Inorganic arsenic (iAs) has been ranked as the number one substance for investigation for over 20 years by the Agency of Toxic Substances and Disease Registry (ASTDR). Arsenic is a potent and highly prevalent environmental toxin that is linked to numerous diseases. These diseases include various cancers, cardiovascular diseases, and metabolic diseases. The world health organization has determined that 10 parts per billion (PPB) is the highest exposure limit. Many areas worldwide exceed 10 PPB, including different regions of the United States. Areas that exceed 10 PPB of arsenic have been shown to have a higher onset of various diseases, including metabolic maladies. Arsenic has previously been shown to impair function in the pancreatic beta cell in vitro and in vivo. Though arsenic is a known mutagen, arsenic’s effect on post-transcriptional regulators, such as microRNAs, and arsenic-altered gene networks are incredibly understudied. I examined, in vitro, the effects of different arsenic species on the transcriptomic landscape of pancreatic beta cells. I identified that miR-29a is significantly upregulated after arsenic exposure, regardless of the arsenic species. Depending on the arsenical, genes potentially regulated by miR-29a functioned primarily in insulin secretion or beta cell maintenance. This suggests that miR-29a is a master regulator of arsenic-induced beta-cell dysfunction. Despite that advance, there remained a major limitation in the field. Past studies of arsenic exposure have utilized rodent models, but these provided limited translation relevance. This is due to the strong species-specific differences in arsenic metabolism. Arsenic is metabolized by the enzyme arsenic +3 methyltransferase (AS3MT). AS3MT is highly conserved in mammals, however, its metabolic efficiency varies greatly across species. This disparity is especially robust between humans and rodents. A novel mouse model in which the human enzyme is expressed instead of the mouse enzyme was developed to overcome this limitation. I characterized the effects of arsenic at the molecular level on our novel humanized mouse model in the liver and white adipose. The main conclusions were 1) metabolic effects of arsenic were only observed in humanized mice, and 2) there was a sex-specific effect that merits deeper investigation.