A critical review of the epigenetic effects of Bisphenols in animal models

Bisphenols, particularly Bisphenol A (BPA) and its analogs such as Bisphenol S (BPS) and Bisphenol F (BPF), are prominent environmental contaminants due to their extensive use in consumer products. These compounds are recognized as endocrine disrupting chemicals (EDCs) and are associated with several adverse effects in humans and wildlife, including reproductive, developmental, and metabolic dysfunctions. Increasing evidence suggests a role for epigenetic mechanisms underlying prolonged or delayed toxicity due to bisphenols. This review critically examines the epigenetic effects of BPA and its analogs across different animal and cell models, including human epidemiological studies, in vitro experiments, mammalian and fish models. Key findings show that bisphenol exposure alters DNA methylation, histone modifications, and non-coding RNA expression, implicating these changes in disrupted gene expression, reproductive impairments, and transgenerational effects. Notably, bisphenols dysregulate genes associated with lipid metabolism ( Srebf1, Srebf2 ), steroidogenesis ( star, cyp11a1, cyp17a1 ), immune function (e.g., Foxp3 ), and neurodevelopment ( Grin2b, IGF-1, COMT ), often through hypo- or hypermethylation of CpG islands and promoter regions. Additionally, histone modifications such as H3K9me3, H3K4me3, and H3K27me3 and altered expression of miRNAs ( miR-27b-3p, miR-200 ) further mediate these toxic effects. The dose-dependent and tissue-specific nature of epigenetic modifications further underscores the complexity of bisphenol toxicity. Molecular docking amongst different taxa also reveals moderate binding affinities of BPA, BPF, and BPS to DNMT enzymes as well as histone proteins, suggesting direct epigenetic effects at the level of the protein. By integrating multidisciplinary research, this review elucidates the molecular pathways underlying bisphenol-induced epigenetic changes and provides critical insights into their broader environmental and health implications. Moving forward, data on comparative toxicity of BPA analogs and the interplay between different epigenetic mechanisms are needed. In addition, greater emphasis should be placed on environmentally relevant exposure conditions, including chronic low-dose exposures and chemical mixtures. Future studies should investigate potential mitigation strategies, including the reversibility of bisphenol-induced epigenetic alterations through interventions. Addressing these challenges will be essential for advancing our mechanistic understanding of bisphenol-induced epigenetic reprogramming in humans and wildlife.