Associations of Environmental Pollutant Mixtures and Red Blood Cell Folate Concentrations: A Mixture Analysis of the U.S. Adult Population Based on NHANES Data, 2007–2016

Background: Folate is critical for many physiological processes, and low folate levels have been associated with a wide range of health outcomes, including chronic diseases and developmental outcomes. Many environmental chemicals are suspected to contribute to the etiology of health outcomes related to folate deficiency. However, little is known about how these pollutants influence folate levels as potential mechanistic pathways. Objective: To investigate the individual and joint associations between a mixture of 39 pollutants and red blood cell (RBC) folate concentrations in the U.S. population. Methods: We used available data on 27,938 participants, aged 18&ndash:80 from the U.S. National Health and Nutrition Examination survey (2007&ndash:2016), with available RBC folate concentrations and 39 environmental pollutants&rsquo: concentrations. We estimated covariate-adjusted independent and joint associations between environmental pollutants and RBC folate, and compared evidence from two complimentary mixture approaches: exposome-wide association study (ExWAS) and quantile-based g computation (Q-gcomp). Results: In the ExWAS analysis, 12 environmental chemicals, including metals (cadmium, arsenic, lead, and mercury), perfluoroalkyl substances, phthalates, phenols and parabens, and polycyclic aromatic hydrocarbons, were inversely associated with RBC folate, whereas four environmental pollutants, including metals (manganese and selenium) and two phthalate metabolites, were positively associated with RBC folate. Q-gcomp showed convergent results with the ExWAS analysis: a quartile increase in the metal and PFAS mixtures was significantly associated with a decrease of &minus:38.4 ng/mL (95%CI: &minus:52.3, &minus:24.4) and &minus:48.9 ng/mL (95%CI: &minus:57.6, &minus:39.6) in RBC folate concentrations, respectively. Conclusion: The present study shows that higher exposure to PFASs, metals, and PAHs are associated with lower RBC folate concentrations. However, given the cross-sectional design, we cannot make inferences about the directionality of the observed associations.