Blood-based transcriptomic profiles associated with chronic mercury exposure in Amazonian riverine populations

Chronic mercury (Hg) exposure remains a major public health concern in Amazonian riverine communities, largely driven by frequent consumption of contaminated fish. In this cross-sectional study, we integrated biomonitoring with genome-wide whole-blood transcriptomic profiling to investigate molecular patterns associated with Hg exposure. The study included 95 adults (>18 years, both sexes) from thirteen riverine communities in the Brazilian Amazon, selected based on residence in the study area, absence of acute infectious disease at the time of sampling, and availability of complete biomonitoring and questionnaire data. Blood Hg concentrations ranged from 2.5 to 114.3 µg/L (mean: 26.9 ± 20.4 µg/L), and participants were stratified into control (7.2 ± 2.7 µg/L), moderate (16.8 ± 4.9 µg/L), and high exposure groups (42.0 ± 22.0 µg/L). Total RNA extracted from whole blood was analyzed using the Clariom™ S HT microarray platform. Raw intensity data were background-corrected, log₂-transformed, and normalized using the Robust Multi-array Average (RMA) method. Probes with low expression across samples were filtered prior to analysis. Differential expression analyses were performed between exposure groups using linear models with empirical Bayes moderation, applying a fold-change threshold ≥ 1.5 and a false discovery rate (FDR) ≤ 0.05. A large number of transcripts showed altered expression patterns in both the moderate (14,348) and high (14,535) exposure groups compared with controls, indicating broad exposure-associated transcriptional variation in whole blood. This extensive signal likely reflects a combination of transcriptional regulation and shifts in circulating blood cell composition associated with Hg exposure. Functional enrichment analyses revealed significant overrepresentation of pathways related to oxidative stress responses, inflammatory and immune signaling, DNA damage response, and cellular stress regulation, including G-protein-coupled receptor signaling, PI3K-Akt signaling, and Toll-like receptor/NF-κB-mediated inflammatory pathways. Stratification by exposure level suggested that moderate Hg exposure was predominantly associated with pathways involved in adaptive stress responses and metabolic regulation, whereas higher exposure levels were characterized by enrichment of inflammatory and apoptotic processes.To our knowledge, this is the first genome-wide transcriptomic study conducted in whole blood from a human population chronically exposed to Hg under real-world environmental conditions in the Amazon region. These findings provide preliminary molecular insights into biological processes associated with Hg exposure and highlight the need for future studies incorporating cell-type adjustment, longitudinal designs, and targeted validation to refine mechanistic interpretation and inform public health strategies for vulnerable Amazonian communities.