Abstract
BACKGROUND: Alzheimer's disease (AD) is characterized by the presence of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Previously, we reported 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: Effects of DDT on inflammation and disease-associated microglia were determined in primary mouse microglia and C57BL/6J mice. RESULTS: PMG exposed to DDT (0.5-5.0 µM) elicited a ∼2-3-fold increase in Il-1b mRNA levels, with similar concentration-dependent upregulation in Il-6, Nos2, and Tnfa . These effects were blocked by the sodium channel antagonist tetrodotoxin, demonstrating the role of DDT-microglial sodium channel interactions in mediating this response. Additionally, NOS2 protein levels increased by ∼1.5-2-fold, while TNFa was elevated by 2-4-fold. C57BL/6J male and female mice exposed to DDT (30 mg/kg) demonstrated significantly increased mRNA levels of Nos2 , Il-1b , and Il-6 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, Cx3cr1 , P2ry12, and Tmem119 , were downregulated, while stage 1 disease-associated microglia genes were upregulated both in vitro and in vivo . Notably, Apoe and Trem2 were only upregulated in the frontal cortex and hippocampus of 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.