Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets.

Epidemiologic evidence has linked chronic exposure to inorganic arsenic (iAs) with an increased prevalence of diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair glucose homeostasis. We have previously shown that micromolar concentrations of arsenite (iAs(III)) or its methylated trivalent metabolites, methylarsonite (MAs(III)) and dimethylarsinite (DMAs(III)), inhibit the insulin-activated signal transduction pathway, resulting in insulin resistance in adipocytes. Our present study examined effects of the trivalent arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs(III), MAs(III) or DMAs(III) inhibited glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs(III) and DMAs(III) were more potent than iAs(III) as GSIS inhibitors with estimated IC(50)≤0.1 µM. The exposures had little or no effects on insulin content of the islets or on insulin expression, suggesting that trivalent arsenicals interfere with mechanisms regulating packaging of the insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs(III), MAs(III) or DMAs(III) could be reversed by a 24-hour incubation of the islets in arsenic-free medium. These results suggest that the insulin producing pancreatic ß-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes.

Spatiotemporal-social association predicts immunological similarity in rewilded mice.

Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual's interaction with its environment. We therefore tracked behavior of rewilded laboratory mice of three inbred strains in outdoor enclosures and examined contributions of behavior, including associations measured from spatiotemporal co-occurrences, to immune phenotypes. We found extensive variation in individual and social behavior among and within mouse strains upon rewilding. In addition, we found that the more associated two individuals were, the more similar their immune phenotypes were. Spatiotemporal association was particularly predictive of similar memory T and B cell profiles and was more influential than sibling relationships or shared infection status. These results highlight the importance of shared spatiotemporal activity patterns and/or social networks for immune phenotype and suggest potential immunological correlates of social life.

The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic.

Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never been thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. In fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring.

The pharmacokinetics of therapeutic arsenic trioxide in acute promyelocytic leukemia patients.

Arsenic trioxide (ATO) treats Acute Promyelocytic Leukemia (APL). ATO is converted from inorganic arsenic (iAs) to methylated (MAs) and dimethylated (DMAs) metabolites, which are excreted in the urine. Methylation of iAs is important in detoxification, as iAs exposure is deleterious to health. We examined ATO metabolism in 25 APL patients, measuring iAs, MAs, and DMAs. Plasma total iAs increased after ATO administration, followed by a rapid decline, reaching trough levels by 4-6 h. We identified two patterns of iAs metabolism between 6 and 24 h after infusion: in Group 1, iAs increased and were slowly converted to MAs and DMAs, whereas in Group 2, iAs was rapidly metabolized. These patterns were associated with smoking and different treatments: ATO with all-trans retinoic acid (ATRA) alone vs. ATO preceded by ATRA and chemotherapy. Our data suggest that smoking and prior chemotherapy exposure may be associated with ATO metabolism stimulation, thus lowering the effective blood ATO dose.

Arsenic (+3 oxidation state) methyltransferase genotype affects steady-state distribution and clearance of arsenic in arsenate-treated mice.

Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes formation of mono-, di-, and tri-methylated metabolites of inorganic arsenic. Distribution and retention of arsenic were compared in adult female As3mt knockout mice and wild-type C57BL/6 mice using a regimen in which mice received daily oral doses of 0.5mg of arsenic as arsenate per kilogram of body weight. Regardless of genotype, arsenic body burdens attained steady state after 10 daily doses. At steady state, arsenic body burdens in As3mt knockout mice were 16 to 20 times greater than in wild-type mice. During the post dosing clearance period, arsenic body burdens declined in As3mt knockout mice to ~35% and in wild-type mice to ~10% of steady-state levels. Urinary concentration of arsenic was significantly lower in As3mt knockout mice than in wild-type mice. At steady state, As3mt knockout mice had significantly higher fractions of the body burden of arsenic in liver, kidney, and urinary bladder than did wild-type mice. These organs and lung had significantly higher arsenic concentrations than did corresponding organs from wild-type mice. Inorganic arsenic was the predominant species in tissues of As3mt knockout mice; tissues from wild-type mice contained mixtures of inorganic arsenic and its methylated metabolites. Diminished capacity for arsenic methylation in As3mt knockout mice prolongs retention of inorganic arsenic in tissues and affects whole body clearance of arsenic. Altered retention and tissue tropism of arsenic in As3mt knockout mice could affect the toxic or carcinogenic effects associated with exposure to this metalloid or its methylated metabolites.