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

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.