Clenie Isingizwe, Gaudence Ndinganire, Abdullateef Isiaka Alagbonsi
Endocrine-disrupting chemicals (EDCs) are widespread environmental pollutants that interfere with hormonal homeostasis and contribute to multisystem toxicity. This systematic review aimed to synthesize available evidence on the protective effect of melatonin against EDC-induced toxicity across tissues. English language articles published between January 2000 and December 2025 were searched on PubMed, Web of Science, and Wiley Online. Eligible studies evaluated the protective or antagonistic effects of melatonin against EDC-induced toxicity in humans, mammals, or in vitro models. Data on study characteristics, EDC exposure, melatonin intervention, affected tissues, outcomes, and mechanisms were extracted, synthesized, and reported in accordance with the PRISMA 2020 guidelines. Sixty-one studies met the inclusion criteria. Melatonin exhibited protective effects against diverse EDCs, including bisphenols, phthalates, heavy metals, pesticides, and microplastics. The principal mechanisms identified were antioxidant and free-radical scavenging activity, modulation of hormone receptors, regulation of gene and protein expression, stabilization of endocrine axes, mitochondrial protection, and epigenetic modulation. These effects were observed across multiple organ systems, particularly the reproductive, neuroendocrine, cardiovascular, adrenal, and immune systems. Melatonin protects against EDC-induced multisystem toxicities by preserving endocrine signaling and coordinating cellular defense mechanisms across tissues, thereby holding therapeutic potential.