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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...

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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
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cited_by cdi_FETCH-LOGICAL-c4836-2f9d60b75e06ecd7a5e2d66a51be5452c473b91fe7a3626f9a6230ae7e7ebf693
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container_title The journal of clinical endocrinology and metabolism
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creator 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
description 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.
doi_str_mv 10.1210/jc.2011-2411
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Exposure of Human Fetal Testis Xenografts to Di-n-Butyl Phthalate</title><source>Oxford Journals Online</source><creator>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</creator><creatorcontrib>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</creatorcontrib><description>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 &gt; 0.05) and SV weight (67.2 vs. 81.9 mg; P &gt; 0.05) also did not differ. Exposure to monobutyl phthalate gave similar results. 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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 &gt; 0.05) and SV weight (67.2 vs. 81.9 mg; P &gt; 0.05) also did not differ. 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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 &gt; 0.05) and SV weight (67.2 vs. 81.9 mg; P &gt; 0.05) also did not differ. Exposure to monobutyl phthalate gave similar results. 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identifier ISSN: 0021-972X
ispartof The journal of clinical endocrinology and metabolism, 2012-03, Vol.97 (3), p.E341-E348
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subjects Animals
Dibutyl Phthalate - pharmacology
Fetus
Humans
Male
Mice
Mice, Nude
Testis - drug effects
Testis - embryology
Testis - metabolism
Testosterone - biosynthesis
Transplantation, Heterologous
title Do Phthalates Affect Steroidogenesis by the Human Fetal Testis? Exposure of Human Fetal Testis Xenografts to Di-n-Butyl Phthalate
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