Male and female mice show significant differences in hepatic transcriptomic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
BACKGROUND
2,3,7,8-tetrachlorodibenzo-p-dixion (TCDD) is the most potent of the dioxin congeners, capable of causing a wide range of toxic effects across numerous animal models. Previous studies have demonstrated that males and females of the same species can display divergent sensitivity phenotypes to TCDD toxicities. Although it is now clear that most TCDD-induced toxic outcomes are mediated by the aryl hydrocarbon receptor (AHR), the mechanism of differential responses to TCDD exposure between sexes remains largely unknown. To investigate the differential sensitivities in male and female mice, we profiled the hepatic transcriptomic responses 4 days following exposure to various amounts of TCDD (125, 250, 500 or 1000 μg/kg) in adult male and female C57BL/6Kuo mice.


RESULTS
Several key findings were revealed by our study. 1) Hepatic transcriptomes varied significantly between the sexes at all doses examined. 2) The liver transcriptome of males was more dysregulated by TCDD than that of females. 3) The alteration of "AHR-core" genes was consistent in magnitude, regardless of sex. 4) A subset of genes demonstrated sex-dependent TCDD-induced transcriptional changes, including Fmo3 and Nr1i3, which were significantly induced in livers of male mice only. In addition, a meta-analysis was performed to contrast transcriptomic profiles of various organisms and tissues following exposure to equitoxic doses of TCDD. Minimal overlap was observed in the differences between TCDD-sensitive or TCDD-resistant models.


CONCLUSIONS
Sex-dependent sensitivities to TCDD exposure are associated with a set of sex-specific TCDD-responsive genes. In addition, complex interactions between the aryl hydrocarbon and sex hormone receptors may affect the observable differences in sensitivity phenotypes between the sexes. Further work is necessary to better understand the roles of those genes altered by TCDD in a sex-dependent manner, and their association with changes to sex hormones and receptors.
Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada. jamieee9166@gmail.com.
Jamie
J
Lee
Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada. Stephenie.Prokopec@oicr.on.ca.
Stephenie D
SD
Prokopec
Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada. John.Watson@oicr.on.ca.
John D
JD
Watson
Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada. Ren.Sun@oicr.on.ca.|Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada. Ren.Sun@oicr.on.ca.
Ren X
RX
Sun
Department of Food Hygiene and Environmental Health, University of Helsinki, Helsinki, Finland. raimo.pohjanvirta@helsinki.fi.|Laboratory of Toxicology, National Institute for Health and Welfare, Kuopio, Finland. raimo.pohjanvirta@helsinki.fi.
Raimo
R
Pohjanvirta
Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada. Paul.Boutros@oicr.on.ca.|Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada. Paul.Boutros@oicr.on.ca.|Department of Medical Biophysics, University of Toronto, Toronto, Canada. Paul.Boutros@oicr.on.ca.
Paul C
PC
Boutros
D000818:Animals; D000090702:Constitutive Androstane Receptor; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012737:Sex Factors; D059467:Transcriptome / Q000187:drug effects*
D000090702:Constitutive Androstane Receptor; C000716328:Nr1i3 protein, mouse; D000072317:Polychlorinated Dibenzodioxins; D018160:Receptors, Cytoplasmic and Nuclear