Association between Heavy Metal Exposure and Parkinson's Disease: A Review of the Mechanisms Related to Oxidative Stress

Abstract

Parkinson's disease (PD) is a gradually progressing neurodegenerative condition that is marked by a loss of motor coordination along with non-motor features. Although the precise cause of PD has not been determined, the disease condition is mostly associated with the exposure to environmental toxins, such as metals, and their abnormal accumulation in the brain. Heavy metals, such as iron (Fe), mercury (Hg), manganese (Mn), copper (Cu), and lead (Pb), have been linked to PD and contribute to its progression. In addition, the interactions among the components of a metal mixture may result in synergistic toxicity. Numerous epidemiological studies have demonstrated a connection between PD and either single or mixed exposure to these heavy metals, which increase the prevalence of PD. Chronic exposure to heavy metals is related to the activation of proinflammatory cytokines resulting in neuronal loss through neuroinflammation. Similarly, metals disrupt redox homeostasis while inducing free radical production and decreasing antioxidant levels in the substantia nigra. Furthermore, these metals alter molecular processes and result in oxidative stress, DNA damage, mitochondrial dysfunction, and apoptosis, which can potentially trigger dopaminergic neurodegenerative disorders. This review focuses on the roles of Hg, Pb, Mn, Cu, and Fe in the development and progression of PD. Moreover, it explores the plausible roles of heavy metals in neurodegenerative mechanisms that facilitate the development of PD. A better understanding of the mechanisms underlying metal toxicities will enable the establishment of novel therapeutic approaches to prevent or cure PD.

Keywords: Parkinson’s disease; copper; heavy metals; iron; lead; manganese; mercury; oxidative stress.

Figure 1

Role of Fe in mitochondrial dysfunction and neuronal death leading to PD. Increased levels of Fe may cause neurodegeneration through the production of large amounts of reactive oxygen species (ROS) via the Fenton reaction. Fe can induce mitochondrial oxidative stress through interactions with different ROS. Free Fe can be released from mitochondrial Fe-sulfur clusters in complexes I and III upon interacting with ROS. The redox pair Fe²⁺-Fe³⁺ can directly stimulate lipid peroxidation (LP), which is an indicator of oxidative stress and contributes to mitochondrial dysfunction via mitochondrial permeability transition pore (mPTP) formation, thus leading to neural damage and the induction of PD.

Figure 2

Receptors and channels involved in Mn homeostasis. Various cellular receptors, such as divalent metal transporter 1 (DMT1) and transferrin receptor (TfR), as well as Ca²⁺ channels, ZIP8/14 transporter, and Mn citrate transporter facilitate the entry of divalent Mn into cells, whereas ferroportin and Ca²⁺ facilitate its expulsion from cells and mitochondria, respectively. Mn²⁺ is passively transported via glutamate-activated ion channels, while Mn³⁺ entry is facilitated by transferrin. All of these mechanisms enhance the trafficking of Mn²⁺ across the cells, leading to mitochondrial dysfunction and increased dopaminergic neuronal death, resulting in PD.

Figure 3

MeHg-induced glutamate and Ca²⁺ dyshomeostasis and oxidative stress involving neuronal death. MeHg inhibits astrocytic glutamate uptake and enhances glutamate release from presynaptic terminals. The increased extracellular glutamate levels lead to the overactivation of N-methyl-D-aspartate (NMDA)-type glutamate receptors, enhancing the influx of Ca²⁺ into postsynaptic neurons. The increased levels of intracellular Ca²⁺ may cause mitochondrial dysfunction and increased reactive oxygen species (ROS) formation. MeHg disrupts the redox state of the cells, which indirectly depletes glutathione (GSH), which will further increase ROS production in both astrocytes and neurons.

Figure 4

Dysregulation of Cu ion homeostasis in PD. Excessive levels of Cu improved dopamine (DA) oxidation, upregulated α-synuclein (αSyn) aggregation, and formation of Lewy bodies. Excess Cu levels in the brain take part in Fenton chemistry as a catalyst to produce free radicals. Both processes lead to ROS production causing dopaminergic neuronal death and PD.

Figure 5

Pb²⁺ induces changes in dopamine transporter (DAT) morphology, leading to an increase in extracellular dopamine level, resulting in neurotoxicity via dopamine oxidation. Moreover, Pb²⁺ and Ca²⁺ share a permeability pathway represented by a Ca²⁺ channel and increased Pb²⁺ level in mitochondria, causing dopaminergic neuron loss. In addition, Pb²⁺ induces α-synuclein aggregation, NMDA receptor (NMDAR) blockade, and the activation of protein kinase C, leading to reduced Ca²⁺ release from mitochondria. Moreover, δ-aminolevulinic acid dehydratase (δ-ALAD) blockade by Pb²⁺ delivered by mitochondria leads to the initiation of lipid peroxidation. These mechanisms ultimately cause the depletion of dopaminergic neurotransmission resulting in the development of PD.