Neurocognitive Analysis of Low-level Arsenic Exposure and Executive Function Mediated by Brain Anomalies Among Children, Adolescents, and Young Adults in India

Key Points Question What is the association of low-level arsenic exposure with brain structure and function and subsequent cognitive functioning? Findings This cohort study of 1014 participants describes a syndrome of impairments in executive function associated with low-level arsenic exposure and characterizes its underlying brain mechanisms. The arsenic-associated impairments are exacerbated by risk factors such as poor nutrition and poverty. Meaning These findings call for a reexamination of the definitions of safe levels of environmental arsenic exposure; improvements in nutrition and socioeconomic conditions may additionally serve as potential mechanisms to ameliorate the harmful consequences of environmental arsenic insults. This cohort study investigates potential arsenic-related syndromic alterations across multiple cognitive domains and associations of arsenic exposure with brain structure and function among children, adolescents, and young adults in India. Importance Arsenic, a contaminant of groundwater and irrigated crops, is a global public health hazard. Exposure to low levels of arsenic through food extends well beyond the areas with high arsenic content in water. ObjectiveTo identify cognitive impairments following commonly prevalent low-level arsenic exposure and characterize their underlying brain mechanisms. Design, Setting, and Participants This multicenter population-based cohort study analyzed cross-sectional data of the Indian Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA) cohort, recruited between November 4, 2016, and May 4, 2019. Participants aged 6 to 23 years were characterized using deep phenotyping measures of behavior, neuropsychology, psychopathology, brain neuroimaging, and exposure to developmental adversities and environmental neurotoxins. All analyses were performed between June 1, 2020, and December 31, 2021. Exposure Arsenic levels were measured in urine as an index of exposure. Main Outcomes and Measures Executive function measured using the cVEDA neuropsychological battery, gray matter volume (GMV) from T1-weighted magnetic resonance imaging, and functional network connectivity measures from resting state functional magnetic resonance imaging. Results A total of 1014 participants aged 6 to 23 years (589 male [58.1%]; mean [SD] age, 14.86 [4.79] years) were included from 5 geographic locations. Sparse-partial least squares analysis was used to describe a negative association of arsenic exposure with executive function (r=-0.12 [P=5.4 x 10(-4)]), brain structure (r=-0.20 [P=1.8 x 10(-8)]), and functional connectivity (within network, r=-0.12 [P=7.5 x 10(-4)]; between network, r=-0.23 [P=1.8 x 10(-10)]). Alterations in executive function were partially mediated by GMV (b=-0.004 [95% CI,-0.007 to -0.002]) and within-network functional connectivity (b=-0.004 [95% CI,-0.008 to -0.002]). Socioeconomic status and body mass index moderated the association between arsenic and GMV, such that the association was strongest in participants with lower socioeconomic status and body mass index. Conclusions and Relevance The findings of this cross-sectional study suggest that low-level arsenic exposure was associated with alterations in executive functioning and underlying brain correlates. These results indicate potential detrimental consequences of arsenic exposure that are below the currently recommended guidelines and may extend beyond endemic risk areas. Precision medicine approaches to study global mental health vulnerabilities highlight widespread but potentially modifiable risk factors and a mechanistic understanding of the impact of low-level arsenic exposure on brain development.