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

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: Humanfetal testes (14-20wkgestation; n = 12) were xenografted into castrate male nude mice that were treated for 4-21 dwith vehicle, or 500 mg/kg.dDBP, 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 (similar to 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. (J Clin Endocrinol Metab 97: E341-E348, 2012)