Oral arsenic administration to humanized UDP-glucuronosyltransferase 1 neonatal mice induces UGT1A1 through a dependence on Nrf2 and PXR

Inorganic arsenic (iAs) is an environmental toxicant that can lead to severe health consequences, which can be exacerbated if exposure occurs early in development. Here, we evaluated the impact of oral iAs treatment on UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and bilirubin metabolism in hu-manized UGT1 (hUGT1) mice. We found that oral adminis-tration of iAs to neonatal hUGT1 mice that display severe neonatal hyperbilirubinemia leads to induction of intestinal UGT1A1 and a reduction in total serum bilirubin values. Oral iAs administration accelerates neonatal intestinal maturation, an event that is directly associated with UGT1A1 induction. As a reactive oxygen species producer, oral iAs treatment activated the Keap-Nrf2 pathway in the intestinal tract and liver. When Nrf2-deficient hUGT1 mice (hUGT1/Nrf2-/-) were treated with iAs, it was shown that activated Nrf2 contributed significantly toward intestinal maturation and UGT1A1 induction. Howev-er, hepatic UGT1A1 was not induced upon iAs exposure. We previously demonstrated that the nuclear receptor PXR re-presses liver UGT1A1 in neonatal hUGT1 mice. When PXR was deleted in hUGT1 mice (hUGT1/Pxr-/-), derepression of UGT1A1 was evident in both liver and intestinal tissue in ne-onates. Furthermore, when neonatal hUGT1/Pxr-/- mice were treated with iAs, UGT1A1 was superinduced in both tissues, confirming PXR release derepressed key regulatory elements on the gene that could be activated by iAs exposure. With iAs capable of generating reactive oxygen species in both liver and intestinal tissue, we conclude that PXR deficiency in neonatal hUGT1/Pxr-/- mice allows greater access of activated tran-scriptional modifiers such as Nrf2 leading to superinduction of UGT1A1.

Automated summary

We evaluated the impact of oral inorganic arsenic on hUGT1 mice and found that it induces UGT1A1 expression in the intestine, reduces serum bilirubin levels, and accelerates intestinal maturation. Additionally, the deficiency of PXR leads to derepression of UGT1A1 in both liver and intestine, and inorganic arsenic activates Nrf2, which contributes to the superinduction of UGT1A1.