Mitigation of hyperglycemia-induced leydig cell dysfunction by gut derived indol 3- propionic acid: Targeting apoptosis, endoplasmic reticulum stress response and steroidogenesis

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology Pub Date : 2025-07-06 DOI:10.1016/j.reprotox.2025.108987

Cyrus Jalili , Touraj Zamir Nasta , Fatemeh Makalani , Elahe Davoodi , Mohammad Reza Tabandeh

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引用次数: 0

Abstract

Indole-3-propionic acid (IPA), a gut-derived compound, has demonstrated promising antidiabetic, anti-inflammatory, and antioxidant properties. However, its potential role in mitigating male reproductive dysfunction, particularly in the context of hyperglycemia, remains poorly understood. This study aims to investigate the effect of IPA on the Leydig cell dysfunction under hyperglycemic (HG) condition. TM3 mouse Leydig cells were cultured in DMEM/F12 medium containing low (5 mM) and high (30 mM) glucose concentrations in the presence of 10 and 20 µM of IPA for 24 h. Cell viability was assessed by MTT method. The expression of steroidogenesis associated genes 3β-hydroxysteroid dehydrogenase; (Hsd3b1), follicle-stimulating hormone receptor (Fshr), cytochrome P450 side-chain cleavage enzyme(P450scc), and steroidogenic acute regulatory protein (Star)) was evaluated by qRT-PCR analysis.The protein levels of endoplasmic reticulum stress (ERS) related proteins (ATF6, IRE1, GRP78, and CHOP) were determined by Western blot analysis. Testosterone levels were measured by ELISA method. Cell apoptosis was determined using Anexinv/PI flow cytometery analysis. Hyperglycemia decreased cell viability, testosterone production, and the expression of Hsd3b1, Fshr, P450scc, and Star in TM3 cells. Under hyperglycemic conditions, TM3 cells exhibited increased apoptosis and elevated expression of ATF6, PERK, GRP78, and CHOP proteins. IPA, particularly at a dose of 20 µM, increased cell viability and enhanced the expression of steroidogenesis-related genes under HG conditions. Additionally, IPA at doses of 10 and 20 µM attenuated apoptosis and reduced the expression of ERS proteins under HG. The potential therapeutic role of IPA in alleviating the complications caused by hyperglycemia in Leydig cells makes it a promising candidate in the treatment of male reproductive dysfunction associated with diabetes.

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肠源性吲哚- 3-丙酸缓解高血糖诱导的间质细胞功能障碍：靶向凋亡、内质网应激反应和甾体生成

吲哚-3-丙酸（IPA）是一种肠道衍生化合物，具有良好的抗糖尿病、抗炎和抗氧化特性。然而，它在减轻男性生殖功能障碍方面的潜在作用，特别是在高血糖的情况下，仍然知之甚少。本研究旨在探讨IPA对高血糖（HG）状态下间质细胞功能障碍的影响。将TM3小鼠间质细胞在含有低（5 mM）和高（30 mM）葡萄糖浓度的DMEM/F12培养基中，在含有10和20 µM IPA的情况下培养24 h。MTT法测定细胞活力。甾体生成相关基因3β-羟基甾体脱氢酶的表达；采用qRT-PCR方法对Hsd3b1、促卵泡激素受体（Fshr）、细胞色素P450侧链切割酶（P450scc）、促甾体急性调节蛋白（Star）进行评价。Western blot法检测内质网应激（ERS）相关蛋白（ATF6、IRE1、GRP78、CHOP）的表达水平。ELISA法检测各组睾酮水平。采用Anexinv/PI流式细胞术检测细胞凋亡。高血糖降低了TM3细胞的细胞活力、睾酮分泌以及Hsd3b1、Fshr、P450scc和Star的表达。在高血糖状态下，TM3细胞凋亡增加，ATF6、PERK、GRP78和CHOP蛋白表达升高。在HG条件下，IPA，特别是在20 µM的剂量下，增加了细胞活力并增强了甾体生成相关基因的表达。此外，10和20 µM剂量的IPA可减弱HG下的细胞凋亡并降低ERS蛋白的表达。IPA在减轻间质细胞高血糖引起的并发症方面的潜在治疗作用使其成为治疗糖尿病相关男性生殖功能障碍的有希望的候选药物。

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来源期刊

Reproductive toxicology 生物-毒理学

CiteScore

6.50

自引率

3.00%

发文量

131

审稿时长

45 days

期刊介绍： Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine. All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.