DNA methylation of extracellular matrix remodeling genes in children exposed to arsenic.

Several novel mechanistic findings regarding to arsenic's pathogenesis has been reported and some of them suggest that the etiology of some arsenic induced diseases are due in part to heritable changes to the genome via epigenetic processes such as DNA methylation, histone maintenance, and mRNA expression. Recently, we reported that arsenic exposure during in utero and early life was associated with impairment in the lung function and abnormal receptor for advanced glycation endproducts (RAGE), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) sputum levels. Based on our results and the reported arsenic impacts on DNA methylation, we designed this study in our cohort of children exposed in utero and early childhood to arsenic with the aim to associate DNA methylation of MMP9, TIMP1 and RAGE genes with its protein sputum levels and with urinary and toenail arsenic levels. The results disclosed hypermethylation in MMP9 promotor region in the most exposed children; and an increase in the RAGE sputum levels among children with the mid methylation level; there were also positive associations between MMP9 DNA methylation with arsenic toenail concentrations; RAGE DNA methylation with iAs, and %DMA; and finally between TIMP1 DNA methylation with the first arsenic methylation. A negative correlation between MMP9 sputum levels with its DNA methylation was registered. In conclusion, arsenic levels were positive associated with the DNA methylation of extracellular matrix remodeling genes;, which in turn could modifies the biological process in which they are involved causing or predisposing to lung diseases.

Association between YAP expression in neoplastic and non-neoplastic breast tissue with arsenic urinary levels.

The Hippo pathway regulates cell proliferation and apoptosis and it has been noted that loss of critical components of this pathway can lead to uncontrolled cell growth. Yes-associated protein (YAP) is an important component of this Hippo pathway because YAP is the nuclear effector of the Hippo tumor suppressor pathway and it is crucial for the response to oxidative stress induced by cellular process and by different xenobiotics, including arsenic. It has been proposed that YAP dysregulation can contribute to a malignant cellular phenotype acting as both a tumor suppressor and an oncogene. The aim of the study was to assess and compare the expression of YAP in neoplastic and non-neoplastic breast tissue of women chronically exposed to arsenic through drinking water. YAP expression was assessed by immunohistochemistry in 120 breast biopsies from women with breast cancer and from women with other non-neoplastic breast pathologies. Arsenic concentration was quantified in urine. The results disclosed a significant lower percentage of cytoplasm YAP expression in cases and that YAP high-intensity staining in the cytoplasm but not in the nucleus decreases the risk for breast cancer. In conclusion, our overall data suggest that YAP may act as a tumor suppressor protein because their reduced expression in cases, which can induce an environment favorable for inhibition of apoptosis and promoting cellular proliferation by increasing genetic instability of cells, which might contribute to the pathogenesis of cancer. Copyright © 2017 John Wiley & Sons, Ltd.

Response to García-Nieto et al. Comments on Beamer et al. Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. Int. J. Environ. Res. Public Health 2016, 13, 521.

We would like to thank the editors for providing us with the opportunity to respond to the points raised by Dr. García Nieto.[...].

Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media.

Arsenic exposure has been associated with decreased club cell secretory protein (CC16) levels in adults. Further, both arsenic exposure and decreased levels of CC16 in childhood have been associated with decreased adult lung function. Our objective was to determine if urinary CC16 levels in children are associated with arsenic concentrations in environmental media collected from their homes. Yard soil, house dust, and tap water were taken from 34 homes. Urine and toenail samples were collected from 68 children. All concentrations were natural log-transformed prior to data analysis. There were associations between urinary CC16 and arsenic concentration in soil (b = -0.43, p = 0.001, R² = 0.08), water (b = -0.22, p = 0.07, R² = 0.03), house dust (b = -0.37, p = 0.07, R² = 0.04), and dust loading (b = -0.21, p = 0.04, R² = 0.04). In multiple analyses, only the concentration of arsenic in soil was associated with urinary CC16 levels (b = -0.42, p = 0.02, R² = 0.14 (full model)) after accounting for other factors. The association between urinary CC16 and soil arsenic may suggest that localized arsenic exposure in the lungs could damage the airway epithelium and predispose children for diminished lung function. Future work to assess this possible mechanism should examine potential associations between airborne arsenic exposures, CC16 levels, lung function, and other possible confounders in children in arsenic-impacted communities.

Inorganic arsenic as a developmental toxicant: in utero exposure and alterations in the developing rat lungs.

In the present study, we characterize the toxic effects of in utero arsenic exposure on the developing lung. We hypothesize that in utero exposure to inorganic arsenic through maternal drinking water causes altered gene and protein expression in the developing lung, indicative of downstream molecular and functional changes. From conception to embryonic day 18, we exposed pregnant Sprague-Dawley rats to 500 ppb arsenic (as arsenite) via the drinking water. Subtracted cDNA libraries comparing control to arsenic exposed embryonic lungs were generated. In addition, a broad Western blot analysis was performed to identify altered protein expression. A total of 59 genes and 34 proteins were identified as being altered. Pathway mapping and analysis showed that cell motility was the process most affected. The most likely affected pathway was alteration in integrin signaling through the beta-catenin pathway, altering c-myc. The present study shows that arsenic induces alterations in the developing lung. These data may be useful in the elucidation of molecular targets and biomarkers of arsenic exposure during lung development and may aid in understanding the etiology of arsenic induced adult respiratory disease and lung cancers.