SUMMARY Individual responses to vaccinations are a critical public health issue and mounting evidence suggests that early life environmental factors may program immune dysregulation that manifests years later. This developmental origins of health and development (DOHaD) theory posits that dose and timing of early life immunotoxic environmental exposures can have long-lasting consequences on the trajectory of immune system function. The immune system begins to develop in utero and, as children age and experience infections and vaccinations, an ever-expanding repertoire of antibodies become part of their lifelong immune memory. Yet research on child immune function and its response to ubiquitous immunotoxic metal exposures—experienced in utero and early in life (0–5 years)—has been largely overlooked.We will address this knowledge gap in the Mexican PROGRESS study, which has measures of immunotoxic metal exposures [arsenic (As), cadmium (Cd), manganese (Mn), and lead (Pb)] at several key developmental time windows and from multiple biomatrices (tooth, blood, and urine). We will assess child immune function by measuring antibody levels at 4, 6, 8, 10–11, and 13–15 years of age in response to scheduled childhood vaccinations (i.e., measles, mumps, rubella, diphtheria, tetanus, and pertussis). Our preliminary data show that (i) exposure to individual metals (Cd, Pb) and a metal mixture (As, Cd, Mn, Pb) may result in poorer antibody responses at age 4 years and that (ii) there are critical windows of susceptibility to As, Mn, and Pb exposures. Additionally, metal exposures induce systemic oxidative stress (OS) leading to suboptimal immune system function. Given the pro-oxidant role of metals, we will also quantify cumulative OS via a novel biomarker—mitochondrial DNA (mtDNA) heteroplasmy, which reflects OS-induced mtDNA mutation counts accumulating over time. Our initial data show that prenatal metal exposures are associated with mtDNA heteroplasmy counts at birth. We will measure mtDNA heteroplasmy at birth and at 8 and 13–15 years of age as a predictor and mediator of antibody responses. In Aim 1, we will determine the association between exposure to individual metals and metal mixtures with child antibody responses to vaccination at specific ages and antibody response trajectories over time. In Aim 2, we will determine critical windows of susceptibility to immunotoxic metals exposure on child immune system at specific ages and over time. In Aim 3, we will investigate associations between mtDNA heteroplasmy levels and (i) exposure to individual metals and metal mixtures and (ii) child antibody response to vaccination at specific ages and antibody response trajectories. We will apply statistical causal modeling strategies to evaluate the mediating role of mitochondrial biomarkers on the metal–immune system relationship. Completion of these aims will drive interventions that may help prevent lifelong immune system dysregulation and related adverse heal...