Academic journal article Environmental Health Perspectives

Low-Dose Arsenic Compromises the Immune Response to Influenza A Infection in Vivo

Academic journal article Environmental Health Perspectives

Low-Dose Arsenic Compromises the Immune Response to Influenza A Infection in Vivo

Article excerpt

BACKGROUND: Arsenic exposure is a significant worldwide environmental health concern. We recently reported that 5-week exposure to environmentally relevant levels (10 and 100 ppb) of As in drinking water significantly altered components of the innate immune response in mouse lung, which we hypothesize is an important contributor to the increased risk of lung disease in exposed human populations.

OBJECTIVES: We investigated the effects of As exposure on respiratory influenza A (H1N1) virus infection, a common and potentially fatal disease.

METHODS: In this study, we exposed C57BL/6J mice to 100 ppb As in drinking water for 5 weeks, followed by intranasal inoculation with a sublethal dose of influenza A/PuertoRico/8/34 (H1N1) virus. Multiple end points were assessed postinfection.

RESULTS: Arsenic was associated with a number of significant changes in response to influenza, including an increase in morbidity and higher pulmonary influenza virus titers on day 7 postinfection. We also found many alterations in the immune response relative to As-unexposed controls, including a decrease in the number of dendritic cells in the mediastinal lymph nodes early in the course of infection.

CONCLUSIONS: Our data indicate that chronic As exposure significantly compromises the immune response to infection. Alterations in response to repeated lung infection may also contribute to other chronic illnesses, such as bronchiectasis, which is elevated by As exposure in epidemiology studies.

KEY WORDS: arsenic, dendritic cells, influenza, innate immune system, mouse lung. Environ Health Perspect 117:1441-1447 (2009). doi:10.1289/ehp.0900911 available via [Online 20 May 2009]


Chronic exposure to arsenic is a significant worldwide environmental health concern [Agency for Toxic Substances and Disease Registry (ASTDR) 1999; National Research Council 1999]. Contamination of drinking water by natural geologic sources of As is the primary route of exposure. The U.S. Environmental Protection Agency (EPA) standard for drinking water As exposure was recently reduced to 10 ppb (0.13 [micro]M) (U.S. EPA 2001). However, this standard does not cover private wells. In many areas of the United States As is naturally found at levels higher than the federal guidelines, and a significant portion of the population may be drinking excess As chronically (Karagas et al. 2002). This may represent as many as 25 million people in the United States, and worldwide hundreds of millions of people are exposed to levels of As far above 10 ppb. In addition, significant biological effects of As have been observed in cell culture and in animal models at and below the current 10-ppb U.S. EPA standard (Andrew et al. 2007; Kozul et al. 2009; Lantz et al. 2007; Straub et al. 2008).

Chronic exposure to As has been associated with many diseases, including lung, liver, skin, kidney, and bladder cancer; cardiovascular disease; diabetes; and reproductive and developmental defects (Abernathy et al. 1999; National Research Council 1999; Smith et al. 1992; Tapio and Grosche 2006; Watanabe et al. 2003). Multiple mechanisms have been associated with As-induced disease risk, including endocrine disruption, oxidative stress, and alterations in cell signaling and DNA repair (Andrew et al. 2006; Aposhian and Aposhian 2006; Kaltreider et al. 2001; Rossman 2003). However, differences in dose, time, and tissue, as well as coexposures, can result in differing mechanisms and complicate the interpretation of disease risk under varying exposure conditions. Recent reports have indicated that chronic As exposure in human populations results in an increased risk of a variety of lung diseases, including impaired lung function, bronchiectasis, lung cancer, and other respiratory illnesses (Ghosh et al. 2007; Raqib et al. 2009; Smith et al. 2006). The ability of As to increase the risk of lung disease through ingestion, as opposed to inhalation, makes it a unique and intriguing lung toxicant. …

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