Inflammatory reaction regulated by microglia plays a role in atrazine-induced dopaminergic neuron degeneration in the substantia nigra

Abstract

Atrazine (ATR) is a widely used herbicide, although it is potentially ecotoxic. Increasing evidence indicates that ATR plays a critical role in inducing physiological changes to the endocrine and reproductive systems, and further may affect the nigrostriatal dopaminergic system in the diencephalon, resulting in altered dopamine (DA) levels in the striatum, transport and storage-related protein abnormalities in the synaptic terminals, motor function deficits, and degeneration of DA neurons in the substantia nigra (SN). As the primary immunocytes in the central nervous system (CNS), microglial function to maintain the CNS microenvironment by preventing damage to healthy cells as well by regulating inflammatory responses. Several studies have demonstrated that microglial activation exerted an important effect on neuronal degeneration. In order to investigate dynamic changes of the microglial phenotype in the SN, rats received consecutive intraperitoneal injections of a vehicle or ATR at 25, 50, or 100 mg/kg body weight for a 14-day period and were then sacrificed at 1, 4, 7, or 14 days post-treatment, respectively. Here, we found that microglial activation by changes to phenotype emerged later in the low ATR exposure group than in the medium and high ATR exposure groups, and proliferating microglia were observed as well. Moreover, as two major inflammatory cytokines, expression of tumor necrosis factor α and interleukin-1β, emerged earlier post-ATR exposure, and a significant upregulation was observed in the medium and high ATR exposure groups. These results suggested that inflammatory reactions regulated by microglia occurred in a dose- and time-dependent manner, which may explain the severe DA neuron degeneration with the phagocytic phenotype of microglia in the SN that emerged earlier in the medium and high ATR exposure groups than in the low ATR exposure group. Taken together, our findings suggest that microglial activation might be involved in the dose- and time-dependent ATR-induced DA neuron degeneration in the SN.