Early-life critical windows of susceptibility to metal mixture exposure and neurocognitive mechanisms underlying adolescent risky decision-making

Introduction: The developing neural circuitry supporting adolescent risk-taking is vulnerable to metals, yet few studies have examined how early-life metal mixture exposure affects neural mechanisms underlying risk-taking. We used novel dentine biomarkers to identify critical windows of early-life metal mixture exposure associated with neurocognitive correlates of risky decision-making in early adolescence. Methods: Participants (ages 8-14, 45% female) were recruited from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) longitudinal birth cohort in Mexico City. Weekly concentrations of barium (Ba), copper (Cu), lithium (Li), magnesium (Mg), manganese (Mn), lead (Pb), tin (Sn), strontium (Sr), and zinc (Zn) were measured in children's deciduous teeth from 19 weeks pre-birth to 43 weeks postnatally. Neural activity during risky decision-making and reward processing was assessed using a functional magnetic resonance imaging gambling paradigm. Risk-taking tendency, risk sensitivity, and reward sensitivity were estimated from participants' decisions. We used lagged weighted quantile sum regression to examine time-varying associations between metal mixture exposure and neurocognitive outcomes, adjusting for child age, child sex, and socioeconomic status. Results: Higher metal mixture exposure during the early to late postnatal period was associated with increased risk-taking tendency and risk sensitivity. Exposure during the prenatal and late postnatal periods was associated with increased reward sensitivity and reduced activation in the angular gyrus/inferior parietal lobule during risky decision-making. Exposure during the late postnatal period was associated with increased activation in the insula/rolandic operculum during reward processing. Postnatal associations for risk-related and reward-related neural activation were primarily driven by Sr and Mg respectively, while postnatal associations for risk-taking tendency, risk sensitivity, and reward sensitivity were driven by multiple metals in the mixture. Conclusions: Early-life metal mixture exposure is differentially associated with neurocognitive correlates of risky decision-making in adolescence, depending on exposure timing.