Arsenic attenuates responsiveness to inflammatory stimuli in the SIM-A9 microglial cell line.

Arsenic (As) is a major public health threat, with more than 200 million people at risk of consuming drinking water that exceeds World Health Organization safety guidelines. Given that inorganic arsenic (iAs) is linked to various neuropsychiatric and neurodegenerative disorders, a better understanding of its mechanisms of toxicity is warranted. Current evidence suggests that microglia are central to the pathophysiology of As-induced effects in the central nervous system. Microglia are resident immune cells in the brain that play a crucial role in surveillance, clearance of pathogens, and wound healing. They undergo distinct stages of development throughout life, and their behavior is known to be disrupted by environmental insults such as iAs. To characterize the mechanisms by which iAs alters microglial function, we examined the impact of subtoxic exposure to trivalent inorganic arsenic (As(III)) on microglial activity, both in the presence and absence of immune challenges, using a spontaneously immortalized murine cell line derived from the neonatal cerebral cortex (SIM-A9). Results indicate that iAs causes early activation of SIM-A9 cells through upregulation of toll-like receptor 4-mediated NF-κB signaling, followed by the slower onset of anti-inflammatory effects mediated through increased Nuclear Factor Erythroid 2-related Factor 2 (Nrf2) activity. This later attenuation of responses to inflammatory stimuli suggests that iAs exposure may impair neonatal microglial function and sensitize individuals to secondary challenges relevant to a range of neurological functions and disorders.