Developmental toxicity of metals: Three decades of insights into mechanisms, epigenetics, and transgenerational inheritance

Since the early 1990s, considerable progress has been made in understanding the teratogenic and embryotoxic effects of metals in mammalian systems. The present updated review synthesizes over three decades of research findings, examining the developmental toxicity of metals across four categories: (a) metals of greatest toxicological significance (arsenic, cadmium, lead, mercury, and uranium), (b) essential trace metals (chromium, cobalt, manganese, selenium, and zinc), (c) other metals with evident biological interest (nickel and vanadium), and (d) metals of pharmacological interest (aluminum and lithium). Recent advances in understanding molecular mechanisms, epigenetic effects, transgenerational impacts, and improved chelation therapies are comprehensively reviewed. The emergence of new analytical techniques has revealed previously unrecognized low-dose effects and complex metal-metal interactions that affect developmental outcomes. Current evidence shows that environmental exposures to multiple metals at concentrations previously considered safe can produce significant developmental toxicity through oxidative stress, epigenetic modifications, and disruption of essential metabolic pathways. Chelating agents, including improved formulations of DMSA and DMPS, continue to show promise in preventing and treating metal-induced developmental toxicity, although their own potential developmental effects require careful consideration.