Evaluation of gene expression changes in human primary lung epithelial cells following 24‐hr exposures to inorganic arsenic and its methylated metabolites and to arsenic trioxide

Abstract

The concentration response for altered gene expression in primary lung epithelial cells was determined following two treatments with arsenicals: (1) a mixture of trivalent arsenic compounds representative of urinary arsenic concentrations in exposed human populations, and (2) arsenite (As2 O3 ) a common form of inhaled arsenic dust that is frequently used in both in vivo and in vitro experimental exposures. Biochemical assays did not detect any evidence of cytotoxicity at the concentrations used, apart from a concentration-related increase in cellular heme oxygenase that was also indicated by the genomic analysis. Cell signal pathway enrichment analysis indicated similar responses to both treatments, with concentration-related responses in pathways related to cell adhesion, cytoskeleton remodeling, development (morphogenesis), cell cycle control, and to a lesser extent inflammatory responses. These cellular responses to arsenic were consistent with those observed in a previous study with primary uroepithelial cells. Benchmark dose analysis also demonstrated similar potency of the two treatments as well as comparable sensitivity of the two cell types. A number of genes showing similar concentration-dependent expression across individuals in both bladder and lung cells were identified, including heme oxygenase 1, thioredoxin reductase, DNA damage binding protein 2, and thrombomodulin. The data on human primary lung cells from this study, together with the data from human primary uroepithelial cells, support a conclusion that biological responses to arsenic by human cells under study conditions are unlikely to occur at concentrations below 0.1 µM. Environ. Mol. Mutagen. 56:477-490, 2015. © 2015 Wiley Periodicals, Inc.

State of the science review of the health effects of inorganic arsenic: Perspectives for future research

“…In endemic areas, arsenic exposure causes hyperkeratosis and squamous cell carcinoma. These dermatologic effects are associated with alterations in cytokeratin (CK) expression . Hence, CK expression has been used as a biomarker of arsenic‐related skin carcinogenicity and biochemical changes in epithelial structures (Markey et al, 1991).…”

Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells

“…This has also been observed in transcriptomic studies of mice exposed to low-dose arsenic in drinking water (Andrew et al, 2007; Kozul et al, 2009b; Ramsey et al, 2013). The gene most responsive to arsenic in our study is a well-known oxidative stress response gene, HMOX1 , which has been proposed as a biomarker of arsenic exposure (Efremenko et al, 2015). Many of the genes that were decreased by arsenic in our study are involved in immune processes.…”

Dose-response for assessing the cancer risk of inorganic arsenic in drinking water: the scientific basis for use of a threshold approach

“…The search also identified two studies that conducted exposures at multiple concentrations in primary human bladder urothelial cells (Yager et al 2013) and lung cells (Efremenko et al 2015) and performed benchmark dose analysis to identify a No Observed Transcriptional Effect Level (NOTEL). The Yager et al (2013) study was conducted to assess the genomic response in human primary urothelial cells from multiple individuals (n ¼ 15) in which the cells were treated in vitro with mixtures of arsenite and its methylated metabolites (trivalent or pentavalent, total arsenic concentrations ranging from 0.06 to 18 mM) that were based on the proportion of arsenic and its metabolites reported in the urine of humans ingesting arsenic in drinking water.…”

“…The Efremenko et al (2015) study was conducted as a complementary experiment to the Yager et al (2013) study; the concentrations used in Efremenko et al (2015) were the same as those in the human urothelial study (Yager et al 2013). In addition to the arsenical trivalent mixture exposures, exposures to arsenic trioxide were also performed to compare responses for exposures of lung epithelial cells at the apical membrane from inhalation and exposures at the basal membrane from oral exposure.…”

“…Because the cells in both Efremenko et al (2015) and Yager et al (2013) studies were treated with arsenic mixtures for 24 h, whereas humans are exposed to arsenic in drinking water throughout their lifetime, it is reasonable to question whether the dose-response for gene expression changes observed following short-term exposure are indicative of the dose-response for potential responses following chronic exposure. Thomas, Philbert et al (2013) and Thomas, Wesselkamper et al (2013) conducted studies with a number of compounds to evaluate this question and concluded that the dose-response for genomic alterations in short-term studies provides a conservative predictor of both cancer and noncancer outcomes in lifetime bioassays.…”