. Carbofuran exposure resulted in reduced expression of key genes and proteins involved in the regulation of oligodendrocyte development and functional myelination. It also affects the survival of oligodendrocytes by inducing apoptotic cell death. The ultrastructural analysis of myelin architecture clearly depicted carbofuran-mediated negative effects on myelin compaction and g-ratio alteration. Conclusively, our study demonstrated that carbofuran alters myelination potential in the hippocampus, which leads to cognitive deficits in rats.
在哺乳动物大脑发育过程中，少突胶质前体细胞（OPC）由神经上皮产生，并迁移到整个大脑。髓鞘形成是一个严格调控的过程，涉及 OPC 增殖、迁移、分化和与轴突相互作用以形成功能性绝缘鞘的时间顺序事件。髓鞘对于电脉冲的有效和快速传导至关重要，其在大脑海马区的损失可能导致记忆受损和长期神经功能缺陷。carbofuran 是一种氨基甲酸酯类农药，已知会导致大鼠海马神经发生抑制和记忆功能障碍。然而，carbofuran 对大鼠大脑海马区 OPC 增殖、命运决定、成熟/分化和髓鞘形成潜能的影响仍完全难以捉摸。在此，我们研究了 carbofuran 在两个不同时期（产前和成年期大脑发育）的亚慢性暴露对大鼠的影响。我们观察到 carbofuran 会抑制 OPC 的增殖（BrdU 掺入）和体外少突胶质分化。在两个时间点，carbofuran 在大脑海马区也观察到类似的作用。carbofuran 暴露导致调节少突胶质细胞发育和功能髓鞘形成的关键基因和蛋白表达减少。它还通过诱导细胞凋亡来影响少突胶质细胞的存活。对髓鞘结构的超微结构分析清楚地描述了 carbofuran 对髓鞘致密化和 g 比值改变的负面影响。总之，我们的研究表明 carbofuran 改变了海马体的髓鞘形成潜力，导致大鼠认知缺陷。
