Transcriptomic Analysis of the effects of DDT, and its metabolite, DDE, on Alzheimer's pathology in 5xFAD mice
Year: 2025
Type: article
Abstract: BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease, with increasing evidence implicating environmental factors in its etiology. We previously reported that DDT exacerbates amyloid pathology in the 3xTG-AD mouse model and that AD patients have significantly higher serum levels of DDE, the long-lived metabolite of DDT that is thought to be non-neurotoxic. However, whether DDE directly contributes to AD pathology remains unclear. METHOD: Male 5xFAD mice, 6 weeks of age, were exposed to 3 mg/kg of DDT, DDE, or corn oil every 3 days for 90 days. At 4.5 months of age, mice were sacrificed one day after behavioral assessment and brain tissue was dissected for RNA-sequencing. Count data was generated using the STAR protocol and analyzed using the DESeq2 pipeline. Moreover, multiplexed gene expression of pooled samples was measured using nCounter for a more targeted approach. RESULT: RNA-sequencing analysis identified 223, 252, and 213 uniquely expressed genes within control 5xFAD, DDT, and DDE-exposed hippocampal samples, respectively. Differential gene expression analysis demonstrated that, while DDT and DDE both significantly alter a broad range of genes compared to control 5xFAD, DDT and DDE target distinct biological pathways. Gene ontology enrichment analysis revealed that DDT-exposed mice had alterations of cellular components relating to the extracellular matrix, while DDE-treated mice were had more pathways altered related to glial cell differentiation. KEGG analysis indicated significant impairment of the PI3K-Akt signaling pathway in DDT-treated mice compared to control 5xFAD, while ECM-receptor interactions were significantly altered compared to DDE-exposed groups. Additionally, neuronal markers, measured using nCounter were differentially expressed, with glutamatergic and dopaminergic synapse pathways affected in both exposure groups. CONCLUSION: Overall, these findings demonstrate that exposure of 5xFAD mice to DDT and DDE differentially affect AD-related pathways and neurodegeneration. Importantly, they provide mechanistic evidence of DDE's neurotoxicity, reinforcing epidemiological findings and challenging the assumption that DDE is biologically inert in the brain.
Source: Alzheimer s & Dementia
Institutions: University of Georgia, Florida International University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
OpenAlex ID: W7117259151
FWCI:
Cites:
Cited by:
Related to: