Sex-dependent effects of preconception exposure to arsenite on gene transcription in parental germ cells and on transcriptomic profiles and diabetic phenotype of offspring.

ABSTRACT

Chronic exposure to inorganic arsenic (iAs) has been linked to diabetic phenotypes in both humans and mice. However, diabetogenic effects of iAs exposure during specific developmental windows have never been systematically studied. We have previously shown that in mice, combined preconception and in utero exposures to iAs resulted in impaired glucose homeostasis in male offspring. The goal of the present study was to determine if preconception exposure alone can contribute to this outcome. We have examined metabolic phenotypes in male and female offspring from dams and sires that were exposed to iAs in drinking water (0 or 200 µg As/L) for 10 weeks prior to mating. The effects of iAs exposure on gene expression profiles in parental germ cells, and pancreatic islets and livers from offspring were assessed using RNA sequencing. We found that iAs exposure significantly altered transcript levels of genes, including diabetes-related genes, in the sperm of sires. Notably, some of the same gene transcripts and the associated pathways were also altered in the liver of the offspring. The exposure had a more subtle effect on gene expression in maternal oocytes and in pancreatic islets of the offspring. In female offspring, the preconception exposure was associated with increased adiposity, but lower blood glucose after fasting and after glucose challenge. HOMA-IR, the indicator of insulin resistance, was also lower. In contrast, the preconception exposure had no effects on blood glucose measures in male offspring. However, males from parents exposed to iAs had higher plasma insulin after glucose challenge and higher insulinogenic index than control offspring, indicating a greater requirement for insulin to maintain glucose homeostasis. Our results suggest that preconception exposure may contribute to the development of diabetic phenotype in male offspring, possibly mediated through germ cell-associated inheritance. Future research can investigate role of epigenetics in this phenomenon. The paradoxical outcomes in female offspring, suggesting a protective effect of the preconception exposure, warrant further investigation.