Long‐term arsenic exposure impairs differentiation in mouse embryonal stem cells. Issue 7 (30th October 2020)

• Record Type: Journal Article
• Authors: McMichael, Benjamin D.; Perego, M. Chiara; Darling, Caitlin L.; Perry, Rebekah L.; Coleman, Sarah C.; Bain, Lisa J.
• Is Part Of: Journal of applied toxicology. Volume 41:Issue 7(2021)
• Page Start: 1089
• Page End: 1102
• Publication Date: 2020-10-30
• Subjects: arsenic -- Gdf3 -- N‐cadherin -- P19 cells -- pluripotency -- Sox2 -- stem cell -- Zeb1; Toxicology -- Periodicals; Industrial toxicology -- Periodicals; Environmentally induced diseases -- Periodicals; Toxicology -- Periodicals; 615.9005
• DOI: 10.1002/jat.4095
• Languages: English
• ISSNs: 0260-437X

Abstract

Abstract: Arsenic is a contaminant found in many foods and drinking water. Exposure to arsenic during development can cause improper neuronal progenitor cell development, differentiation, and function, while in vitro studies have determined that acute arsenic exposure to stem and progenitor cells reduced their ability to differentiate. In the current study, P19 mouse embryonal stem cells were exposed continuously to 0.1‐μM (7.5 ppb) arsenic for 32 weeks. A cell lineage array examining messenger RNA (mRNA) changes after 8 and 32 weeks of exposure showed that genes involved in pluripotency were increased, whereas those involved in differentiation were reduced. Therefore, temporal changes of select pluripotency and neuronal differentiation markers throughout the 32‐week chronic arsenic exposure were investigated. Sox2 and Oct4 mRNA expression were increased by 1.9‐ to 2.5‐fold in the arsenic‐exposed cells, beginning at Week 12. Sox2 protein expression was similarly increased starting at Week 16 and remained elevated by 1.5‐fold to sixfold. One target of Sox2 is N‐cadherin, whose expression is a hallmark of epithelial–mesenchymal transitions (EMTs). Exposure to arsenic significantly increased N‐cadherin protein levels beginning at Week 20, concurrent with increased grouping of N‐cadherin positive cells at the perimeter of the embryoid body. Expression of Zeb1, which helps increase the expression of Sox2, was also increased started at Week 16. In contrast, Gdf3 mRNA expression was reduced by 3.4‐ to 7.2‐fold beginning at Week 16, and expression of its target protein, phospho‐Smad2/3, was also reduced. These results suggest that chronic, low‐level arsenic exposure may delay neuronal differentiation and maintain pluripotency. Abstract : Arsenic is a contaminant found in drinking water, and exposure to arsenic can impair cellular differentiation. P19 mouse embryonal stem cells were exposed to 0.1‐μM (7.5 ppb) arsenic for 32 weeks. The results indicate that transcripts involved in differentiation were reduced starting at Week 16, including Gdf3, a marker of early neuronal differentiation. In contrast, expression of pluripotency markers, including Sox2 and Zeb1, and their target proteins, such as N‐cadherin, was increased.