<i>In Utero</i>Exposure to Arsenic Alters Lung Development and Genes Related to Immune and Mucociliary Function in Mice

Ramsey, Kathryn; Bosco, Anthony; McKenna, Katherine L.; Carter, Kim W.; Elliot, John; Berry, Luke J.; Sly, Peter D.; Larcombe, Alexander N.; Zosky, Graeme R.

doi:10.1289/ehp.1205590

Cited by 39 publications

(32 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In utero exposure to arsenic reduces birth weight, and increases susceptibility to lower respiratory tract infections in infancy (McCall and Acheson , 1968), to impaired lung function during childhood (Chan et al, 1989), and to increased risk of death from chronic lung diseases in adulthood (Barker et al, 1991). Taken together these data suggest that arsenic-induces impairments in growth and development of the lung (Ramsey et al, 2013). In our study, we did not find any significant differences in the prevalence of respiratory symptoms or diseases between groups, except, chronic phlegm which was significantly higher in subjects from Group 3 than recorded in the least exposed group (p<0.05).…”

Section: Discussionmentioning

confidence: 71%

Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

Olivas-Calderón

Recio-Vega

Gandolfi

et al. 2015

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero is associated with an increase in respiratory symptoms and diseases in adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that exposure to arsenic during early childhood or in utero was associated with impairment in the lung function in children and suggested that this adverse effect could be due to a chronic inflammatory response to the metalloid. Therefore, a cross-sectional study was designed in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their As levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the Soluble Receptor for Advanced Glycation Endproducts (sRAGE) sputum level was significantly lower and Matrix Metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsenic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/Tissue Inhibitor of Metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern.

show abstract

Section: Discussionmentioning

confidence: 71%

Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

Olivas-Calderón

Recio-Vega

Gandolfi

et al. 2015

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

show abstract

“…Over the last 20 years, researchers have identified several stimuli that are correlated with changes in MUC5B expression in in vivo models. In mouse models, exposure to Pseudomonas aeruginosa pyocyanin [305] and in utero exposure to arsenic [306] are associated with increased expression of MUC5B. In Pigs, infection with actinobacillus pleuropneumoniae is associated with increased expression of MUC5B [307].…”

Section: Introductionmentioning

confidence: 99%

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is the most common and the most aggressive fibrosing interstitial lung disease (ILD). Despite recent promising clinical trials, IPF remains incurable and largely untreatable. Genetic studies have identified several risk loci for both sporadic and familial forms of IPF. A single variant upstream of MUC5B is predicted to account for more than 30% of all IPF risk. This variant, rs35705950, is associated with expression of MUC5B in healthy lung tissue. However, the mechanism underlying the relationship between rs35705950 and MUC5B expression remains unclear.The first goal of my thesis research was to determine whether rs35705950 is also a risk factor for other forms of ILD. Genomic DNA from individuals with IPF, HP, COPD, iNSIP, and RB-ILD was obtained and genotyped for the common MUC5B promoter variant. In these populations the risk allele was associated with IPF and iNSIP which suggested a potential shared disease mechanism. Additionally, I showed that in the IPF and control populations rs35705950 is associated with lung MUC5B expression.The second goal of my thesis research was to investigate MUC5B promoter DNA methylation which has previously been shown to play a role in MUC5B expression.Methylation analysis of the 4KB region upstream of MUC5B identified two differentially methylated regions (DMRs) associated with IPF, one DMR associated with MUC5B iv expression, and one DMR associated with rs35705950. The IPF, MUC5B expression, and rs35705950 associated DMRs are all differentially methylated at a cluster of 11 CpG motifs. overlapping DMR, including the motif disrupted by rs35705950. These findings suggest that DNA methylation may play a role in MUC5B gene regulation and IPF risk.Next, I used cross species analysis to identify highly conserved domains within the overlapping DMR. Evolutionary conservation indicated selective pressures to maintain sequences overtime and suggests biological importance. The overlapping DMR contains a highly conserved binding motif for FOXA2, a transcription factor. Further analysis using ChIP-qPCR, reporter constructs, and siRNA, established a role for FOXA2 in regulation of MUC5B expression in lung tissue. Additionally, siRNA knock down identified 3 other transcription factors which are associated with MUC5B expression; STAT3, HOXA9 and ZBTB7A. These transcriptional regulators provide insight into possible therapeutic intervention for MUC5B dysregulation and IPF.The form and content of this abstract are approved. I recommend its publication.

show abstract

“…This dose-response dichotomy seems to exist within oncogenesis as inorganic arsenic is a very effective cancer chemotherapeutic at pharmacologic doses, but can also enhance xenograft tumor growth and angiogenesis at lower doses (Soucy et al, 2003; Kamat et al, 2005; Liu et al, 2006). In addition, functional or genetic changes relevant to chronic lung disease and cancer have been reported after exposure in early life (including in utero exposure) to inorganic arsenic at doses as low as 100–500 ppb in rodents (Petrick et al, 2009; Lantz et al, 2009; Kozul et al, 2009; Ramsey et al, 2013a,b; Farzan et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Lung tumors in mice induced by “whole-life” inorganic arsenic exposure at human-relevant doses

Waalkes

Tokar

et al. 2014

Arch Toxicol

View full text Add to dashboard Cite

In mice, inorganic arsenic in the drinking water in the parts per million (ppm) range via the dam during in utero life or with whole life exposure is a multi-site carcinogen in the offspring. However, human arsenic exposure is typically in the parts per billion (ppb) range. Thus, we studied “whole life” inorganic arsenic carcinogenesis in mice at levels more relevant to humans. Breeder male and female CD1 mice were exposed to 0, 50, 500 or 5000 ppb arsenic (as sodium arsenite) in the drinking water for three weeks prior to breeding, during pregnancy and lactation, and after weaning (at week 3) groups of male and female offspring (initial n = 40) were exposed for up to 2 years. Tumors were assessed in these offspring. Arsenic exposure had no effect on pregnant dam weights or water consumption, litter size, offspring birth weight, or weight at weaning compared to control. In male offspring mice, arsenic exposure increased (p < 0.05) bronchiolo-alveolar tumor (adenoma or carcinoma) incidence at 50 ppb (51%) and 500 ppb (54%), but not at 5000 ppb (28%) compared to control (22%). These arsenic-induced bronchiolo-alveolar tumors included increased (p < 0.05) carcinoma at 50 ppb (27%) compared to controls (8%). An increase (p < 0.05) in lung adenoma (25%) in the 50 ppb group compared to control (11%) occurred in female offspring. Thus, in CD1 mice whole life arsenic exposure induced lung tumors at human relevant doses (i.e. 50 and 500 ppb).

show abstract

In UteroExposure to Arsenic Alters Lung Development and Genes Related to Immune and Mucociliary Function in Mice

Cited by 39 publications

References 54 publications

Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Lung tumors in mice induced by “whole-life” inorganic arsenic exposure at human-relevant doses

Contact Info

Product

Resources

About