Male and female mice show significant differences in hepatic transcriptomic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Jamie Lee,John D Watson,Ren X Sun,Paul C Boutros,Raimo Pohjanvirta,Stephenie D Prokopec

doi:10.1186/s12864-015-1840-6

Abstract

Background2,3,7,8–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.ResultsSeveral 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.ConclusionsSex-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1840-6) contains supplementary material, which is available to authorized users.

Highlights

Chlorinated dioxins are a large class of environmental contaminants generated as by-products of a variety of industrial processes [1]
Sex-dependent sensitivities to TCDD exposure are associated with a set of sex-specific TCDD-responsive genes
Complex interactions between the aryl hydrocarbon and sex hormone receptors may affect the observable differences in sensitivity phenotypes between the sexes

Summary

Introduction

Chlorinated dioxins are a large class of environmental contaminants generated as by-products of a variety of industrial processes [1]. Mice expressing mutations which prevent nuclear translocation, heterodimerization of AHR with ARNT, or AHRE binding are highly refractory to dioxininduced toxicities [11, 19, 20]. Mice lacking hepatic ARNT show reduced hepatotoxicity following treatment with TCDD [21]. These studies indicate that DNA binding of ligand-activated AHR is essential for the development of TCDD-induced toxic effects. In order to elucidate the specific mechanisms by which TCDD and the AHR elicit toxic outcomes, several groups have examined the AHR-mediated transcriptional events in various animal models and tissues following TCDD exposure [12, 13, 22,23,24,25,26]. One possible explanation for this variation involves the structure of the AHR: different isoforms were found to exist between species and strains

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