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.
Hypospadias is a frequent congenital malformation in boys and is characterized by incomplete fusion of the urethral folds. The steroidogenic factor-1 (SF-1, NR5A1) gene plays a key role in hypothalamic-pituitary-steroidogenic organ development, and has previously been reported to be mutated in individuals with 46,XY disorder of sex development. Here, we investigated the role of SF-1 in hypospadias, a milder form of 46,XY disorder of sex development. We performed direct sequencing analysis of the SF-1 gene in 2 male Caucasian twins exhibiting very severe hypospadias, and in 95 Caucasian boys with mild and severe hypospadias. We further extended the analysis by investigating 332 mild and severe hypospadias cases and 422 male controls using TaqMan assays. Our sequencing revealed a novel heterozygous p.R313H (c.938G>A) missense mutation in each twin, and no mutations in the 95 Caucasian cases. Instead, a missense p.G146A (c.437G>C), and a silent known p.P125P (c.375C>T) polymorphism, respectively, was found in several of the latter cases. Further investigation of the 2 polymorphisms in the larger material of cases and controls showed no significant genotypic or allelic association. In conclusion, the SF-1 gene may not play a significant role in the development of hypospadias in Caucasians.
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