Language
English
Publication Date
12-1-2025
Journal
Neurotoxicology
DOI
10.1016/j.neuro.2025.103343
PMID
41187876
PMCID
PMC13036457
PubMedCentral® Posted Date
4-1-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
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.
Keywords
Animals, Microglia, DDT, Mice, Inbred C57BL, Mice, Alzheimer Disease, Male, Female, Cells, Cultured, Insecticides, Alzheimer’s Disease, DDT, Neuroinflammation, Microglia, DAM
Published Open-Access
yes
Recommended Citation
Mhatre-Winters, Isha; Eid, Aseel; Blum, Nicole; et al., "DDT Exposure Induces Microglial Activation and Disease-Associated Microglial Signatures: Relevance to Mechanisms of Alzheimer’s Disease" (2025). The Brown Foundation: Institute of Molecular Medicine. 78.
https://digitalcommons.library.tmc.edu/molecular_med/78