Protective effects of sulforaphane on di-n-butylphthalate-induced testicular oxidative stress injury in male mice offsprings via activating Nrf2/ARE pathway.

Zhiqiang Qin,Jingyuan Tang,Xuping Jiang,Wei Zhang,Min Tang,Chengdi Yang,Chao Qin,Peng Han,Wei Wang,Ran Li,Baixin Shen

doi:10.18632/oncotarget.19981

Abstract

Di-N-butylphthalate (DBP) is one of the most common endocrine-disrupting chemicals which can disrupt human endocrine system, especially in the male reproductive system. Here, this study was aimed to determine whether sulforaphane (SFN) could protect against testicular oxidative stress injury induced by DBP in male mice offsprings. Wild-type (Nrf2+/+) and Nrf2-deficient (Nrf2-/-) timed-pregnant mice were given DBP orally from embryonic day (E)14.5 to E19.5. Subsequently, the oxidative stress markers were evaluated. Besides, Nrf2, NF-κB, I-kB, HO-1 and NQO-1 expression levels in the testis were measured by immunohistochemical staining or western blot analysis. DBP significantly reduced anogenital distance (AGD) and influenced testes growth in male mice offsprings, while SFN ameliorated these phenotypes. After DBP stimulation, the testicular morphology, testicular cell apoptosis index and the oxidative stress markers exhibited statistical differences compared with Control group, while SFN supplementation showed obvious improvements. In addition, administration of SFN could obviously increase the expression level of Nrf2 and its downstream ARE gene battery, such as HO-1, NQO-1 in the testis. Meanwhile, SFN pretreatment did not confer protection against DBP-induced testicular oxidative stress injury in Nrf2 knockout mice. Therefore, the present findings suggested that SFN could effectively protect against DBP-induced testicular oxidative stress injury through Nrf2/ARE signaling pathways in male mice offsprings.

Highlights

Endocrine-disrupting chemicals (EDCs), as one of ubiquitous chemical pollutants, have been considered as a potential risk-factors in male reproductive malformation and infertility, including hypospadias, cryptorchidism, and other birth defects [1, 2]
We found DBP led to the sparse arrangement of seminiferous tubules, Leydig cell hypoplasia and decreased number of Sertoli cells
We found DBP induced testicular oxidative stress injury, which was confirmed by decreased capability of antioxidant www.impactjournals.com/oncotarget defense system as well as increased MDA level, indicating that DBP induced male reproductive damage might be associated with oxidative stress

Summary

Introduction

Endocrine-disrupting chemicals (EDCs), as one of ubiquitous chemical pollutants, have been considered as a potential risk-factors in male reproductive malformation and infertility, including hypospadias, cryptorchidism, and other birth defects [1, 2]. Di-N-butylphthalate (DBP) has been suggested as one of the most critical EDCs, which is extensively used for plasticizers [3]. As. DBP doesn’t covalently bound to the plastic matrix, it can leach into surrounding environment [4]. DBP can cause the oxidative stress injury in a variety of organs, such as brain, lung, and liver. DBP has the highest affinity for testes and induces the oxidative stress injury, causing male reproductive dysfunction [5, 6]. Our previous studies have suggested DBP could induce oxidative stress injury in testicular Leydig cells [7]

Objectives

Methods

Results

Discussion

Conclusion