Urinary neonicotinoid exposure and NAFLD in U.S. adults: The non-monotonic association of 5-hydroxyimidacloprid predominantly in males.

Environmental exposure to neonicotinoids (NEOs) is ubiquitous, yet epidemiological evidence linking them to non-alcoholic fatty liver disease (NAFLD) remains hindered by diagnostic limitations and linear modeling assumptions. This study analyzed 1281 adults from the NHANES 2017-2018 cycle, utilizing Vibration-Controlled Transient Elastography (VCTE) to objectively quantify hepatic steatosis. Through mutually adjusted multi-pollutant models, restricted cubic splines (RCS), and piecewise parallel mediation analyses, we evaluated the associations between five urinary NEO biomarkers and liver outcomes. Among the evaluated NEOs, only the imidacloprid metabolite 5-hydroxyimidacloprid (5OHIMI) exhibited a significant, independent association with NAFLD risk. This non-monotonic association was predominantly observed in males, displaying an inverted U-shaped dose-response trajectory with the highest odds at moderate exposure (OR = 3.17, 95% CI: 1.43 - 7.03, p = 0.016); no significant associations were found in females. Furthermore, piecewise mediation analysis indicated that systemic triglyceride dysregulation acted as a modest yet statistically significant potential mediator (9.13% proportion) during the initial positive association phase. These findings suggest that environmental 5OHIMI exposure is associated with early fatty liver disease predominantly in men, and disruptions in systemic lipid homeostasis may serve as a potential contributing pathway. This study provides population-based epidemiological evidence to refine neonicotinoid health risk assessment.