Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China; Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China.
Toxicol Appl Pharmacol. 2022 Dec 1;456:116262. doi: 10.1016/j.taap.2022.116262. Epub 2022 Oct 2.
Testicular dysgenesis syndrome in male neonates manifests as cryptorchidism and hypospadias, which can be mimicked by in utero phthalate exposure. However, the underlying phthalate mediated mechanism and therapeutic effects of taxifolin remain unclear. Di-(2-ethylhexyl) phthalate (DEHP) is the most abundantly used phthalate and can induce testicular dysgenesis syndrome in male rats. To explore the mechanism of DEHP mediated effects and develop a therapeutic drug, the natural phytomedicine taxifolin was used. Pregnant Sprague-Dawley female rats were daily gavaged with 750 mg/kg/d DEHP or 10 or 20 mg/kg/d taxifolin alone or in combination from gestational day 14 to 21, and male pup's fetal Leydig cell function, testicular MDA, and antioxidants were examined. DEHP significantly reduced serum testosterone levels of male pups, down-regulated the expression of SCARB1, CYP11A1, HSD3B1, HSD17B3, and INSL3, reduced the cell size of fetal Leydig cells, decreased the levels of antioxidant and related signals (SOD2 and CAT, SIRT1, and PGC1α), induced abnormal aggregation of fetal Leydig cells, and stimulated formation of multinucleated gonocytes and MDA levels. Taxifolin alone (10 and 20 mg/kg/d) did not affect these parameters. However, taxifolin significantly rescued DEHP-induced alterations. DEHP exposure in utero can induce testicular dysgenesis syndrome by altering the oxidative balance and SIRT1/PGC1α levels, and taxifolin is an ideal phytomedicine to prevent phthalate induced testicular dysgenesis syndrome.
睾丸发育不良综合征在男婴中表现为隐睾和尿道下裂，这可通过宫内邻苯二甲酸酯暴露来模拟。然而，潜在的邻苯二甲酸酯介导机制和松属素的治疗效果尚不清楚。邻苯二甲酸二（2-乙基己基）酯（DEHP）是使用最广泛的邻苯二甲酸酯之一，可在雄性大鼠中诱导睾丸发育不良综合征。为了探讨 DEHP 介导作用的机制并开发治疗药物，使用了天然植物药松属素。从妊娠第 14 天到 21 天，每天给妊娠的 Sprague-Dawley 雌性大鼠灌胃 750mg/kg/d DEHP 或单独或联合使用 10 或 20mg/kg/d 松属素，检查雄性幼鼠胎儿睾丸间质细胞功能、睾丸 MDA 和抗氧化剂。DEHP 显著降低雄性幼鼠血清睾酮水平，下调 SCARB1、CYP11A1、HSD3B1、HSD17B3 和 INSL3 的表达，减少胎儿睾丸间质细胞的细胞大小，降低抗氧化剂和相关信号（SOD2 和 CAT、SIRT1 和 PGC1α）的水平，诱导胎儿睾丸间质细胞异常聚集，并刺激多核性生殖细胞和 MDA 水平的形成。单独的松属素（10 和 20mg/kg/d）不会影响这些参数。然而，松属素显著挽救了 DEHP 诱导的改变。宫内 DEHP 暴露可通过改变氧化平衡和 SIRT1/PGC1α 水平来诱导睾丸发育不良综合征，松属素是预防邻苯二甲酸酯诱导的睾丸发育不良综合征的理想植物药。
