Arsenic and Child Respiratory Health in Bangladesh


The lung is a surprisingly important target for the long-term health effects of ingestion of inorganic arsenic in drinking water, but the impact of exposure during childhood is largely unknown. Children are likely to be especially susceptible since the development of the lung continues into childhood.  In Chile, we have found that people who were exposed to arsenic in drinking water as children have 10-fold increased risks of lung cancer and chronic respiratory disease mortality when they become adults. In West Bengal, India we have found that adults with arsenic-caused skin lesions and high arsenic drinking water exposures have impaired lung function and increased rates of chronic respiratory disease. To date however, the impact of arsenic ingestion on lung function and respiratory health has not so far been studied in children.  This study takes advantage of the fact that our collaborators in Bangladesh have examined 167,000 people for skin lesions and measured the arsenic concentrations in their drinking water. We plan to study 300 children aged 6-16 years living in the families having tube well water arsenic concentration mostly over 300 µg/L, and in which at least one member of the family has developed arsenic-related skin lesions. An unexposed comparison group of 300 children will be selected from families with no skin lesions, and whose water contains less than 50 µg/L.  Lung function and respiratory symptoms, including chronic cough and shortness of breath, will be assessed in relation to current and past arsenic concentrations in all sources of drinking water throughout childhood, including in utero exposure. Potential susceptibility and interactions associated with indoor air pollution, diet, and nutritional status, will be investigated. Differences in susceptibility due to individual variability in the degree to which children metabolize arsenic to highly toxic methylated compounds identified in urine samples will also be assessed. The children in these exposed and unexposed families provide a unique opportunity to identify the effects of arsenic exposure during critical time periods of lung growth and development.  The public health impact of adverse respiratory effects due to arsenic exposure in early life could be substantial given the large number of children exposed to arsenic in drinking water worldwide and the relevance of these outcomes for future population morbidity and mortality.





University of California

Toxic Substances in the Environment: Arsenic Biomarkers Epidemiology


Arsenic is ranked number one on the Superfund Priority List of Hazardous Substances. Our findings indicate that early life (i.e. in utero and early childhood) exposure to arsenic causes increases in adult mortality greater than that from any other known toxic exposure. During the last five years, our arsenic research program has discovered that early life exposure to arsenic results in major mortality increases among young adults aged 30-49 from lung cancer and bronchiectasis , myocardial infarction, and kidney cancer. More recently we found increased young adult deaths from bladder cancer (20-fold increased mortality), laryngeal cancer (10-fold increased mortality), and chronic renal failure (2.7-fold increased mortality) (in preparation for publication). Our recent work has also identified even more causes of death related to arsenic, including cancers of the thyroid, penis and cervix. Among non-cancer outcomes, pulmonary tuberculosis had a clear latency pattern of increased mortality following exposure to arsenic, and we have also found evidence of increased mortality from respiratory and urinary tract infections (in preparation for publication).


In light of these surprising new findings, the study focuses on the effects of early life exposure to arsenic with studies in targeted Chile and Bangladesh populations, both having unique features related to arsenic exposure in early life which make them ideal study populations. Our findings of multiple cancer and non-cancer outcomes call for identification of mechanisms of action consistent with these effects. We have found in two independent populations that urinary protein levels of an important tumor suppressor gene, human beta defensin 1 (HBD1), are markedly reduced in men exposed to high versus low levels of arsenic. Using new, enhanced technology, two-dimensional differential in-gel electrophoresis (2D-DIGE), we will now be able to identify other differentially expressed proteins in urine from arsenic-exposed populations. Moreover, we found that arsenic treatment of kidney and bladder cells led to a persistent down-regulation of HBD1 gene expression. One possible mode of action is that arsenic exposure results in epigenetic alterations in genes such as HBD1 that can lead to their suppression, with global changes affecting multiple organs and multiple cell types, especially during exposure in early life.


This study is an integrated research strategy assessing multiple outcomes in population studies, focusing on effects from early life exposure and pursuing evidence concerning mechanisms of action of arsenic in the same study populations. The studies in Bangladesh and Chile contain the four following aims:


Aim 1: Investigate preliminary new findings of increased mortality due to pulmonary tuberculosis, chronic renal failure, and increased mortality from cancers of the larynx, penis, cervix and thyroid gland, including assessment of the consequences of early life exposure to arsenic in Chile.


Aim 2: (a) Investigate the effects of arsenic in a unique cohort of Bangladesh children who were exposed in utero and in early childhood, assessing the incidence of chronic respiratory disease, including measuring lung function, upper respiratory tract infections and pneumonia, measuring blood pressure, and measuring β2-microglobulin in serum, a marker of reduced kidney glomerular filtration rate; (b) In this same cohort, collect urine samples and buccal cells to identify epigenetic alterations and proteomic biomarkers of arsenic exposure, susceptibility, and disease.


Aim 3: Assess the effects of early life arsenic exposure on lung function and respiratory symptoms in northern Chile by (a) administering high resolution CTs and questionnaires on past lung infections; (b) collecting buccal and urine samples for studies of genetic, epigenetic and proteomic biomarkers of exposure, susceptibility, or disease that might be found many years after high exposure;. (c) collecting saliva for high-throughput genotyping studies to determine the effects of genetic variation in N6AMT1, MYST1, FEN1 and other genes identified in Project 2 on lung function in individuals with previous exposure to arsenic.


Aim 4: Conduct in vitro studies to determine the mechanism and downstream effects involved in the persistent down-regulation of HBD1 gene expression by the toxic arsenic metabolite, MMA3. We will perform epigenetic studies using kidney and other target organ cell lines, including knocking down HBD1 gene expression to determine the genes that are affected by HBD1 down-regulation.

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