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.
All Science Journal Classification (ASJC) codes
- Differential sensitivity
- Double negative T cells
- Double positive T cells
- Multidrug resistance-associated transporters