Endocrine Disruptors and Prostate Cancer.

Margherita Corti,Stefano Lorenzetti,Daniele Marcoccia,Alessandro Ubaldi,Romano Zilli

doi:10.3390/ijms23031216

Abstract

The role of endocrine disruptors (EDs) in the human prostate gland is an overlooked issue even though the prostate is essential for male fertility. From experimental models, it is known that EDs can influence several molecular mechanisms involved in prostate homeostasis and diseases, including prostate cancer (PCa), one of the most common cancers in the male, whose onset and progression is characterized by the deregulation of several cellular pathways including androgen receptor (AR) signaling. The prostate gland essentiality relies on its function to produce and secrete the prostatic fluid, a component of the seminal fluid, needed to keep alive and functional sperms upon ejaculation. In physiological condition, in the prostate epithelium the more-active androgen, the 5α-dihydrotestosterone (DHT), formed from testosterone (T) by the 5α-reductase enzyme (SRD5A), binds to AR and, upon homodimerization and nuclear translocation, recognizes the promoter of target genes modulating them. In pathological conditions, AR mutations and/or less specific AR binding by ligands modulate differently targeted genes leading to an altered regulation of cell proliferation and triggering PCa onset and development. EDs acting on the AR-dependent signaling within the prostate gland can contribute to the PCa onset and to exacerbating its development.

Highlights

The prostate is the main accessory gland of the male reproductive system, which plays an essential role in male reproduction
A reduction of the PSA secretion could influence sperm fertilization potential; on the contrary, an increase in PSA secretion can be used as a prostate cancer (PCa) biomarker [2]
The androgenic hormones regulate normal prostate gland growth and function by interacting with the androgen receptor (AR), whose gene expression in PCa appears to be deregulated; this plays a central role in development and metastatic progression [7,8]

Summary

Introduction

The prostate is the main accessory gland of the male reproductive system, which plays an essential role in male reproduction. The androgenic hormones regulate normal prostate gland growth and function by interacting with the androgen receptor (AR), whose gene expression in PCa appears to be deregulated; this plays a central role in development and metastatic progression [7,8]. At the same time, the incidence of androgen-related pathologies, such as PCa and benign prostate hyperplasia (BPH), increases with age This increased incidence could be related to the local enzymatic conversion of T to DHT by 5α-reductase, since the up-regulation of SRD5A, the gene. At the same time, the incidence of androgen-related pathologies, such as PCa and benign prostate hyperpla4sioaf 17 (BPH), increases with age This increased incidence could be related to the local enzymatic conversion of T to DHT by 5α-reductase, since the up-regulation of SRD5A, the gene encmpseorpaeiindonnrnrtsictkentcirrasenoageetd-daiyn5pclsiyoαtrneroui-agimnrsnnteti5agyado9rαto0umikau-%ccnerantreddalaogdlestyftuseimhomi,c[enh3ataeaE7l9annes]R0sdse.o%b,o[tle3hdhvoe7eeeafn]rrs.mEestRbxhhepenaooenrwvoenel8sndrs0see[ih3oxyro5pnetwh,ar3aear6npssn]sp.b[i8Ieo3e0na5ncdyr,a3aeeut6poaes]rpde.bse,ebbabIonheretcdinthgaoeiuhgtebhsendeere,lhbweebosisgheittohrhneonneitggsrhcnesewonuemlh/cestehtepsrnisaoaotrcsgoneoesBsdmtnPes/tprHoutoaectnirshhneetaodcaitrsnstetpotearrBrsaetoPeh--nHaet. The effects elicited by androgens are obtained by different signal transduction pathways (e.g., nuclear and extra-nuclear), whose activation depends on the cellular context of the target cell, the AR intracellular localization (e.g., membrane-bound, cytosolic, nuclear), and the ligand itself (e.g., T vs. DHT)

Androgen Receptor Mutations and Splice Variants in the Prostate Gland

Findings

Conclusions