Do Phthalates Affect Steroidogenesis by the Human Fetal Testis? Exposure of Human Fetal Testis Xenografts to Di-n-Butyl Phthalate

• Published in: The journal of clinical endocrinology and metabolism 2012-03, Vol.97 (3), p.E341-E348
• Main Authors: Mitchell, R. T, Childs, A. J, Anderson, R. A, van den Driesche, S, Saunders, P. T. K, McKinnell, C, Wallace, W. H. B, Kelnar, C. J. H, Sharpe, R. M
• Format: Article
• Language: English
• Subjects: Animals; Dibutyl Phthalate - pharmacology; Fetus; Humans; Male; Mice; Mice, Nude; Testis - drug effects; Testis - embryology; Testis - metabolism; Testosterone - biosynthesis; Transplantation, Heterologous
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2011-2411

Context: Phthalates are ubiquitous environmental chemicals. Fetal exposure to certain phthalates [e.g. di-n-butyl phthalate (DBP)] causes masculinization disorders in rats, raising concern for similar effects in humans. We investigated whether DBP exposure impairs steroidogenesis by the human fetal testis. Objective: The aim of the study was to determine effects of DBP exposure on testosterone production by normally growing human fetal testis xenografts. Design: Human fetal testes (14–20 wk gestation; n = 12) were xenografted into castrate male nude mice that were treated for 4–21 d with vehicle, or 500 mg/kg · d DBP, or monobutyl phthalate (active metabolite of DBP); all mice were treated with human chorionic gonadotropin to mimic normal human pregnancy. Rat fetal testis xenografts were exposed for 4 d to DBP as a positive control. Main Outcome Measures: Testosterone production was assessed by measuring host serum testosterone and seminal vesicle (SV) weights at termination, plus testis gene expression (rats). Results: Human fetal testis xenografts showed similar survival (∼80%) and total graft weight (8.6 vs. 10.1 mg) in vehicle and DBP-exposed hosts, respectively. Serum testosterone (0.56 vs. 0.64 ng/ml; P > 0.05) and SV weight (67.2 vs. 81.9 mg; P > 0.05) also did not differ. Exposure to monobutyl phthalate gave similar results. In contrast, exposure of rat fetal xenografts to DBP significantly reduced SV weight and testis Cyp11a1/StAR mRNA expression and lowered testosterone levels, confirming that DBP exposure can inhibit steroidogenesis in xenografts, further validating the negative findings on testosterone production in the human. Conclusions: Exposure of human fetal testes to DBP is unlikely to impair testosterone production as it does in rats. This has important safety and regulatory implications.