Dimethylarsinic acid modulates the aryl hydrocarbon receptor-regulated genes in C57BL/6 mice: in vivo study

Abstract

1. Dimethylarsinic acid (DMA(V)) is the major metabolite of inorganic arsenic in human body. Thus we investigated the effect of DMA(V) on the alteration of phase I (typified by Cyp1a) and phase II (typified by Nqo1) AhR-regulated genes in vivo. C57BL/6 mice received DMA(V) (13.3 mg/kg, i.p.) with or without TCDD (15 μg/kg, i.p.), thereafter the liver, lung, and kidney were harvested at 6 and 24 h post-treatment.

2. Results demonstrated that DMA(V) has no significant effect on Cyp1a mRNA and protein expression or catalytic activity in the liver. On the other hand, DMA(V) significantly potentiated the TCDD-mediated induction of Cyp1a mRNA and protein expression, with a subsequent potentiation of catalytic activity in the lung. Moreover, DMA(V) significantly inhibited the TCDD-mediated induction of Cyp1a mRNA and protein expression with subsequent inhibition of catalytic activity in the kidney.

3. Regarding to phase II AhR-regulated genes, DMA(V) has no significant effect on Nqo1 mRNA and protein expression, or activity neither in the liver, lung, or kidney.

4. In conclusion, the present work demonstrates for the first time that DMA(V) modulates AhR-regulated genes in a tissue- and enzyme-specific manner. This modulation may play a crucial role in arsenic-induced toxicity and carcinogenicity.

Keywords:

• AhR
• arsenic
• cacodylic acid
• carcinogen-activating enzymes
• Cyp1a
• dimethylarsinic acid
• DMA(V)
• Nqo1

Acknowledgements

This work was supported by Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant to A.O.S., RGPIN 250139. O.H.E. is the recipient of Alberta Cancer Foundation Graduate Studentship and Alberta Innovates-Health Solutions Graduate Studentship.

Declaration of interest

The authors report no declarations of interest. The authors are responsible for the content and writing the article.