Methylmercury-induced neural degeneration in rat dorsal root ganglion is associated with the accumulation of microglia/macrophages and the proliferation of Schwann cells

Abstract

Exposure to organic mercury, especially methylmercury (MeHg), causes Minamata disease, a severe chronic neurological disorder. Minamata disease predominantly affects the central nervous system, and therefore, studies on the mechanisms of MeHg neurotoxicity have focused primarily on the brain. Although the peripheral nervous system is also affected by the organometallic compound and shows signs of neural degeneration, the mechanisms of peripheral MeHg neurotoxicity remain unclear. In the present study, we performed quantitative immunohistochemical analyses of the dorsal root ganglion (DRG) and associated sensory and motor fibers to clarify the mechanisms of MeHg-induced peripheral neurotoxicity in Wistar rats. Methylmercury chloride (6.7 mg/kg/day) was orally administrated for 5 days, followed by 2 days without administration, and this cycle was repeated once again. Seven and 14 days after the beginning of MeHg exposure, rats were anesthetized, and their DRGs and sensory and motor nerve fibers were removed and processed for immunohistochemical analyses. The frozen sections were immunostained for neuronal, Schwann cell, microglial and macrophage markers. DRG sensory neuron somata and axons showed significant degeneration on day 14. At the same time, an accumulation of microglia and the infiltration of macrophages were observed in the DRGs and sensory nerve fibers. In addition, MeHg caused significant Schwann cell proliferation in the sensory nerve fibers. In comparison, there was no noticeable change in the motor fibers. Our findings suggest that in the peripheral nervous system, MeHg toxicity is associated with neurodegenerative changes to DRG sensory neurons and the induction of a neuroprotective and/or enhancement of neurodegenerative host response.

Cellular and Molecular Mechanisms Mediating Methylmercury Neurotoxicity and Neuroinflammation

“…The mRNA levels of CD16 and CD32, markers of microglial reactivity were also found to be enhanced [135]. Accordingly, several animal studies indicate that chronic MeHg administration has an effect in the enhancement of microglial cells staining, reactivity, and number in several areas of the CNS, including occipital lobes [141], prelimbic and motor cortex [66], cerebellum [137,142], hippocampus [136], dorsal root ganglions and sensory fibers [143], dorsal root nerve and dorsal column of the spinal cord [138]. However, the increased staining detected in spinal nerves and sensory fibers may be derived from macrophages recruited to the area.…”

“…However, the increased staining detected in spinal nerves and sensory fibers may be derived from macrophages recruited to the area. Nevertheless, microglial cells account for the most part of the detected signal [143].…”

“…Although some studies have observed deleterious effects in the peripheral nervous system, the CNS is the main target of MeHg, as evidenced by symptoms following an acute or chronic exposure [143]. For this reason, MeHg-mediated neurotoxicity has been extensively studied using both in vitro and in vivo biological models (Table S4).…”

Toxic Peripheral Neuropathies: Agents and Mechanisms

“…239 In addition to neuron loss in the visual area of the calcarine cortex and granule cells of the cerebellum, methylmercury also produces degeneration of neurons in the DRG along with their associated axons while sparing the peripheral nerve motor axons. [239][240][241][242][243] Methylmercury exerts its neurotoxic affects in DRG partly through the ability to accumulate there due to the high density of fenestrated capillaries. [26][27][28][29] Although the molecular targets and mechanisms of methylmercury are still being delineated, the experimental evidence supports contributions from several processes including disrupted calcium homeostasis, increased oxidative stress, and altered glutamate homeostasis leading to excitotoxicity.…”

“…239 In addition to neuron loss in the visual area of the calcarine cortex and granule cells of the cerebellum, methylmercury also produces degeneration of neurons in the DRG along with their associated axons while sparing the peripheral nerve motor axons. 239 –243…”