Integrated Proteomic and Metabolomic Analysis of the Testes Characterizes BDE-47-Induced Reproductive Toxicity in Mice.

Liang Xu,Xin Dong,Jing Xi,Yang Luan,Liupeng Wang,Xinyu Zhang,Yiyi Cao,Hongxia Zhao,Songyan Gao

doi:10.3390/biom11060821

Abstract

A representative congener of polybrominated diphenyl ethers in the environment, 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), is associated with male reproductive toxicity, yet the underlying mechanisms remain largely unclear. In this study, mice were administered environmentally relevant concentrations of BDE-47 for six weeks. Histopathological observations showed that BDE-47 induced inflammatory reactions and damaged the testes. By conducting an integrated proteomic and metabolomic analysis coupled with a bioinformatic analysis using ingenuity pathway analysis (IPA) methods, we found that BDE-47 mainly affected the molecules involved in free radical scavenging, cell death and survival, neurological disease, and inflammatory response. IPA canonical pathways showed inflammatory and apoptosis pathways, including hepatic fibrosis/hepatic stellate cell activation, the GP6 signaling pathway, tight junction signaling, acute phase response signaling, LXR/RXR activation, unfolded protein response, and FXR/RXR activation, which are related to male reproductive toxicity. Key transcriptional regulator networks were activated via a focus on upstream regulator analysis. The expression of MYC and Clu as the core transcriptional factor and targeted protein, respectively, was verified. It is further proposed that MYC may contribute to the etiology of male reproductive toxicity. These findings will improve our understanding of the mechanisms responsible for BDE-47-induced male reproductive toxicity, which may promote the discovery of useful biomarkers indicative of BDE-47 exposure.

Highlights

Introduction published maps and institutional affilPolybrominated diphenyl ethers (PBDEs) are flame retardants widely used in various commercial products
No existing study has integrated proteomics and metabolomics to study male reproductive toxicity induced by BDE-47
We conducted an integrated proteomic and metabolomic analysis coupled with a bioinformatic analysis of ingenuity pathway analysis (IPA) methods to improve the understanding of the mechanisms responsible for BDE-47-induced male reproductive toxicity

Summary

Introduction

Introduction published maps and institutional affilPolybrominated diphenyl ethers (PBDEs) are flame retardants widely used in various commercial products. As PBDEs are lipophilic and persistent, PBDE congeners have accumulated in the environment and biota over recent decades [1,2,3,4]. PBDE accumulation in humans has increased exponentially [1,5]. PBDEs are of increasing concern owing to their endocrine disruption effects, neurodevelopmental toxicity, and potential carcinogenicity [6,7,8]. Based on the physicochemical properties and health effects of PBDEs, commercial penta-, octa-, and deca-PBDE mixtures have been declared persistent organic pollutants under the Stockholm Convention. 2,20 ,4,40 -tetrabromodiphenyl ether (BDE-47) is a major component of commercial penta-PBDE. And biologically, BDE-47 exhibits relatively higher detection rates and concentrations, as well as a higher toxicity than elevated PBDE congeners [9,10,11]. Considering its exposure and toxicity potential, BDE-47 may significantly contribute to the toxicity associated with PBDE iations

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Conclusion