The prostaglandin synthases, COX-2 and L-PGDS, mediate prostate hyperplasia induced by low-dose bisphenol A

Shuangshuang Wu,Jianhui Wu,Xin Su,Zuyue Sun,Aicui Ma,Han Yan,Dongyan Huang,Lei Li

doi:10.1038/s41598-020-69809-y

Shuangshuang Wu, Jianhui Wu + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-69809-y

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Abstract

This study aimed to identify prostaglandin synthases (PGS) that mediate bisphenol A (BPA)-induced prostatic hyperplasia and explore their underlying mechanisms. In an in vivo study, male adult Sprague–Dawley rats were treated with different concentrations of BPA (10, 30, 90, or 270 μg/kg, i.g., daily), or with vehicle for 4 weeks. Results revealed that low-dose BPA induced prostatic hyperplasia with increased PCNA/TUNEL ratio. It significantly upregulated the expression of cyclooxygenase-2 (COX-2) and NF-κB in the dorsolateral prostate (P < 0.05) and the expression of lipocalin-type prostaglandin D synthase (L-PGDS) in ventral prostate (P < 0.05). The level of estradiol (E2)/testosterone (T) and expression of androgen receptor (AR) and estrogen receptor α (ERα) were also altered. In vitro studies showed that low-dose BPA (0.1–10 nM) promoted the proliferation of human prostate fibroblasts and epithelial cells, and significantly upregulated the expression of COX-2 and L-PGDS in the cells. The two types of cell proliferation induced by BPA were inhibited by COX-2 inhibitor (NS398) and L-PGDS inhibitor (AT56), with increased apoptosis level. These findings suggested that COX-2 and L-PGDS could mediate low-dose BPA-induced prostatic hyperplasia through pathways involved in cell proliferation and apoptosis, which might be related to the functions of ERα and AR. The role of COX-2/NF-κB pathway in dorsolateral prostate requires further research.

Highlights

Bisphenol A (BPA) is a synthetic plasticizer that is widely used to package daily n ecessities[1]
The organ coefficients of the whole prostate and the ventral prostate were significantly increased in the bisphenol A (BPA) (30 μg/kg)-treated group compared to the control (P < 0.05) (Fig. 1)
In vivo studies demonstrated that adult SD rats treated with 10–270 μg/kg BPA for 4 weeks could suffer from prostatic hyperplasia, and in vitro studies indicated that low-dose BPA (0.1 nM and 1 nM) significantly promoted the proliferation of prostate fibroblasts and epithelial cells in humans

Summary

Introduction

Bisphenol A (BPA) is a synthetic plasticizer that is widely used to package daily n ecessities[1]. In the male reproductive system, the overexpression of COX-2 is related to testosterone-induced hyperplasia, proliferation of seminal vesicle cells, and prostate cancer invasion[10]. COX-2/PGE signaling pathway is involved in the progression of benign prostatic hyperplasia (BPH). As a responsive inflammatory factor, NFκB interacts with the COX-2/ PGE pathway to mediate the progressions of p rostatitis[14] and prostate c ancer[15]. Our previous study revealed that BPA upregulated the transcriptional level of prostaglandin D 2 synthase (PTGDS) gene, inducing prostate hyperplasia in adult r ats[19]. As BPA can interfere with the action of hormones and affect the normal development of prostate during the interaction of PGS with endocrine hormones, we hypothesized that PGS is involved in BPA-induced prostatic hyperplasia

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