Chloroacetic acids induce skin aging via cGAS/STING/NF-κB pathway in HaCaT cells, human explants and rats

Abstract

Chloroacetic acids, including monochloroacetic acid (MCA), dichloroacetic acid (DCA), and trichloroacetic acid (TCA), are non-volatile disinfection by-products. They are frequently detected at high concentrations in swimming pools, raising concerns about potential detrimental effects on skin health. However, the mechanisms underlying their toxicity remain poorly understood. In this study, we established a full-thickness skin model to replicate realistic environmental conditions and investigated the signaling pathways involved in chloroacetic acid-induced skin aging at multiple levels. In HaCaT cells, exposure to chloroacetic acids, increased intracellular reactive oxygen species (ROS), triggered the release of inflammatory factors, induced cell cycle arrest, and activated senescence markers. In human skin explants, such exposure reduced the expression of skin barrier proteins and caused epidermal contraction, indicating barrier disruption. Furthermore, in a rat model, treatment with chloroacetic acids led to scab formation, inflammatory infiltration, and histological alterations exhibiting aging-like features. Further more, our findings reveal that chloroacetic acids impair skin health via activation of the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)–nuclear factor kappa B (NF-κB) signaling pathway. These findings provide novel insights into the pathogenesis of chloroacetic acid exposure and underscore the urgent need for environmental regulations to mitigate their harmful effects.