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

{"Background": "Arsenic is a highly toxic environmental contaminant affecting millions worldwide, particularly in Asia where arsenic-laden Himalayan rocks contaminate major river systems and rice-growing regions. While most research has focused on high-dose arsenic exposure, the neurocognitive effects of chronic low-level exposure remain poorly characterized. This study investigated the association between low-level arsenic exposure and brain structure, function, and cognition in a large Indian cohort of children, adolescents, and young adults.", "Methods": "The study analyzed cross-sectional baseline data from 1,014 participants (mean age 14.86 years, 58.1% male) of the cVEDA cohort recruited from 5 sites across India between November 2016 and May 2019. Urinary arsenic was measured using atomic absorption spectrometry. Cognitive assessment employed a comprehensive battery testing 9 domains including attention, working memory, set shifting, cognitive flexibility, and risk-taking. Brain imaging included T1-weighted MRI for gray matter volume and resting-state fMRI for functional connectivity. Sparse partial least squares (sPLS) analysis established multivariate associations, followed by bootstrapped mediation and moderated mediation analyses controlling for age, sex, site, education, and intracranial volume.", "Key Results": "Urinary arsenic ranged from 0.26 to 46.50 \u00b5g/L (mean 9.65 \u00b5g/L), comparable to global levels and below WHO drinking water guidelines. Arsenic was significantly associated with a cognitive syndrome (r = -0.12, P = 5.4 \u00d7 10\u207b\u2074) characterized by deficits in attention (\u03b2 = -0.05, 95% CI -0.09 to -0.01), working memory (\u03b2 = -0.05, 95% CI -0.08 to -0.01), set shifting (\u03b2 = -0.03, 95% CI -0.07 to -0.004), cognitive flexibility (\u03b2 = -0.03, 95% CI -0.06 to -0.003), and increased risk-taking (\u03b2 = 0.06, 95% CI 0.01-0.13). Gray matter volume alterations were found in the inferior frontal cortex (right pars triangularis \u03b2 = 0.13, left pars triangularis \u03b2 = 0.12), right inferior temporal cortex (\u03b2 = -0.13), right rostral anterior cingulate (\u03b2 = -0.09), and left insula (\u03b2 = -0.11). Within-network functional connectivity was reduced in cognitive, visual, and sensorimotor domains (r = -0.12, P = 7.5 \u00d7 10\u207b\u2074). Between-network functional connectivity showed both negative and positive associations with arsenic (r = -0.23, P = 1.8 \u00d7 10\u207b\u00b9\u2070). Mediation analysis revealed significant indirect effects through brain structure (b = -0.004, 95% CI -0.007 to -0.002; 28.13% mediation) and within-network functional connectivity (b = -0.004, 95% CI -0.008 to -0.002; 29.86% mediation). Socioeconomic status and BMI significantly moderated the arsenic-brain structure-cognition pathway, with stronger effects in low SES and low BMI individuals.", "Clinical Implications": "This study demonstrates that even low-level arsenic exposure, below current WHO safety thresholds, is associated with measurable brain changes and executive function deficits in developing children and adolescents. The findings suggest that current definitions of safe arsenic exposure may need reexamination. The moderating effects of SES and BMI indicate that improving nutrition and socioeconomic conditions could potentially ameliorate arsenic-related neurocognitive harms. Given that dietary intake (particularly rice) was the primary exposure source, simple interventions like modified rice cooking methods (which can remove 50-74% of arsenic) may offer accessible mitigation strategies. The identified executive function deficits, while mild at the individual level, could have significant population-level consequences including increased school failure, reduced economic productivity, and vulnerability to future psychopathology."}