Impact of Environmental Risk Factors on Mitochondrial Dysfunction, Neuroinflammation, Protein Misfolding, and Oxidative Stress in the Etiopathogenesis of Parkinson's Disease

Abstract

As a prevalent progressive neurodegenerative disorder, Parkinson's disease (PD) is characterized by the neuropathological hallmark of the loss of nigrostriatal dopaminergic (DAergic) innervation and the appearance of Lewy bodies with aggregated α-synuclein. Although several familial forms of PD have been reported to be associated with several gene variants, most cases in nature are sporadic, triggered by a complex interplay of genetic and environmental risk factors. Numerous epidemiological studies during the past two decades have shown positive associations between PD and several environmental factors, including exposure to neurotoxic pesticides/herbicides and heavy metals as well as traumatic brain injury. Other environmental factors that have been implicated as potential risk factors for PD include industrial chemicals, wood pulp mills, farming, well-water consumption, and rural residence. In this review, we summarize the environmental toxicology of PD with the focus on the elaboration of chemical toxicity and the underlying pathogenic mechanisms associated with exposure to several neurotoxic chemicals, specifically 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat (PQ), dichloro-diphenyl-trichloroethane (DDT), dieldrin, manganese (Mn), and vanadium (V). Our overview of the current findings from cellular, animal, and human studies of PD provides information for possible intervention strategies aimed at halting the initiation and exacerbation of environmentally linked PD.

Keywords: Parkinson’s disease; environmental factors; histone modification; metals; mitochondrial dysfunction; neuroinflammation; neurotoxicity; oxidative stress; pesticides; protein misfolding.

Figure 1

Cellular stress signaling in neurotoxicant-induced neuronal degeneration. Mitochondrial dysfunction is a central driver of PD and plays a significant role in PD pathogenesis. In the brain, MPTP is first metabolized to MPP⁺ by the enzyme MAO-B in glial cells. Upon uptake via DA transporter, MPP⁺ inhibits mitochondrial complex I. Similar to MPTP, rotenone, dieldrin, and PQ inhibit the mitochondrial respiratory chain, induce increased ROS release, and alter epigenetic modifications directly or indirectly via mitonuclear communication. Rotenone and dieldrin can also favor ROS production through PKCδ and NOX1, while PQ induces the generation of superoxide by transforming from PQ²⁺ to PQ⁺. Like other pesticides, DDT exposure induces oxidative stress, and it also causes mitochondrial impairment by altering the gene expression of the apoptosis regulator Bcl-2. DTT also induces neuroinflammation through the NFκB pathway. Similarly, excessive Mn increases the levels of inflammatory mediators, such as NLRP3, IL-1β, IL-6, and TNFα. Mn overload likely puts mitochondria under stress and promotes α-synuclein aggregation. V overexposure can not only induce neuroinflammation but also can bring about ROS production and DNA damage.