Prenatal Arsenic Exposure — Results in Long-Term Adverse Effects on Immune Gene Expression in Response to Influenza A Infection

An estimated (at least) 200 million people, worldwide, are exposed to elevated levels of arsenic in their drinking water [i.e. levels that exceed the 10 parts-per-billion (ppb) limit established in 2001 by the U.S. Environmental Protection Agency (EPA) as the maximum municipal drinking water concentration]. Approximately 44 million individuals in the U.S. rely on unregulated private wells for their water; of those, it is estimated that ~2.5 million are exposed to >10 ppb of arsenic in their drinking water (which included ~40 ppb in the rural farmhouse of yours truly until 2011). Arsenic concentrations in the U.S. typically fall in the moderate range, but higher levels of contamination (>100 ppb) have been documented. Arsenic is an established carcinogen and is also associated with numerous non-cancerous adverse health outcomes; for example, multiple epidemiological studies have shown an association between arsenic ingestion and endocrine dysfunction, as well as increased respiratory infections.

Recent epidemiological studies suggest that adverse respiratory health effects of arsenic exposure are more prominent in individuals that had been exposed to arsenic prenatally. Results from retrospective studies of arsenic exposure in Chile have linked perinatal arsenic exposure to bronchiectasis (a disease characterized by chronic airway infection), inflammation, and significant morbidity resulting from progressive airway damage — in adulthood — decades after cessation of arsenic exposure. Additional clinical correlations were observed in a study of a well-characterized U.S. cohort of 412 infants born to mothers drinking well water during pregnancy; in this study, maternal urinary arsenic concentrations were positively correlated with respiratory infections in infants requiring a physician visit (yes, physician visits still do happen in rural America).

Associations of prenatal arsenic exposure were also observed with reported respiratory symptoms and respiratory infections sufficiently clinically significant (as judged by a primary care provider) to be treated with prescription medications. However, investigating effects of early life exposures on morbidity in adulthood is challenging in human populations, and no studies to date have examined effects of prenatal arsenic exposure in a U.S. population on immune function in adulthood.

Authors exposed pregnant C57BL/6J mice to 100 ppb sodium arsenite (in the drinking water, and — after maturation of these fetuses to adulthood — authors infected these adults with an adult influenza A virus (IAV), H1N1, and then assessed lung tissue and bronchoalveolar lavage fluid at various time points, after IAV infection. Authors found greater lung damage and inflammation in the adults that had been exposed in utero to arsenic, compared with control mice. Single-cell RNA-sequencing analysis (RNA-Seq) of immune cells harvested from IAV-infected lungs suggested that the enhanced inflammatory response is mediated by dysregulation of the innate immune response (in monocyte-derived macrophages, neutrophils, natural killer cells, and alveolar macrophages).

[Recall that the innate immune response is an organism’s first response to foreign invaders; it consists of physical barriers such as: skin and mucous membranes; various cell types such as neutrophils, macrophages, and monocytes; and soluble factors including cytokines and complement. In contrast to the adaptive immune response, the innate response is not specific to any one foreign invader and, as a result, works quickly to rid the body of pathogens. On the other hand, the adaptive immune response is the body’s second line of defense; the cells of the adaptive immune system are extremely specific because, during early developmental stages, the B and T cells develop antigen receptors that are specific only to certain antigens; this is extremely important for B and T cell activation.]

These data [see attached article] suggest that prenatal arsenic exposure in mice results in lasting effects (months later) on the adult host innate immune response to IAV infection — long after the exposure to arsenic. This leads to increased immune pathology in the adult that had been exposed in utero. Authors claim that this study provides the first direct evidence that exclusive prenatal exposure to arsenic in drinking water causes predisposition to a hyperinflammatory response to IAV infection in adult mice — which can be associated with significant lung damage in the adult. 😊


Toxicol Sci Aug 2020; 176: 312–328

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