苯并(a)芘宫内暴露加剧 A53T 人α-突触核蛋白转基因小鼠帕金森病样α-突触核蛋白病。

Benzo(a)pyrene exposure in utero exacerbates Parkinson's Disease (PD)-like α-synucleinopathy in A53T human alpha-synuclein transgenic mice.

机构信息

Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100191, China.

出版信息

Toxicol Appl Pharmacol. 2021 Sep 15;427:115658. doi: 10.1016/j.taap.2021.115658. Epub 2021 Jul 29.

DOI:10.1016/j.taap.2021.115658

PMID:34332006

Abstract

BACKGROUND

Previous work indicated that benzo[a]pyrene (B(a)P) exposure in utero might adversely affect neurodevelopment and cause Parkinson's Disease (PD)-like symptoms. However, the effect of utero exposure to B(a)P on PD-like α-synucleinopathy and the mechanism under are unclear.

OBJECTIVE

The A53T human alpha-synuclein (α-syn) transgenic mice (M83) were used in this study to gain insights into the role of B(a)P exposure in utero in the onset of α-syn pathology and neuronal damage.

METHOD

Timed-pregnant M83 dams were exposed to 1) corn oil (vehicle) or 2) 5 mg/kg bw/d B(a)P or 3) 20 mg/kg bw/d B(a)P at gestational day 10-17 by oral gavage and then the SNCA transcription, α-syn accumulation and aggregation, neuroinflammation and nigral dopaminergic neurodegeneration of 60-day-old pups were evaluated.

RESULT

SNCA mRNA and α-syn protein expression in the midbrain of 60 days adult mice were found to be remarkably elevated after B(a)P exposure in utero, the protein degradation capacity was injured (in 20 mg/kg dose group) and α-syn aggregation could be observed in the substantia nigra (SN); Enhanced Iba1 expression in the midbrain and microglial activation (in 20 mg/kg dose group) in the SN were also figured out; Besides, dopaminergic neurons in the SN of 60 days adult mice were significantly decreased.

CONCLUSIONS

Our findings demonstrated that B(a)P exposure in utero could exacerbate α-syn pathology and induce activation of microglia which might further lead to dopaminergic neuronal loss in the SN.

摘要

背景

先前的研究表明，母体暴露于苯并[a]芘（B(a)P）可能会对神经发育产生不利影响，并导致帕金森病（PD）样症状。然而，母体暴露于 B(a)P 对 PD 样α-突触核蛋白病的影响及其机制尚不清楚。

目的

本研究使用 A53T 人类α-突触核蛋白（α-syn）转基因小鼠（M83），深入研究母体暴露于 B(a)P 对α-突触核蛋白病理和神经元损伤的起始作用。

方法

在妊娠第 10-17 天，通过口服灌胃，将怀有时间的 M83 孕鼠暴露于 1）玉米油（载体）或 2）5mg/kg bw/d B(a)P 或 3）20mg/kg bw/d B(a)P，然后评估 60 日龄幼鼠的 SNCA 转录、α-突触核蛋白积累和聚集、神经炎症和黑质多巴胺能神经退行性变。

结果

母体暴露于 B(a)P 后，60 日龄成年小鼠中脑的 SNCA mRNA 和 α-syn 蛋白表达显著升高，蛋白质降解能力受损（在 20mg/kg 剂量组），并可观察到黑质（SN）中的α-突触核蛋白聚集；在 SN 中还发现中脑的 Iba1 表达增强和小胶质细胞活化（在 20mg/kg 剂量组）；此外，60 日龄成年小鼠 SN 中的多巴胺能神经元明显减少。