Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10915287 | Mutation Research/Reviews in Mutation Research | 2012 | 76 Pages |
Abstract
Di(ethylhexyl) phthalate (DEHP) is a manufactured chemical commonly added to plastics: it is a ubiquitous environmental contaminant to which humans are exposed through multiple routes. DEHP is a rodent carcinogen with an extensive data base on genotoxicity and related effects spanning several decades. Although DEHP has been reported to be negative in most non-mammalian in vitro mutation assays, most studies were performed under conditions of concurrent cytotoxicity, precipitation, or irrelevant metabolic activation. However, a number of in vitro rodent tissue assays have reported DEHP to be positive for effects on chromosomes, spindle, and mitosis. A robust database shows that DEHP increases transformation and inhibits apoptosis in Syrian hamster embryo cells. In a transgenic mouse assay, in vivo DEHP exposure increased the mutation frequency only in the liver, which is the target organ for cancer. In vitro exposure of human cells or tissues to DEHP induced DNA damage; altered mitotic rate, apoptosis, and cell proliferation; increased proliferation, tumor mobility, and invasiveness of tumor cell lines; and activated a number of nuclear receptors. DEHP has been shown to be an agonist for CAR2, a novel constitutive androstane receptor occurring only in humans. Environmental exposures of humans to DEHP have been associated with DNA damage. After taking into account study context and relevant issues affecting interpretation, in vitro studies reported that a similar DEHP concentration range induced both mutagenic and non-mutagenic effects in human tissues and, using a much more limited rodent database, transformation of embryonic rodent tissues. The human and rodent data suggest that DEHP induces cancer through multiple molecular signals, including DNA damage. The analyses presented here may provide guidance for similar data sets used in structure-activity relationships, computational-toxicology extrapolations, and attempts to extrapolate in vitro results to predict in vivo effects for hazard characterization.
Keywords
IPCsADMENADPHGSTFRAPRT-PCRFskPPARGJICCpGforskolinIKKDnmtDEHPIkappaB kinasePXRTIMP-2DNA methyltransferasesMEHPSteroid and xenobiotic receptorSXRNIEHSMEHHPCERHRS-9IARCIC50NADPEPASCECyPNTPMMPDMSOHCCmono-(2-ethyl-5-hydroxyhexyl) phthalatemono(2-ethylhexyl) phthalateNFκBROSInternational Agency for Research on CancerEnvironmental Protection AgencyGap junction intercellular communicationSHEEpigeneticsChoNational Toxicology ProgramQSARSister chromatid exchangeChinese Hamster Ovaryabsorption, distribution, metabolism and eliminationSyrian hamster embryoDimethylsulfoxideQuantitative structure–activity relationshipWorld Health OrganizationCarcinogenicityGenotoxicityCytochrome P450Inhibitory concentration of 50%nuclear factor kappa Blactate dehydrogenaseLDHmatrix metalloproteinaseCARnicotinamide adenine dinucleotidenicotinamide adenine dinucleotide phosphatereal-time polymerase chain reactionHepatocellular carcinomaWHOglutathione-S-transferaseReactive oxygen speciesconstitutive androstane receptorperoxisome proliferator-activated receptorPregnane X receptor
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Authors
Jane C. Caldwell,