Species differences in response to PPs

There are marked species differences in response to nongenotoxic carcinogens and the data available support the position that human and some animal species such as guinea pigs are nonresponsive to the adverse effects of PPs seen in rodents. Studies with cultured human hepatocytes show that there is no peroxisome proliferation or induction of S-phase in response to PPs. Follow up studies of patients receiving fibrate PP dmg therapy confirm a lack of adverse effects. In addition, there was no increased rate of cancer in workers exposed to DEHP. The lack of response provides clear evidence that humans are 

Since the rodent effects of PPs ate mediated via PPARa and humans appear to be non-responsive to these adverse effects, species differences in PPARa expression levels provide a plausible explanation for the lack of hitman response. However, humans do respond to PPs by altering etqtression of enzymes that regulate serum cholesterol and lipid homeostasis. In addition, human liver does contain a functional PPARa although the expression of PPARa in humans is around 10-fold lower when compared with responsive species such as rat and mouse. In total, these data support a quantitative hypothesis whereby PPARa expression in humans is sufficient to mediate the beneficial effects of hypolipidaemic dmgs via regulation of genes for enzymes and lipid transporters. 

Expression levels are too low, however, for modulation of the full battery of genes that are activated in rats and mice such as those involved in peroxisome proliferation and perturbation of hepatocyte growth control. 

In summary, the adverse response of rodents to PPs is mediated by PPARa. The scientific evidence demonstrates that humans are non-responsive to peroxisome proliferation and tumors induced by PPs such as DEHP. These species differences may be attributed to both differences in the quantity of PPARa and to DNA sequence differences in the promoter regions of genes found to be responsive to PPs in the rodent. At least for one gene that is a marker of rodent peroxisome proliferation, these sequence differences result in a non- 

Health and Safety Issues with Plasticizers and Plasticized Materials 

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Woodyatt, N.J., Lambe, K.G, Myers, K.A., Tugwood, J.D. Roberts, R.A. (1999) The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population significance for species differences in response to PPs. Carcinogenesis, 20, 369-372... 

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