Trichloroethylene induces cardiomyocyte senescence through an AhR-ROS-IL-1 axis and amplified by Wnt/β-catenin suppression.

Abstract

Trichloroethylene (TCE), a pervasive groundwater contaminant, has been epidemiologically linked to cardiovascular diseases, yet its potential to initial cardiac aging remains uncharacterized. Using H9c2 cardiomyocytes and zebrafish larvae, we dissected the molecular mechanisms underlying TCE-induced cardiac senescence. Exposure to an environmentally relevant dose of TCE (60 μg/L) triggered a robust premature aging program, characterized by flattened morphology, elevated senescence-associated SA-β-gal activity, up-regulation of p16/p21 expression, and reduced Lamin B1 levels, without compromising acute cell viability. Mechanistically, TCE engaged the aryl hydrocarbon receptor (AhR) pathway, leading to ROS overproduction and ATM-dependent DNA damage. Pharmacologic inhibition of AhR, ROS scavenging, or ATM blockade each abrogated senescence onset. Transcriptomic profiling identified IL-1 as the dominant senescence-associated secretory phenotype cytokine downstream of ROS. Critically, IL-1 receptor antagonism attenuated DNA damage and reversed senescence markers, establishing a feed-forward inflammatory loop that perpetuates cardiac senescence. Concurrently, AhR suppressed canonical Wnt/β-catenin signaling by upregulating components of the β-catenin destruction complex, thereby amplifying IL-1-driven inflammation. Restoration of Wnt activity with a GSK-3β inhibitor curbed IL-1 expression and attenuated senescence phenotype. Importantly, in vivo TCE exposure in zebrafish validated the in vitro findings: AhR signaling, oxidative DNA damage, Wnt suppression, IL-1β induction, and p53/p21-mediated senescence in cardiac tissue, confirming the translational relevance of our mechanistic axis. These results identify TCE as an exogenous trigger of premature cardiac senescence and uncover the AhR- IL-1 axis as a druggable pathway for mitigating environmentally accelerated cardiac senescence.