Abstract
The predisposition, severity, and progression of many diseases differ between males and females. Sex-related differences in susceptibility to neurotoxicant exposures may provide insight into the cause of the observed discrepancy. Early adolescence, a period of substantial structural and functional brain changes, may present a critical window of vulnerability to environmental exposures. This study aimed to examine sex-specific associations between co-exposure to multiple metals and visuospatial memory in early adolescence. Manganese (Mn), lead (Pb), chromium (Cr), and copper (Cu) were measured in blood, urine, hair, nails, and saliva of 188 participants (88 girls; 10–14 years of age). Visuospatial memory skills were assessed using a computerized maze task, the virtual radial arm maze (VRAM). Using generalized weighted quantile sum regression, we investigated sex-specific associations between the combined effect of exposure to the metal mixture and visuospatial working memory and determined the contribution of each component to the outcome. The results suggest that sex moderates the association between the metal mixture and visuospatial learning for all outcomes measured. In girls, exposure was associated with slower visuospatial learning and driven by Mn and Cu. In boys, exposure was associated with faster visuospatial learning, and driven by Cr. These results suggest that (a) the effect of metal co-exposure on learning differs in magnitude, and in the direction between sexes, and (b) early adolescence may be a sensitive developmental period for metal exposure.
Highlights
Sex-specific differences in the prevalence, severity, and progression of neurodevelopmental diseases is a growing field of interest in biomedical research, motivated by sexspecific behaviors and physiology[1]
Among the 408 adolescents who were enrolled in the second study phase, the virtual radial arm maze (VRAM) was administered to 402 participants, and 367 (91%) completed all eight trials as a sub-study designed to promote the use of neurobehavioral instruments that cross animal and human studies (R01ES013744-S)
Results from generalized weighted quartile sum (gWQS) analysis suggest sex-specific vulnerabilities to the combined effect of metal exposure on visuospatial learning in adolescents in all VRAM outcomes: time to complete the maze (β = 0.87, p < 0.01), the distance traveled (β = 222, p < 0.001), the number of working memory errors (β = 0.06, p < 0.01), and the number of reference memory errors (β = 0.06, p < 0.001) (Fig. 2, Supplementary Table 3)
Summary
Sex-specific differences in the prevalence, severity, and progression of neurodevelopmental diseases is a growing field of interest in biomedical research, motivated by sexspecific behaviors and physiology[1]. Substantial evidence from recent neuroimaging studies support sex differences in human brain structure and function beginning in utero and persisting throughout the life course[2,3,4,5,6]. We focus on adolescence as a sensitive period of brain development[12,13,14] and an understudied window of vulnerability to environmental exposures[15,16]. Similar to early life sensitive periods of brain development, the adolescent. Rechtman et al Translational Psychiatry (2020)10:358 brain undergoes substantial structural and functional changes involving synaptogenesis, myelination, and synaptic pruning[12,17,18]. Neural circuitry and synapses are sculpted to support the transition from basic to more complex skills reliant on executive functioning[12]
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