New Insights Into Cellular Stress Responses to Environmental Metal Toxicants

Exposures to metal toxicants in the environment disrupt normal physiological functions and have been linked to the development of a myriad of human diseases. While the molecular and cellular mechanisms underlying metal toxicities remain to be fully understood, it is well appreciated that metal toxicants induce cellular stresses and that how cells respond to the stresses plays an important role in metal toxicity. In this review, we focus on how metal exposures induce stresses in the endoplasmic reticulum (ER) to elicit the unfolded protein response (UPR). We document the emerging evidence that induction of ER stress and UPR in the development of human diseases is associated with metal exposures. We also discuss the role of the interplay between ER stress and oxidative stress in metal toxicity. Finally, we review recent advances in functional genomics approaches and discuss how applications of these new tools could help elucidate the molecular mechanisms underlying cellular stresses induced by environmental metal toxicants.