Sexual dimorphism in the programming effects of prenatal manganese multi-media biomarker on temporal cognition in school-aged children

There is limited knowledge about the sexually dimorphic effects of manganese (Mn) on children’s temporal cognition (i.e., time perception), an important component of executive function, and whether impacts differ by sex. We proposed that the effects of prenatal Mn exposure on children’s ability to perceive time could be best assessed using a multi-media biomarker (MMB) to estimate cumulative exposure. Children aged 6–7 from Mexico City were administered a temporal response differentiation task, an operant test in which a reward is provided if they correctly hold a lever down between 10 and 14 s (s). Short (< 10s) and long holds (> 14s) were incorrect and not rewarded. Blood and urinary Mn levels were assessed from mothers in the 2nd and 3rd trimesters. A covariate-adjusted generalized weighted quantile sum (WQS) regression estimated the effect of a Mn MMB index (combining blood and urine biomarkers into a single metric) on temporal cognitive performance. Sex-stratified models were also assessed. Higher prenatal Mn MMB index, representing higher exposure levels, was significantly associated with impaired performance across multiple cognitive timing measures. When examining Mn exposure in sex-stratified analyses, girls exhibited significantly poorer performance than boys. Among girls, higher prenatal Mn MMB index was associated with fewer timing holds (β = -2.14; 95%CI: -3.57, -0.72), fewer total holds (β = -2.11; 95%CI: -4.18, -0.04), and lower timing accuracy, reflected in total holds excluding durations of 2s or less (β = -1.29; 95%CI: -1.49, -1.09), and greater variability in lever hold durations for total holds (β = 0.67; 95%CI: 0.09, 1.24). High Mn exposure impacts temporal assessment pathways with greater impacts in girls. Our results also highlight the necessity of assessing sex as a biological factor in prenatal Mn exposure, as the sex specificity of results was clear in the stratified models. Results may reflect sex-specific susceptibility via dopamine signaling, neurodevelopmental timing, and/or hormonal influences, warranting further research on these mechanisms.