Environmental stress-induced mitochondrial metabolic reprogramming as a central driver of endocrine dysfunction: A food and chemical toxicology perspective.

Dietary and environmental chemical exposures including food contact materials, pesticide residues, heavy metals, mycotoxins, and synthetic food additives are increasingly recognized as contributors to endocrine and metabolic disease via mitochondrial mechanisms not captured by classical receptor-based screening. Mitochondria function as central integrators of metabolism, redox signaling, and stress responses, extending beyond bioenergetics to regulate endocrine function. These chemicals disrupt oxidative phosphorylation, mitochondrial dynamics, and metabolite fluxes, inducing metabolic reprogramming in hormone-sensitive tissues. Consequences include impaired ATP production, altered reactive oxygen species signaling, and epigenetic dysregulation, leading to defects in hormone synthesis, secretion, and tissue responsiveness. Developmental vulnerability and genetic variation in mitochondrial and nuclear-encoded genes further modulate susceptibility. Mechanistically, a cascade progresses from oxidative damage and impaired biogenesis to disrupted dynamics and mitophagy, followed by retrograde metabolite signaling that epigenetically stabilizes endocrine dysfunction. This underlies insulin resistance, steroidogenic impairment, thyroid imbalance, and neuroendocrine dysregulation. Tissue-specific mitochondrial vulnerabilities align with distinct chemical classes across endocrine cell types. While pharmacological and lifestyle interventions show promise, limitations in bioavailability and safety of food-derived bioactives remain. This review integrates causal evidence, chemical classification, and tissue-specific mapping to provide a translational framework for food toxicology and regulatory assessment.