Liver insufficiency and damage is a major cause of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARβ/δ −/− mouse is more susceptible to chemically-induced hepatotoxicity than its wildtype counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARβ/δ confers protection to hepatocytes. We hypothesized that PPARβ/ δ plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadeca-dienoic acid (13(S)-HODE) and 4-HNE are PPARβ/δ ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARβ/δ subtype while 4-hyroxy-hexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARβ/δ activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARβ/δ-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARβ/δ activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

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Aflatoxin B1 (AFB1), one of the most common mycotoxins found in human foods, is principally hepatotoxic; however, it also affects reproduction. The aim of the present study was to elucidate the reproductive toxic effects and possible mechanism of action of AFB1 in rats. Male Wistar rats were injected intramuscularly with doses of 10, 20, or 50 µg AFB1/kg body weight on alternate days from 45 to 100 days of age. Significant reductions in body weights, relative weights of reproductive organs, daily sperm production, epididymal sperm count, viable sperm, motile sperm, and hypoosmotic swelling-tail coiled sperm were observed. Significant decreases in testicular steroidogenic enzymes and serum testosterone levels were also observed indicating decreased steroidogenesis. In silico docking studies illustrated AFB1 binds with steroidogenic acute regulatory (StAR) protein thereby affecting the transport of cholesterol into mitochondria resulting in decreased steroidogenesis.

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