Epigenetic mechanisms linking hexavalent chromium exposure to pancreatic cancer risk: a systematic review.

Pancreatic cancer remains one of the most lethal malignancies, largely due to late diagnosis and limited treatment options. Hexavalent chromium (Cr(VI)) is a well-established environmental and occupational carcinogen, and emerging epidemiological observations have raised questions about its potential involvement in cancers beyond the lung. This systematic review synthesizes current evidence on the epigenetic effects of Cr(VI) exposure, including DNA methylation, histone modifications, and microRNA dysregulation, and evaluates whether these mechanisms converge on pathways relevant to pancreatic carcinogenesis. A structured literature search of EMBASE and PubMed (including MEDLINE) identified 11 studies that met predefined inclusion criteria. Across these studies, Cr(VI) exposure was consistently associated with hypermethylation of tumour suppressor genes (including and ), alterations in histone methylation (such as increased H3K9me2), and dysregulation of oncogenic microRNAs including miR-3940-5p. Collectively, these epigenetic alterations affect processes central to carcinogenesis, including DNA repair, genomic stability, inflammatory signalling, and cellular stress responses. Notably, several of the genes affected by Cr(VI) exposure such as , and are well-recognized contributors to pancreatic ductal adenocarcinoma (PDAC) development. Although none of the identified studies directly examined Cr(VI)-associated epigenetic changes in pancreatic tissue or pancreatic cell systems, the convergence of Cr(VI)-induced epigenetic alterations on molecular pathways central to PDAC biology highlights a set of biologically plausible and testable hypotheses linking chromium exposure to pancreatic cancer risk. Together, the available evidence suggests that Cr(VI) exposure could plausibly promote pancreatic carcinogenesis through epigenetic silencing of DNA repair pathways and activation of stress-response and stemness-associated signalling networks. By integrating findings across diverse experimental systems, this review identifies mechanistic intersections between chromium-induced epigenetic dysregulation and established drivers of PDAC. These findings highlight a clear opportunity for targeted investigation of Cr(VI)-associated epigenetic signatures in pancreatic-relevant experimental models and in chromium-exposed human populations. Such studies could determine whether environmentally induced epigenetic alterations contribute to pancreatic cancer susceptibility and may reveal previously under-recognized environmental drivers of pancreatic carcinogenesis.