Efflux transporters regulate arsenite-induced genotoxicity in double negative and double positive T cells

Huan Xu, Sebastian Medina, Fredine T. Lauer, Christelle Douillet, Ke Jian Liu, Laurie G. Hudson, Miroslav Stýblo, Lauren M. Aleksunes, Scott W. Burchiel

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Arsenite (As+3) exposure is known to cause immunotoxicity in human and animal models. Our previous studiesdemonstrated that As+3 at 50-500nM concentrations induced both genotoxicity and nongenotoxicity in mouse thymuscells. Developing T cells at CD4-CD8- double negative (DN) stage, the first stage after early T cells are transported from bonemarrow to thymus, were found to be more sensitive to As+3 toxicity than the T cells at CD4 + CD8 + double positive (DP)stage in vitro. Induction of Mdr1 (Abcb1) and Mrp1 (Abcc1), 2 multidrug resistance transporters and exporters of As+3, wasassociated with the reversal of As+3-induced double strand breaks and DNA damage. In order to confirm that the thymuscell populations have different sensitivity to As+3 in vivo, male C57BL/6J mice were exposed to 0, 100, and 500 ppb As+3 indrinking water for 30 d. A significant decrease in DN cell percentage was observed with exposure to 500 ppb As+3. Low tomoderate concentrations of As+3 were shown to induce higher genotoxicity in sorted DN than DP cells in vitro. Calcein AMuptake and Mdr1/Mrp1 mRNA quantification results revealed that DN cells not only had limited As+3 exporter activity, butalso lacked the ability to activate these exporters with As+3 treatments, resulting in a higher accumulation of intracellularAs+3. Knockdown study of As+3 exporters in the DN thymic cell line, D1 using siRNA, demonstrated that Mdr1 and Mrp1regulate intracellular As+3 accumulation and genotoxicity. Taken together, the results indicate that transporter regulationis an important mechanism for differential genotoxicity induced by As+3 in thymocytes at different developmental stages.

Original languageEnglish (US)
Pages (from-to)127-139
Number of pages13
JournalToxicological Sciences
Volume158
Issue number1
DOIs
StatePublished - Jul 1 2017

All Science Journal Classification (ASJC) codes

  • Toxicology

Keywords

  • Arsenite
  • Differential sensitivity
  • Double negative T cells
  • Double positive T cells
  • Genotoxicity
  • Multidrug resistance-associated transporters

Fingerprint

Dive into the research topics of 'Efflux transporters regulate arsenite-induced genotoxicity in double negative and double positive T cells'. Together they form a unique fingerprint.

Cite this