DDT exposure induces microglial activation and disease-associated microglial signatures: Relevance to mechanisms of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is characterized by the presence of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the primary metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were significantly higher in AD patients compared to age-matched controls and that DDT exposure worsened AD pathology in animal models. OBJECTIVE: Here, we investigated the effect of DDT on neuroinflammation in primary mouse microglia (PMG) and C57BL/6J mice. METHODS: DDT-induced inflammatory and disease-associated microglial (DAM) gene expression were determined in PMG by qPCR and immunocytochemistry, with and without pretreatment with the sodium channel antagonist tetrodotoxin (TTX). Furthermore, 4-5-month-old C57BL/6J mice received a single oral dose of 30 mg/kg DDT for 24 h, and the hippocampal and frontal cortical expression of proinflammatory and DAM genes was measured. RESULTS: PMG exposed to DDT (0.5-5.0 µM) elicited a concentration-dependent upregulation in Il-1b, Il-6, Nos2, and Tnfa mRNA levels. These effects were blocked by TTX, demonstrating the role of DDT-microglial sodium channel interactions in mediating this response. C57BL/6J mice exposed to DDT demonstrated significantly increased Nos2, Il-1b, and Il-6 mRNA in the frontal cortex (1.5-2.3-fold), and Nos2, Il-1b, and Tnfa (1.5-1.8-fold) in the hippocampus. Furthermore, microglial homeostatic genes were downregulated, while stage-1 DAM genes were upregulated both in vitro and in vivo. Notably, Apoe and Trem2 were only upregulated in the females. CONCLUSION: These data indicate that DDT increases neuroinflammation, which may result from direct actions of DDT on microglia, providing a novel pathway by which DDT may contribute to AD risk.