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.
Highlights
Activation of the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, is required for production of toxic effects by a group of polyhalogenated hydrocarbons, a common class of environmental toxins of which dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) is the most notorious member[1, 2]
We examined effects of another AhR ligand, β-naphthoflavone (β-NF), on the endpoints affected by TCDD to learn whether our findings were specific for TCDD or applied to other AhR ligands. β-NF activated the AhR in both liver and thymus as evidenced by increased CYP1A4 mRNA expression, and, like TCDD, suppressed NAD+ levels in both liver and thymus and produced steatosis and thymic atrophy (Supplementary Fig. S9a–d)
The findings reported here identify NAD+ loss through PARP activation as a novel unifying mechanism for diverse effects produced by dioxin in vivo
Summary
Activation of the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, is required for production of toxic effects by a group of polyhalogenated hydrocarbons, a common class of environmental toxins of which dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) is the most notorious member[1, 2]. Activation of the AhR by TCDD increases transcription of a large number of genes[6], none of which has yet been able to account for the production of toxic effects by TCDD in multiple organs in vivo. We investigated whether NAD+ depletion has a role in TCDD toxicity in vivo based on our prior evidence from experiments conducted in cultured chick embryo hepatocytes (CEH) that TCDD decreased NAD+ levels while increasing expression of TiPARP (TCDD-inducible poly (ADP-ribose) polymerase, PARP7, ARTD14)[7]. NAD+ repletion with nicotinamide (NAM) or the PARP inhibitor PJ34 prevented both NAD+ depletion and the production of thymus atrophy and hepatosteatosis by TCDD, supporting a role for NAD+ loss in different TCDD toxicities in vivo Correspondence and requests for materials should be addressed to A.B.R. (email: arifkind@med. cornell.edu) www.nature.com/scientificreports/
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