Department of Anesthesiology.
Center of Scientific Research, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Toxicol Sci. 2017 Dec 1;160(2):329-340. doi: 10.1093/toxsci/kfx181.
Ziram [zinc, bis (dimethyldithiocarbamate)] is an agricultural dithiocarbamate fungicide. By virtual screening, we have identified that ziram is a potential endocrine disruptor. To investigate its effects on pubertal development of Leydig cells, 35-day-old male Sprague Dawley rats orally received ziram (2 or 4 mg/kg/d) for 4 weeks and immature Leydig cells isolated from 35-day-old rat testes were treated with ziram (0.5-50 μM in vitro). Serum hormones, Leydig cell number and specific gene or protein expression levels after in vivo treatment were determined and medium androgen levels were measured as well as apoptosis of Leydig cells after in vitro treatment were determined. In vivo exposure to ziram lowered testosterone and follicle-stimulating hormone levels, and reduced Leydig cell number, and downregulated Leydig cell specific gene or protein expression levels. Ziram exposure in vitro inhibited androgen production and steroidogenic enzyme activities in Leydig cells by downregulating expression levels of P450 cholesterol side cleavage enzyme (Cyp11a1), 3β-hydroxysteroid dehydrogenase 1 (Hsd3b1), 17α-hydroxylase/17,20-lyase (Cyp17a1), and 17β-hydroxysteroid dehydrogenase 3 (Hsd17b3) via downregulating the steroidogenic factor 1 (Nr5a1) at a concentration as low as 5 μM. In conclusion, ziram exposure disrupts Leydig cell development during puberty possibly via downregulating Nr5a1.
锌代二硫代氨基甲酸盐（Ziram）是一种农业用二硫代氨基甲酸盐类杀菌剂。通过虚拟筛选，我们发现 Ziram 是一种潜在的内分泌干扰物。为了研究其对睾丸间质细胞青春期发育的影响，35 日龄雄性 Sprague Dawley 大鼠经口给予 Ziram（2 或 4mg/kg/d）4 周，并用 Ziram（0.5-50μM 体外）处理从小鼠睾丸分离的 35 日龄未成熟睾丸间质细胞。测定体内治疗后血清激素、睾丸间质细胞数量和特定基因或蛋白表达水平，以及体外治疗后培养基中雄激素水平和睾丸间质细胞凋亡情况。体内暴露于 Ziram 降低了睾酮和促卵泡激素水平，减少了睾丸间质细胞数量，并下调了睾丸间质细胞特定基因或蛋白的表达水平。Ziram 体外暴露通过下调类固醇生成因子 1（Nr5a1）的表达水平，抑制了睾丸间质细胞中雄激素的产生和类固醇生成酶的活性（下调 P450 胆固醇侧链裂解酶（Cyp11a1）、3β-羟类固醇脱氢酶 1（Hsd3b1）、17α-羟化酶/17,20-裂解酶（Cyp17a1）和 17β-羟类固醇脱氢酶 3（Hsd17b3）），其浓度低至 5μM 时即可发挥作用。总之，Ziram 暴露可能通过下调 Nr5a1 来破坏青春期睾丸间质细胞的发育。
