A Neurocognitive Investigation of Low-Level Arsenic Exposure Reveals Impaired Executive Function Mediated by Brain Anomalies

Background: 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 water content. While isolated impairments of cognitive function following chronic exposure to high arsenic levels have been described, a comprehensive assessment of the scope of such impairments and their underlying brain mechanisms does not exist, especially not in the case of the much more common low-level arsenic exposure. Methods: We analyse 1014 participants aged 6 to 23 years of the Indian Consortium-on-Vulnerability-to-Externalizing-Disorders-and-Addictions (cVEDA). Participants were characterised using deep phenotyping measures of behaviour, neuropsychology, psychopathology, brain neuroimaging and exposure to developmental adversities and environmental neurotoxins. Arsenic was measured in urine as an index of exposure.  Findings: Using sparse-partial least square analysis (sPLS) we describe a correlation of arsenic exposure with impairments in executive function (r=-0.12, p=5.4x10-4), brain structure (r=-0·2, p=1·8x10-8) and functional connectivity (within-network: r=-0·12, p=7·5x10-4, between-network: r=-0·23, p=1·8x10-10).  Impairments in executive function were partially mediated by localised changes in grey-matter volume (b=-0·004, CIs=-0·007 to -0·002) and within-network functional connectivity (b=-0·004, CIs=-0·008 to -0·002). Socio Economic Status (SES) and Body Mass Index (BMI) moderated the link between arsenic and changes in grey-matter volume, with the effect of arsenic being strongest in participants from lower SES and with low BMI. Interpretation: We describe a syndrome of impairments in executive function and their brain correlates associated with low-level arsenic exposure. Our results demonstrate detrimental consequences of arsenic exposure well below currently recommended guidelines that affects people 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. Funding Information: Indian Council for Medical Research and Medical Research Council, United Kingdom. Declaration of Interests: All authors report no competing interests. Ethics Approval Statement: The cVEDA Study was approved by the Health Ministry Screening Committee, Ministry of Health and Family Welfare, Government of India. The study protocol was approved by the Institutional Ethics Review Boards of National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore, India (Item No. VII, SI. No. 7·08, Behavioural Sciences) and all other regional collaborating institutions. Informed consent was obtained from participants over the age of 18 and from parents of participants under 18 years of age (along with assent from minor participants).