1. Academic Validation
  2. NAD+ loss, a new player in AhR biology: prevention of thymus atrophy and hepatosteatosis by NAD+ repletion

NAD+ loss, a new player in AhR biology: prevention of thymus atrophy and hepatosteatosis by NAD+ repletion

  • Sci Rep. 2017 May 23;7(1):2268. doi: 10.1038/s41598-017-02332-9.
Silvia Diani-Moore 1 Jenny Shoots 1 Rubi Singh 1 Joshua B Zuk 1 Arleen B Rifkind 2
Affiliations

Affiliations

  • 1 Department of Pharmacology and Pharmacology PhD Program, Weill Cornell Medicine, 1300 York Avenue, NY, NY, 10021, USA.
  • 2 Department of Pharmacology and Pharmacology PhD Program, Weill Cornell Medicine, 1300 York Avenue, NY, NY, 10021, USA. arifkind@med.cornell.edu.
Abstract

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) is a carcinogenic and highly toxic industrial byproduct that persists in the environment and produces a pleiotropic toxicity syndrome across vertebrate species that includes wasting, hepatosteatosis, and thymus atrophy. Dioxin toxicities require binding and activation of the Aryl Hydrocarbon Receptor (AhR), a ligand activated transcription factor. However, after nearly 50 years of study, it remains unknown how AhR activation by dioxin produces toxic effects. Here, using the chick embryo close to hatching, a well-accepted model for dioxin toxicity, we identify NAD+ loss through PARP activation as a novel unifying mechanism for diverse effects of dioxin in vivo. We show that NAD+ loss is attributable to increased PARP activity in thymus and liver, as cotreatment with dioxin and the PARP Inhibitor PJ34 increased NAD+ levels and prevented both thymus atrophy and hepatosteatosis. Our findings additionally support a role for decreased NAD+ dependent SIRT6 activity in mediating dioxin toxicity following PARP activation. Strikingly, treatment in vivo with the NAD+ repleting agent nicotinamide, a form of vitamin B3, prevented thymus atrophy and hepatosteatosis by dioxin and increased Sirtuin activity, providing a therapeutic approach for preventing dioxin toxicities in vivo.

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