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

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 (E 2)/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. Bisphenol A (BPA) is a synthetic plasticizer that is widely used to package daily necessities 1. Environmental exposure to BPA has potential toxicity to the tissues of male system including those of the testes and prostate 2 , leading to abnormal prostate development and a trend of hyperplasia 3. Prostate epithelial cells and prostate fibroblasts are the two main cell that constitute prostate tissues. Excessive proliferation of epithelial cells and prostate fibroblasts, and the transformation of epithelial cells to mesenchymal cells are involved in the pathogenesis of prostate hyperplasia 4,5. Low-dose BPA (0.01-1 nM) has been reported to promote the proliferation of primary prostate epithelial cells in rats 6. Similar to estradiol (E 2), BPA promotes the proliferation of human prostate epithelial stem cells and increases the possibility of human prostate epithelial carcinoma 7. However, the underlying mechanism of its effect on prostate cell proliferation and prostate hyperplasia remains unclear. As a typical environmental endocrine disruptor (EDC), BPA can disturb the endocrine functions by mimicking, enhancing, or inhibiting the endogenous estrogen activity, interfering with the androgen system 8 , and affecting the expressions of endocrine hormone-related genes and pathways. Prostaglandin synthases (PGS) catalyze the formation of different active prostaglandins (PGs) in the arachidonic acid metabolic pathway. There are four main PGS that are closely associated with hormonal function. Cyclooxygenase-2 (COX-2) is an inducible prostaglandin H synthase that is less expressed i...

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“…AT56 has been involved in several diseases processes and therapy, including neurogenic hypertension [ 35 ], metabolic syndrome [ 36 ], cardiovascular diseases [ 37 ], prostatic hyperplasia [ 38 ], and Crohn’s disease [ 39 ]. Nevertheless, the effect of AT56 in tumor therapy remains unexplored.…”

Phloretin Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia in Rats by Regulating the Inflammatory Response, Oxidative Stress and Apoptosis

“…Additionally, NF-κB could upregulate the gene-producing IL-6 and possibly stimulate the abovementioned loop, further enhancing the proliferation of prostatic cells [ 17 ]. A study also mentioned that in low-dose bisphenol A (BPA)-induced BPH, increased levels of NF-κB were also noted [ 19 ]. In our experimental rat models, 100 mg/kg/day of phloretin not only attenuated both NF-κB and Bcl-2 but also exerted its pro-apoptotic function by upregulating the apoptotic gene Bax.…”

“…Among them, COX-2, a PG H synthase, will be significantly upregulated when induced by various factors such as hormone and inflammation-related signals. In low-dose BPA-induced BPH, COX-2 was associated with the proliferation of prostatic cells, and suppressing it could promote apoptosis and inhibit proliferation [ 19 ]. In our experiment, phloretin 100 mg/kg/day could lower the COX-2 level.…”

Biochemical and Structural Characteristics, Gene Regulation, Physiological, Pathological and Clinical Features of Lipocalin-Type Prostaglandin D2 Synthase as a Multifunctional Lipocalin

“…Administration of a low dose of bisphenol A to male SD rats induces prostatic hyperplasia and upregulates Ptgs2 and L-Pgds gene expression in the prostate. The prostatic hyperplasia is suppressed by administration of inhibitors for Cox-2 and L-PGDS with increased apoptosis levels, indicating that Cox-2 and L-PGDS mediate low-dose bisphenol A-induced prostatic hyperplasia (Wu et al, 2020).…”

“…Cox-2 inhibitor NS398 and L-PGDS inhibitor AT56 suppress the cell proliferation enhanced by bisphenol A and increase apoptosis of those cells. Thus, Cox-2 and L-PGDS mediate low-dose bisphenol A-induced prostatic hyperplasia through pathways involved in cell proliferation and apoptosis (Wu et al, 2020).…”