Co-exposure to environmental lead and hypertension exacerbates anxiety and depression via mtDNA-mediated cGAS phase separation

Environmental exposure to heavy metals such as lead (Pb) and the growing prevalence of hypertension (HTN) represent significant and often coexisting global health threats. However, the combined neurotoxic effects of Pb and HTN, particularly in terms of mood disorders such as anxiety and depression, remain poorly understood. Herein, using a combined exposure model, we found co-exposure to Pb and HTN markedly aggravates anxiety- and depression-like behaviors in mice compared with Pb and HTN exposure alone. The prefrontal cortex was identified as the most vulnerable brain region, with astrocytes as the most susceptible cell type to senescence. Notably, treatment with dasatinib and quercetin, a senolytic regimen that selectively eliminates senescent cells, significantly alleviated the behavioral deficits induced by Pb and HTN co-exposure. Further investigation revealed Pb and angiotensin II (AngII) co-exposure promoted phase separation of cyclic GMP-AMP synthase (cGAS), a key DNA sensor. Pharmacological disruption of biomolecular condensates with 1,6-hexanediol (1,6-HD) partially rescued astrocyte senescence induced by Pb and AngII co-exposure. Inhibition of mitochondrial DNA (mtDNA) replication with ethidium bromide (EtBr) markedly reduced cytosolic mtDNA accumulation caused by co-exposure, suppressed cGAS phase separation, and downregulated the expression of senescence-associated proteins including P16, P211, γH2AX, and SASP. These findings uncover a previously unrecognized role of mtDNA-dependent cGAS phase separation in driving astrocyte senescence and environment-related neuropsychiatric dysfunction, and highlight cGAS phase separation as a promising therapeutic target for preventing anxiety and depression in individuals simultaneously exposed to Pb and HTN.