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Final Progress Reports: University of California-San Diego: Antioxidant Protection by Hyperbilirubinemia in Toxicity and Disease

Superfund Research Program

Antioxidant Protection by Hyperbilirubinemia in Toxicity and Disease

Project Leader: Robert H. Tukey
Grant Number: P42ES010337
Funding Period: 2000-2017
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Final Progress Reports

Year:   2016  2009  2004 

The gastrointestinal (G.I.) track is the first organ of contact for environmental exposure to harmful toxicants. Importantly, the composition of the G.I. track changes dramatically throughout the neonatal period, being more susceptible to toxic insult. The research team uncovered an unusual toxic response in neonatal mice following oral exposure to arsenic (As3+) and cadmium (Cd2+). The G.I. track undergoes cellular maturation or proliferation of epithelial cells during development, a process that is tightly repressed by the transcriptional repressor protein NCoRI. Phosphorylation of NCoR1 by cellular kinases leads to the release of NCoR1 from the chromatin, resulting in derepression of target genes that control the maturation process. One of the kinases that targets NCoRI phosphorylation is IKKbeta, which is a key target in the process of oxidative stress that can be induced by either As3+ or Cd2+. When NCoRI is selectively eliminated in the G.I. track by targeted knockout of the gene, the intestinal track accelerates epithelial cell maturation, resulting in large genomic changes. These genomic changes are accelerated in transgenic mice that express constitutively active IKKbeta; an experiment that links IKKbeta activation to NCoRI derepression. The research team demonstrated that when neonatal mice are exposed orally to either As3+ or Cd2+, a similar pattern of intestinal epithelial cell specific gene expression occurs in a fashion that is like what is observed in NCoRI deficient mice. Early exposure during development to As3+, and event that occurs in humans that experience life-long As3+ exposure, may lead to significant and permanent alterations in G.I. track physiology.

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