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Title: Activation of peroxisome proliferator-activated receptor alpha enhances apoptosis in the mouse liver

Author
item XIAO, SHEN - CIIT, RTP, NC
item ANDERSON, STEVEN - GLAXOSMITHKLINE, RTP, NC
item SWANSON, CYNDI - CIIT, RTP, NC
item BAHNEMANN, RAINER - BASF,LUDWIGSHAFEN,GERMANY
item Voss, Kenneth
item STAUBER, ANJA - CIIT, RTP, NC
item CORTON, J. CHRISTOPHER - CIIT, RTP, NC

Submitted to: Toxicological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/13/2006
Publication Date: 8/1/2006
Citation: Xiao, S., Anderson, S.P., Swanson, C., Bahnemann, R., Voss, K.A., Stauber, A., Corton, J. 2006. Activation of peroxisome proliferator-activated receptor alpha enhances apoptosis in the mouse liver. Toxicological Sciences. 92(2):368-377.

Interpretive Summary: Fumonisins are fungal toxins found in corn and food. They cause cancer in rodents and possibly in humans. To better understand how fumonisins impact human health, it is important to define their direct and indirect effects in cells and tissues. Fumonisins disrupt fat metabolism and cause accumulation of a fat known as sphingosine. Sphingosine activates a specific signaling molecule under some conditions. Signaling regulates genes involved in fat metabolism, cell growth, and cell death, processes that are involved in both cancer development and fumonisin toxicity. To better understand how signaling works, intact mice and genetically altered mice lacking the signaling molecule (PPAR-alpha/peroxisome proliferator-activated receptor alpha) were exposed to the antibody that causes cell death by activating a specific molecular pathway that is involved in fumonisin toxicity under some circumstances. Liver damage and death occurred only in the intact mice and the effects were enhanced when the intact mice were treated with the signaling molecule along with the antibody. A series of signaling molecules affecting cell death were then evaluated to explore intact and signal-treated mice react differently to the antibody. Treating intact mice with this signaling molecule decreased the amount of a protein which inhibits cell death in liver. In contrast, levels of this protein in mice lacking the signaling molecule were higher than those of intact mice and were unaffected by the specific signaling activators. Thus, a mechanism by which fumonisins might cause cell death has been identified. Further experiments to determine the extent to which signaling by this specific molecule is involved in fumonisin toxicity will improve understanding of how the fumonisins affect animal and human health.

Technical Abstract: Fumonisin mycotoxins are produced by Fusarium verticillioides. They occur in corn and corn-based foods. They are carcinogenic to rodents and while their human health impact is unclear, fumonisins are implicated as risk factors for some cancers. Fumonisins inhibit ceramide synthase, increase cell sphingoid base concentrations, cause apoptosis, and affect tissue regeneration but the molecular events linking enzyme inhibition, apoptosis and cancer are not known. Sphingoid bases have been found to bind recombinant mouse peroxisome proliferator-activated response element alpha (PPAR-alpha) in vitro, suggesting that PPAR-alpha-dependent signaling is involved in fumonisin toxicity and carcinogenicity. To further characterize how PPAR-alpha-related pathways affect apoptosis, Jo2 antibody, which activates the Fas apoptosis pathway, was administered to wild type (WT) mice, PPAR-alpha null mice, WT mice treated with the peroxisome proliferator WY 14,643 (WY) and PPAR-alpha null mice treated with WY. Jo2 was toxic to both groups of WT mice although deaths occurred earlier, liver apoptosis and necrosis were more severe, and caspase-3 activation was greater in those treated with WY. In contrast, both groups of PPAR-alpha null mice were resistant to the effects of Jo2. In the absence of Jo2 treatment, WT mice treated with WY or the peroxisome proliferator trichloroacetate (TCA) exhibited increased caspase-9 and caspase-9 activity, while caspase-3 and -8 were unaffected. Mcl-1 protein suppresses cytochrome c release from mitochondria, apoptosome (involves caspase-9) activation and apoptosis. Expression of Mcl-1 mRNA and protein was decreased in WT mice treated with WY but increased in WY-treated and -untreated PPAR-alpha null mice. Together, the results identify a nongenotoxic mechanism by which peroxisomal proliferators, possibly including sphingoid bases accumulating as a result of fumonisin exposure, cause apoptosis in liver.