Epigenetic vulnerability in endocrine disruption: bridging mechanisms, models, and environmental inequities

This narrative mini-review examines how endocrine-disrupting chemicals (EDCs) induce persistent epigenetic alterations that shape endocrine, metabolic, and developmental trajectories across the lifespan. It addresses the emerging gap in integrating mechanistic epigenetic evidence with population-level vulnerability, particularly in underrepresented regions such as Latin America. These effects are especially critical during sensitive windows-including fetal development, childhood, and puberty-when DNA methylation, histone modifications, and non-coding RNA networks establish long-term molecular programming. While animal models have provided key mechanistic insights, their translational limitations highlight the need for human-relevant systems capable of capturing endocrine-specific and epigenetic endpoints under environmentally realistic conditions. We propose that epigenetic programming represents a central biological interface linking EDC exposure to context-dependent vulnerability. New Approach Methodologies (NAMs)-including organoids, micro-physiological systems, and computational models-offer a translational bridge aligned with Adverse Outcome Pathway frameworks. Importantly, susceptibility to endocrine disruption is shaped not only by biological factors but also by environmental, nutritional, and socioeconomic determinants. Evidence from Latin American populations-including altitude gradients, nutritional transitions, and structural inequalities-illustrates how these contextual factors interact with epigenetic mechanisms to influence metabolic and endocrine outcomes. This integrative perspective supports the development of more equitable and context-sensitive approaches to endocrine toxicology.