PARP1 promoter hypermethylation promotes arsenic-induced skin damage by driving telomere dysfunction-mediated keratinocyte senescence

Abstract

Arsenic, a common environmental pollutant, causes skin damage with long-term exposure. Although its pathogenic mechanism remains unclear, skin cell senescence creates a microenvironment that promotes cancer development, with the mechanisms accelerating disease progression in arsenic-induced skin damage attracting significant attention. This study utilised previously collected skin samples to evaluate the associations between skin senescence and damage indicators. According to the presence or absence of arsenic exposure, participants were divided into a reference group and an arsenic exposure group. Additionally, the arsenic exposure group was further divided into a common pathological changes group, a hyperkeratosis group, and a skin cancer group, based on skin histopathological examination. Compared with the reference group, the arsenic exposure group exhibited increased expression of senescence-associated secretory phenotypes (IL-6 and IL-17) and shortened relative telomere length (RTL). With increasing severity of skin damage, IL-6 and IL-17 levels progressively increased, while RTL progressively decreased. Examination of representative indicators of arsenic-induced skin damage (epithelial-mesenchymal transition [EMT] indicators) revealed decreased E-cadherin expression and increased vimentin expression. With increasing severity of skin damage, E-cadherin expression progressively decreased, while vimentin expression progressively increased. Moreover, clear correlations were observed between senescence-related markers (IL-6, IL-17, and RTL) and arsenic-induced skin damage markers (E-cadherin, vimentin) in the human samples. In vitro experiments demonstrated that arsenic induced lower expression of the telomere-related gene PARP1, reducing its binding to TERF2 and weakening its recruitment of BLM, thereby causing telomere dysfunction, promoting the senescence of HaCaT cells, and resulting in EMT. Additionally, arsenic exposure induced high expression of DNMT3, which mediated PARP1 hypermethylation and low expression. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine restored PARP1 expression in arsenic-treated HaCaT cells, regulated telomere dysfunction, improved cellular senescence, and alleviated EMT. This study provides new insights into the mechanisms underlying arsenic-induced skin damage from an epigenetic and genetic perspective.