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Species-specific regulation of PXR/CAR/ER-target genes in the mouse and rat liver elicited by o, p'-DDT.

AbstractBACKGROUND:
Dichlorodiphenyltrichloroethane (DDT) is a persistent estrogenic organochlorine pesticide that is a rodent hepatic tumor promoter, with inconclusive carcinogenicity in humans. We have previously reported that o, p'-DDT elicits primarily PXR/CAR-mediated activity, rather than ER-mediated hepatic responses, and suggested that CAR-mediated effects, as opposed to ER-mediated effects, may be more important in tumor promotion in the rat liver. To further characterize species-specific hepatic responses, gene expression analysis, with complementary histopathology and tissue level analyses were investigated in immature, ovariectomized C57BL/6 mice treated with 300 mg/kg o, p'-DDT, and compared to Sprague-Dawley rat data.
RESULTS:
Rats and mice exhibited negligible histopathology with rapid o, p'-DDT metabolism. Gene expression profiles were also similar, exhibiting PXR/CAR regulation with the characteristic induction of Cyp2b10 and Cyp3a11. However, PXR-specific target genes such as Apoa4 or Insig2 exhibited more pronounced induction compared to CAR-specific genes in the mouse. In addition, mouse Car mRNA levels decreased, possibly contributing to the preferential activation of mouse PXR. ER-regulated genes Cyp17a1 and Cyp7b1 were also induced, suggesting o, p'-DDT also elicits ER-mediated gene expression in the mouse, while ER-mediated effects were negligible in the rat, possibly due to the inhibitory effects of CAR on ER activities. In addition, o, p'-DDT induced Gadd45a, Gadd45b and Cdkn1, suggesting DNA damage may be an additional risk factor. Furthermore, elevated blood DHEA-S levels at 12 h after treatment in the mouse may also contribute to the endocrine-related effects of o, p'-DDT.
CONCLUSION:
Although DDT is known to cause rodent hepatic tumors, the marked species differences in PXR/CAR structure, expression patterns and ligand preference as well as significant species-specific differences in steroidogenesis, especially CYP17A1 expression and activity, confound the extrapolation of these results to humans. Nevertheless, the identification of potential modes of action as well as species-specific responses may assist in the selection and further development of more appropriate models for assessing the toxicity of DDT to humans and wildlife.
AuthorsNaoki Kiyosawa, Joshua C Kwekel, Lyle D Burgoon, Edward Dere, Kurt J Williams, Colleen Tashiro, Brock Chittim, Timothy R Zacharewski
JournalBMC genomics (BMC Genomics) Vol. 9 Pg. 487 (Oct 16 2008) ISSN: 1471-2164 [Electronic] England
PMID18925944 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Constitutive Androstane Receptor
  • Insecticides
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Receptors, Steroid
  • Transcription Factors
  • Androstenedione
  • Dichlorodiphenyl Dichloroethylene
  • Dehydroepiandrosterone Sulfate
  • Steroid 17-alpha-Hydroxylase
Topics
  • Androstenedione (blood)
  • Animals
  • Cluster Analysis
  • Constitutive Androstane Receptor
  • Dehydroepiandrosterone Sulfate (blood)
  • Dichlorodiphenyl Dichloroethylene (metabolism, toxicity)
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Insecticides (metabolism, toxicity)
  • Liver (drug effects, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • Pregnane X Receptor
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear (drug effects, genetics, metabolism)
  • Receptors, Estrogen (drug effects, genetics, metabolism)
  • Receptors, Steroid (drug effects, genetics, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Species Specificity
  • Steroid 17-alpha-Hydroxylase (drug effects, genetics, metabolism)
  • Transcription Factors (drug effects, genetics, metabolism)

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