title: Sex-related differences in murine hepatic transcriptional and proteomic responses to TCDD.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that produces myriad toxicities in most mammals. In rodents alone, there is a huge divergence in the toxicological response across species, as well as among different strains within a species. But there are also significant differences between males and females animals of a single strain. These differences are inconsistent across model systems: the severity of toxicity is greater in female rats than males, while male mice and guinea pigs are more sensitive than females. Because the specific events that underlie this difference remain unclear, we characterized the hepatic transcriptional response of adult male and female C57BL/6 mice to 500μg/kg TCDD at multiple time-points. The transcriptional profile diverged significantly between the sexes. Female mice demonstrated a large number of altered transcripts as early as 6h following treatment, suggesting a large primary response. Conversely, male animals showed the greatest TCDD-mediated response 144h following exposure, potentially implicating significant secondary responses. Nr1i3 was statistically significantly induced at all time-points in the sensitive male animals. This mRNA encodes the constitutive androstane receptor (CAR), a transcription factor involved in the regulation of xenobiotic metabolism, lipid metabolism, cell cycle and apoptosis. Surprisingly though, changes at the protein level (aside from the positive control, CYP1A1) were modest, with only FMO3 showing clear induction, and no genes with sex-differences. Thus, while male and female mice show transcriptional differences in their response to TCDD, their association with TCDD-induced toxicities remains unclear.
authors.affiliation: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Stephenie D
authors.initials: SD
authors.lastname: Prokopec
authors.affiliation: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Watson
authors.affiliation: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada.
authors.forename: Jamie
authors.initials: J
authors.lastname: Lee
authors.affiliation: Laboratory of Toxicology, National Institute for Health and Welfare, Kuopio Finland; Department of Food Hygiene and Environmental Health, University of Helsinki, Helsinki, Finland.
authors.forename: Raimo
authors.initials: R
authors.lastname: Pohjanvirta
authors.affiliation: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada. Electronic address: Paul.Boutros@oicr.on.ca.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D004785:Environmental Pollutants / Q000633:toxicity; D005260:Female; D006168:Guinea Pigs; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D020543:Proteome / Q000187:drug effects* / Q000235:genetics*; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012737:Sex Factors; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000090702:Constitutive Androstane Receptor; D004785:Environmental Pollutants; C000716328:Nr1i3 protein, mouse; C000716329:Nr1i3 protein, rat; D000072317:Polychlorinated Dibenzodioxins; D020543:Proteome; D012333:RNA, Messenger; D014157:Transcription Factors
keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin; AH receptor; Aryl hydrocarbon receptor; Computational biology; Sex differences; TCDD