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Persistent proteomic changes in glutamatergic and GABAergic signaling in the amygdala of adolescent rats exposed to chlorpyrifos as juveniles
NeuroToxicology ( IF 3.4 ) Pub Date : 2021-05-28 , DOI: 10.1016/j.neuro.2021.05.012
Navatha Alugubelly 1 , Afzaal N Mohammed 1 , Russell L Carr 1
Affiliation  

Chlorpyrifos (CPF) remains one of the most widely used organophosphorus insecticides (OPs) despite the concerns about its developmental neurotoxicity. Developmental exposure to CPF has long-lasting negative impacts, including abnormal emotional behaviors. These negative impacts are observed at exposure levels do not cause inhibition of acetylcholinesterase, the canonical target of OPs. Exposure to CPF at these levels inhibits the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) but it is not clear what the persistent effects of this inhibition are. To investigate this, male rat pups were exposed orally to either corn oil, 0.75 mg/kg CPF, or 0.02 mg/kg PF-04457845 (PF; a specific inhibitor of FAAH) daily from postnatal day 10 (PND10) - PND16. This dosage of CPF does not inhibit brain cholinesterase activity but inhibits FAAH activity. On PND38 (adolescence), the protein expression in the amygdala was determined using a label-free shotgun proteomic approach. The analysis of control vs CPF and control vs PF led to the identification of 44 and 142 differentially regulated proteins, respectively. Gene ontology enrichment analysis revealed that most of the proteins with altered expression in both CPF and PF treatment groups were localized in the synapse-related regions, such as presynaptic membrane, postsynaptic density, and synaptic vesicle. The different biological processes affected by both treatment groups included persistent synaptic potentiation, glutamate receptor signaling, protein phosphorylation, and chemical synaptic transmission. These results also indicated disturbances in the balance between glutamatergic (↓ Glutamate AMPA receptor 2, ↓ Excitatory amino acid transporter 2, and ↑ vesicular glutamate transporter 2) and GABAergic signaling (↑ GABA transporter 3 and ↑ glutamate decarboxylase 2). This imbalance could play a role in the abnormal emotional behavior that we have previously reported. These results suggest that there is a similar pattern of expression between CPF and PF, and both these chemicals can persistently alter emotional behavior as a consequence of inhibition of FAAH.



中文翻译:

幼年暴露于毒死蜱的青春期大鼠杏仁核中谷氨酸能和 GABA 能信号的持续蛋白质组学变化

毒死蜱 (CPF) 仍然是最广泛使用的有机磷杀虫剂 (OPs) 之一,尽管人们担心它的发育神经毒性。对 CPF 的发育暴露具有长期的负面影响,包括异常的情绪行为。在暴露水平上观察到这些负面影响不会导致乙酰胆碱酯酶的抑制,而乙酰胆碱酯酶是 OP 的典型靶标。暴露于这些水平的 CPF 会抑制内源性大麻素代谢酶脂肪酸酰胺水解酶 (FAAH),但尚不清楚这种抑制的持续影响是什么。为了研究这一点,雄性幼鼠从出生后第 10 天 (PND10) - PND16 开始每天口服暴露于玉米油、0.75 mg/kg CPF 或 0.02 mg/kg PF-04457845(PF;FAAH 的特异性抑制剂)。该剂量的 CPF 不会抑制脑胆碱酯酶活性,但会抑制 FAAH 活性。在 PND38(青春期),杏仁核中的蛋白质表达是使用无标记鸟枪蛋白质组学方法确定的。对照与 CPF 和对照与 PF 的分析分别导致了 44 和 142 种差异调节蛋白的鉴定。基因本体富集分析显示,CPF 和 PF 治疗组中表达改变的大多数蛋白质都位于突触相关区域,如突触前膜、突触后密度和突触小泡。两个治疗组影响的不同生物过程包括持续的突触增强、谷氨酸受体信号传导、蛋白质磷酸化和化学突触传递。这些结果还表明谷氨酸能(↓ 谷氨酸 AMPA 受体 2、↓ 兴奋性氨基酸转运蛋白 2 和 ↑ 泡状谷氨酸转运蛋白 2)和 GABA 能信号传导(↑ GABA 转运蛋白 3 和 ↑ 谷氨酸脱羧酶 2)之间的平衡紊乱。这种不平衡可能在我们之前报道的异常情绪行为中起作用。这些结果表明,CPF 和 PF 之间存在相似的表达模式,并且由于 FAAH 的抑制,这两种化学物质都可以持续改变情绪行为。这种不平衡可能在我们之前报道的异常情绪行为中起作用。这些结果表明,CPF 和 PF 之间存在相似的表达模式,并且由于 FAAH 的抑制,这两种化学物质都可以持续改变情绪行为。这种不平衡可能在我们之前报道的异常情绪行为中起作用。这些结果表明,CPF 和 PF 之间存在相似的表达模式,并且由于 FAAH 的抑制,这两种化学物质都可以持续改变情绪行为。

更新日期:2021-06-11
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