Is peroxisome proliferation an obligatory precursor step in the carcinogenicity of di(2-ethylhexyl)phthalate (DEHP)?
Di(2-ethylhexyl)phthalate (DEHP), a peroxisome proliferator, has been listed by the International Agency for Research on Cancer (IARC) and by the National Toxicology Program as a possible or reasonably anticipated human carcinogen because it induces dose-related increases in liver tumors in both sexes of rats and mice. Recently, the suggestion has been advanced that DEHP should be considered unlikely to be a human carcinogen because it is claimed that the carcinogenic effects of this agent in rodents are due to peroxisome proliferation and that humans are nonresponsive to this process. An IARC working group recently downgraded DEHP to "not classifiable as to its carcinogenicity to humans" because they concluded that DEHP produces liver tumors in rats and mice by a mechanism involving peroxisome proliferation, which they considered to be not relevant to humans. The literature review presented in this commentary reveals that, although our knowledge of the mechanism of peroxisome proliferation has advanced greatly over the past 10 years, our understanding of the mechanism(s) of carcinogenicty of peroxisome proliferators remains incomplete. Most important is that published studies have not established peroxisome proliferation per se as an obligatory pathway in the carcinogenicity of DEHP. No epidemiologic studies have been reported on the potential carcinogenicity of DEHP, and cancer epidemiologic studies of hypolipidemic fibrate drugs (peroxisome proliferators) are inconclusive. Most of the pleiotropic effects of peroxisome proliferators are mediated by the peroxisome proliferator activated receptor (PPAR), a ligand-activated transcription factor that is expressed at lower levels in humans than in rats and mice. In spite of this species difference in PPAR expression, hypolipidemic fibrates have been shown to induce hypolipidemia in humans and to modulate gene expression (e.g., genes regulating lipid homeostasis) in human hepatocytes by PPAR activation. Thus, humans are responsive to agents that induce peroxisome proliferation in rats and mice. Because peroxisome proliferators can affect multiple signaling pathways by transcriptional activation of PPAR-regulated genes, it is likely that alterations in specific regulated pathways (e.g., suppression of apoptosis, protooncogene expression) are involved in tumor induction by peroxisome proliferators. In addition, because DEHP also induces biological effects that occur independently of peroxisome proliferation (e.g., morphologic cell transformation and decreased levels of gap junction intercellular communication), it is possible that some of these responses also contribute to the carcinogenicity of this chemical. Last, species differences in tissue expression of PPARs indicate that it may not be appropriate to expect exact site correspondence for potential PPAR-mediated effects induced by peroxisome proliferators in animals and humans. Because peroxisome proliferation has not been established as an obligatory step in the carcinogenicity of DEHP, the contention that DEHP poses no carcinogenic risk to humans because of species differences in peroxisome proliferation should be viewed as an unvalidated hypothesis.
Melnick
R L
RL
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. melnickr@niehs.nih.gov
D000818:Animals; D017209:Apoptosis; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D004051:Diethylhexyl Phthalate / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced*; D051379:Mice; D020025:Peroxisome Proliferators / Q000494:pharmacology / Q000633:toxicity*; D020675:Peroxisomes / Q000187:drug effects*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018570:Risk Assessment; D015398:Signal Transduction; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism
D002273:Carcinogens; D020025:Peroxisome Proliferators; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D004051:Diethylhexyl Phthalate