Yang Ying, Snigireva Anastasiia, Barron Jessika, Tirado Noemi, Alvarez Aliaga Maria Teresa, Torres Gina, Manghi Paolo, Gérard Philippe, Levi Michael, Gardon Jacques, Alenius Harri, Broberg Karin
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Genetics Institute, Universidad Mayor de San Andrés, La Paz, Bolivia.
Environ Int. 2025 Sep;203:109727. doi: 10.1016/j.envint.2025.109727. Epub 2025 Aug 12.
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.
长期饮用含有无机砷（As）的水是一个严重的健康问题，但人们的易感性存在差异。最近有报道称玻利维亚饮用水中存在天然砷，然而，其对血液转录组的长期影响仍未得到探索。为了填补这一空白，我们对玻利维亚安第斯山脉地区个体的全血细胞进行了全转录组分析。收集血液和尿液样本用于转录组分析、AS3MT基因多态性基因分型以及尿液中无机砷代谢物的测量。采用线性回归模型提取与砷相关的基因，并通过细胞反卷积从转录组中估计细胞比例。使用 Ingenuity Pathway Analysis（IPA）和 ClusterProfiler 对与砷相关的基因进行功能注释。进行蛋白质 - 蛋白质相互作用分析以识别与砷相关基因之间的网络。通过线性回归分析共鉴定出588个基因，这些基因与自噬相关功能的下调和活化自然杀伤细胞的减少有关。按性别分层显示，女性中与致癌作用、氧化应激、葡萄糖代谢和表观遗传调控相关的通路显著富集，例如PI3K/AKT/MTOR信号通路、HIF-1信号通路、胰岛素受体信号通路和微小RNA生物合成通路。与砷代谢较差相关的AS3MT基因型携带者在DNA复制和细胞增殖方面表现出富集，而与高效砷代谢相关的基因型携带者则表现出自噬和DNA损伤通路的抑制。我们的数据表明自噬通路在砷暴露中的重要性，以及它与PI3K/AKT/mTOR和微小RNA生物合成的相互作用，为砷暴露下的生物学通路提供了新的见解。总体而言，本研究确定了在玻利维亚这个代表性不足的人群中，长期砷暴露后血液mRNA中全基因组范围内的新变化，为进一步研究奠定了基础。
