Blood transcriptome changes linked to long-term arsenic exposure through drinking water – a cross-sectional study from the Bolivian Andes

Chronic exposure to inorganic arsenic (As) in drinking water is a serious health concern but people differ in susceptibility. Naturally occurring As in Bolivian drinking water was recently reported, however, its long-term effects on the blood transcriptome remain unexplored. To bridge this gap, we conducted a transcriptome-wide analysis of whole blood cells from individuals in the Bolivian Andes. Blood and urine samples were collected for transcriptomic analysis, genotyping of AS3MT polymorphisms, and measurements of inorganic As metabolites in urine. Linear regression models were employed for extracting As-associated genes, and cell deconvolution to estimate cell fractions from the transcriptome. Functional annotations of the As-associated genes were performed using Ingenuity Pathway Analysis (IPA) and ClusterProfiler. Protein-protein interaction analysis was conducted to identify networks between As-associated genes. A total of 588 genes were identified from linear regression analysis and associated with downregulation of autophagy-related functions and a reduction in activated NK cells. Stratification by gender showed a significant enrichment of pathways related to carcinogenesis, oxidative stress, glucose metabolism, and epigenetic regulation in females, e.g., PI3K/AKT/MTOR signaling, HIF-1 signaling, insulin receptor signaling, and microRNA biogenesis pathway. Carriers of the AS3MT genotypes associated with a poorer As metabolism showed enrichment in DNA replication and cell proliferation, whereas carriers of the genotype associated with an efficient As metabolism showed suppression of autophagy and DNA damage pathways. Our data indicate the importance of the autophagy pathway in relation to As exposure, and its crosstalk with PI3K/AKT/mTOR and miRNA biogenesis, providing new insights into the biological pathway under As exposure. Overall, this study identified novel genome-wide changes in blood mRNA in response to long-term As exposure in Bolivia, an underrepresented population, laying groundwork for further study.