Novel Mechanisms of Pesticide-Induced Neurotoxicity

点击翻译按钮获取中文摘要

Abstract Environmental exposure to neurotoxic pesticides has been increasingly recognized as a key etiological factor of sporadic Parkinson’s disease (PD). Despite the established link, deciphering the neurotoxicological mechanisms associated with chronic pesticide exposure and its role in the etiopathogenesis of PD has been challenging. Thus, our research proposal intends to explore a novel paradigm in environmental neurotoxicology by studying the acetylation of histone proteins during pesticide exposure using animal models of pesticide neurotoxicity. Among various classes of pesticides, exposure to mitochondria-impairing neurotoxic pesticides, e.g., rotenone, has been linked to the etiology of PD. Mechanistically, exposure to rotenone and another related pesticide, pyridaben, inhibits mitochondrial complex-1 and impairs proteasomal function in neuronal cells. Dopaminergic neurons have been shown to be highly vulnerable to rotenone-induced neurotoxicity. While studying proteasomal dysfunction in mitochondria-impairing pesticide-induced neurotoxicity, we unexpectedly discovered that rotenone- and pyridaben-induced proteasomal inhibition resulted in the accumulation of the major histone acetyltransferase enzyme CBP (CREB-binding protein), which further contributed to acetylation of histones H3 and H4 to promote apoptotic cell death in dopaminergic neurons. Since hyperacetylation of histones is emerging as a key molecular mechanism capable of producing long-term changes in gene expression profiles due to chromatin remodeling, we propose to explore this novel mechanism in the molecular events underlying nigral dopaminergic neuronal damage in chronic mitochondria- impairing pesticide-induced neurotoxicity models. This work will be accomplished by pursuing the following specific objectives: i) Map the hyperacetylation sites of core histones H3 and H4 in dopaminergic neuronal cultures following mitochondria-inhibiting neurotoxic pesticide exposure, ii) Characterize cellular mechanisms of pesticide-induced hyperacetylation of histones H3 and H4 by examining the contributions of various isoforms of histone acetyltransferases (HATs) and histone deacetylases (HDACs), and iii) Determine histone acetylation pattern in chronic rotenone or pyridaben animal models of pesticide neurotoxicity as well as in a progressive mitochondrial dysfunction-induced transgenic mouse model of PD, confirm the changes in acetylation patterns and HAT/HDAC homeostasis in human PD brain tissues, and define the functional significance of histone hyperacetylation-dependent signaling relevant to neurotoxic pesticide-induced neuronal degeneration. Cellular, molecular and neurochemical approaches will be used to delineate these objectives. Collectively, the proposed study represents a novel approach in pesticide neurotoxicological research since the work will provide a comprehensive understanding of the histone hyperacetylation mechanisms pertaining to environmentally- induced nigral dopaminergic neuronal toxicity as it relates to the etiopathogenesis of environmentally-linked PD.