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. 2017 Jul;91(7):2617-2627.
doi: 10.1007/s00204-016-1890-9. Epub 2016 Nov 15.

Knockout of Arsenic (+3 Oxidation State) Methyltransferase Is Associated With Adverse Metabolic Phenotype in Mice: The Role of Sex and Arsenic Exposure

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Free PMC article

Knockout of Arsenic (+3 Oxidation State) Methyltransferase Is Associated With Adverse Metabolic Phenotype in Mice: The Role of Sex and Arsenic Exposure

Christelle Douillet et al. Arch Toxicol. .
Free PMC article

Abstract

Susceptibility to toxic effects of inorganic arsenic (iAs) depends, in part, on efficiency of iAs methylation by arsenic (+3 oxidation state) methyltransferase (AS3MT). As3mt-knockout (KO) mice that cannot efficiently methylate iAs represent an ideal model to study the association between iAs metabolism and adverse effects of iAs exposure, including effects on metabolic phenotype. The present study compared measures of glucose metabolism, insulin resistance and obesity in male and female wild-type (WT) and As3mt-KO mice during a 24-week exposure to iAs in drinking water (0.1 or 1 mg As/L) and in control WT and As3mt-KO mice drinking deionized water. Results show that effects of iAs exposure on fasting blood glucose (FBG) and glucose tolerance in either WT or KO mice were relatively minor and varied during the exposure. The major effects were associated with As3mt KO. Both male and female control KO mice had higher body mass with higher percentage of fat than their respective WT controls. However, only male KO mice were insulin resistant as indicated by high FBG, and high plasma insulin at fasting state and 15 min after glucose challenge. Exposure to iAs increased fat mass and insulin resistance in both male and female KO mice, but had no significant effects on body composition or insulin resistance in WT mice. These data suggest that As3mt KO is associated with an adverse metabolic phenotype that is characterized by obesity and insulin resistance, and that the extent of the impairment depends on sex and exposure to iAs, including exposure to iAs from mouse diet.

Keywords: Arsenic; As3mt-knockout mice; Insulin resistance; Metabolic phenotype; Obesity.

Figures

Figure 1
Figure 1
Fasting blood glucose in male and female wild-type (WT) and As3mt-knockout (KO) mice after 1, 8, 12 and 24 weeks of exposure to 0, 0.1, or 1 ppm As in drinking water (Mean +SE, N = 10–14). P<0.05 for the following comparisons: d, 0.1 vs 0 ppm or 1 vs 0 ppm for mice of the same sex and genotype; d*, 1 vs. 0.1 ppm for mice of the same sex and genotype; g, KO vs WT mice of the same sex and at the same exposure level; s, females vs males of the same genotype and at the same exposure level.
Figure 2
Figure 2
I.p. glucose tolerance test (IP-GTT) in male and female wild-type (WT) and As3mt-knockout (KO) mice after 1 and 8 weeks of exposure to 0, 0.1, or 1 ppm As in drinking water. Area under the curve (AUC) was calculated for a plot of blood glucose vs time (Mean +SE, N = 10–14). P<0.05 for the following comparisons: d, 0.1 vs 0 ppm or 1 vs 0 ppm for mice of the same sex and genotype; g, KO vs WT mice of the same sex and at the same exposure level; s, females vs males of the same genotype and at the same exposure level.
Figure 3
Figure 3
Fasting plasma insulin in male and female wild-type (WT) and As3mt-knockout (KO) mice after 12 and 24 weeks of exposure to 0, 0.1, or 1 ppm As in drinking water (Mean +SE, N = 10–14). P<0.05 for the following comparisons: d, 0.1 vs 0 ppm or 1 vs 0 ppm for mice of the same sex and genotype; d*, 1 vs. 0.1 ppm for mice of the same sex and genotype; g, KO vs WT mice of the same sex and at the same exposure level; s, females vs males of the same genotype and at the same exposure level.
Figure 4
Figure 4
Blood glucose (upper panel) and plasma insulin (lower panel) 15 minutes after i.p. injection of glucose; male and female wild-type (WT) and As3mt-knockout (KO) mice were exposed to 0, 0.1, or 1 ppm As in drinking water for 12 weeks (Mean +SE, N = 10–14). P<0.05 for the following comparisons: d, 0.1 vs 0 ppm or 1 vs 0 ppm for mice of the same sex and genotype; g, KO vs WT mice of the same sex and at the same exposure level; s, females vs males of the same genotype and at the same exposure level.
Figure 5
Figure 5
Linear correlation between the average p-Akt/Akt ratio in the liver and the average concentration of insulin in fasting plasma of male (M) and female (F) wild-type (WT) and As3mt-knockout (KO) mice after 24-week exposure to 0, 0.1, or 1 ppm As in drinking water.
Figure 6
Figure 6
Body composition of male and female wild-type (WT) and As3mt-knockout (KO) mice exposed to 0, 0.1, or 1 ppm As in drinking water for 19 weeks (Mean +SE, N = 10–14). Upper panel: lean mass (lower bar) and fat mass (upper hatched bar). Lower panel: % body fat. P<0.05 for the following comparisons: d, 0.1 vs 0 ppm or 1 vs 0 ppm for mice of the same sex and genotype; g, KO vs WT mice of the same sex and at the same exposure level; s, females vs males of the same genotype and at the same exposure level
Figure 7
Figure 7
Arsenic species in urine and livers of male and female wild-type (WT) and As3mt-knockout (KO) mice after 24 weeks of exposure to 0, 0.1, or 1 ppm As in drinking water (Mean +SE, N = 10–14). P<0.05 for the following comparisons: d, 0.1 vs 0 ppm or 1 vs 0 ppm for mice of the same sex and genotype; d*, 1 vs. 0.1 ppm for mice of the same sex and genotype; g, KO vs WT mice of the same sex and at the same exposure level; s, females vs males of the same genotype and at the same exposure level.

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