Piecing together the puzzles: Aryl hydrocarbon receptor-mediated genetic and epigenetic signatures in dioxin-induced carcinogenicity- A systematic review and meta-analysis.

[BACKGROUND] Dioxins, are highly potent environmental carcinogens. Their toxic effects are mediated primarily by the Aryl Hydrocarbon Receptor (AhR). A comprehensive understanding of how AhR-induced genetic and epigenetic alterations drive carcinogenesis, especially through effects on cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and transgenerational inheritance, remains imperative.

[OBJECTIVES] This study investigated the interplay between AhR signaling and some molecular modifications in dioxin-induced carcinogenicity. We aimed to characterize resultant gene expression signatures, cell-specific responses, identify novel AhR targets and susceptible organs, and develop a molecular profile for biomarker and therapeutic development.

[METHODS] We searched databases for peer-reviewed experimental and epidemiological studies on AhR activation by dioxins and its effects on genetic/epigenetic mechanisms, cancer pathways, EMT/CSCs, or transgenerational impacts. Two reviewers performed selection, data extraction, and bias assessment.

[RESULTS] From 7510 records, 39 studies were incorporated in the qualitative synthesis including 19 in the meta-analyses. Dioxin/AhR significantly increased the expression of certain DNA methylating enzymes. AhR upregulates Gadd45b and LAT1/SLC7A5, induces IL-6, promotes cell cycle progression and interacts with key cancer pathways. AhR signaling alters DNA methylation at promoters, modulates histone modifications, dysregulates ncRNAs, facilitates EMT, influences CSCs, and elicits cell-specific liver responses. Evidence for transgenerational epigenetic inheritance of disease susceptibility was identified.

[CONCLUSION] Dioxin-induced carcinogenicity involves intricate AhR-mediated genetic damage and profound epigenetic reprogramming. These alterations, which are often cell-type and species-specific, disrupt critical cellular processes, including EMT and CSC biology, and are susceptible to transgenerational inheritance. The identified molecular signatures offer a foundation for improved biomarkers and targeted therapeutic interventions.