Epigenetic and epitranscriptomic landscape of phthalate toxicity: Implications for human health and disease

Phthalates (PAEs) are endocrine-disrupting chemicals widely used in industrial applications, with significant implications for human health. Growing evidence highlights epigenetic and epitranscriptomic mechanisms, specifically DNA methylation, histone modification, RNA modification and non-coding RNAs, as pivotal mediators of PAE toxicity. This review synthesizes current knowledge on how PAEs disrupt these regulatory layers, linking their dysregulation to diseases such as psoriasis, diabetes, atherosclerosis, reproductive disorders, and cancer. We recapitulate PAE-induced alterations in global and gene-specific DNA methylation patterns, chromatin remodeling via histone acetylation and methylation, and dynamic RNA modifications, alongside the aberrant expression of miRNAs and lncRNAs, which collectively drive pathological outcomes. Additionally, we discuss the potential of epigenetic and epitranscriptomic markers as diagnostic tools and therapeutic targets for PAE-associated diseases. By integrating these dual regulatory perspectives, our work bridges a gap in understanding PAE toxicity and underscores the need for interdisciplinary research to mitigate exposure risks. Finally, we outline future directions to unravel long-term epigenetic/epitranscriptomic impacts, offering novel insights into molecular mechanisms and intervention strategies.