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Updated: Apr 5, 2026
A Hyperandrogenic Mouse Model to Study Polycystic Ovary Syndrome
Published on: October 2, 2018
Male and female mice show significant differences in hepatic transcriptomic response to
Jamie Lee1, Stephenie D Prokopec2, John D Watson3
1Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada. jamieee9166@gmail.com.
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.
Insights
Male and female mice show different responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity, with males exhibiting more significant liver gene expression changes. Sex-specific genes and hormone interactions likely drive these divergent sensitivities.
Area of Science:
- Toxicology
- Genomics
- Environmental Health
Background:
- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent dioxin congener causing diverse toxic effects.
- Sexes exhibit differential sensitivity to TCDD, mediated by the aryl hydrocarbon receptor (AHR).
- Mechanisms underlying sex-specific TCDD responses remain largely unknown.
Purpose of the Study:
- To investigate sex-dependent hepatic transcriptomic responses to TCDD in mice.
- To identify genes and pathways involved in differential TCDD sensitivity between males and females.
Main Methods:
- Adult male and female C57BL/6Kuo mice were exposed to varying doses of TCDD (125-1000 μg/kg).
- Hepatic transcriptomic profiles were analyzed 4 days post-exposure.
- A meta-analysis compared transcriptomic data across different species and tissues.
Main Results:
- Significant sex-based differences in hepatic transcriptomes were observed at all TCDD doses.
- Male mouse livers showed greater TCDD-induced transcriptomic dysregulation than females.
- Sex-specific TCDD-responsive genes, such as Fmo3 and Nr1i3, were identified, primarily induced in males.
- Minimal overlap in transcriptomic changes was found between TCDD-sensitive and resistant models.
Conclusions:
- Sex-dependent TCDD sensitivities are linked to sex-specific TCDD-responsive genes.
- Interactions between AHR and sex hormone receptors may influence differential sensitivity.
- Further research is needed to elucidate the role of sex-specific genes and sex hormones in TCDD toxicity.
