Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz

Peter Laier, Stine Broeng Metzdorff, Julie Boberg, Marie Hagen, Ulla Hass, Sofie Christiansen, Marta Axelstad Petersen, Thuri Kledal, Majken Dalgaard, C. McKinnell, L. J. S. Brokken, Anne Vinggaard

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The fungicide prochloraz has got multiple mechanisms of action that may influence the demasculinizing and reproductive toxic effects of the compound. In the present study, Wistar rats were dosed perinatally with prochloraz (50 and 150 mg/kg/day) from gestational day (GD) 7 to postnatal day (PND) 16. Caesarian sections were performed on selected dams at GD 21, while others were allowed to give birth to pups that were followed until PND 16. Prochloraz caused mild dysgenesis of the male external genitalia as well as reduced anogenital distance and retention of nipples in male pups. An increased anogenital distance indicated virilization of female pups. Effects on steroidogenesis in male fetuses became evident as decreased testicular and plasma levels of testosterone and increased levels of progesterone. Ex vivo synthesis of both steroid hormones was qualitatively similarly affected by prochloraz. Immunohistochemistry of fetal testes showed increased expression of 17 alpha-hydroxylase/17,20-lyase (P450c17) and a reduction in 17 beta-hydroxysteroid dehydrogenase (type 10) expression, whereas no changes in expression of genes involved in testicular steroidogenesis were observed. Increased expression of P450c17 mRNA was observed in fetal male adrenals, and the androgen-regulated genes ornithine decarboxylase, prostatic binding protein C3 as well as insulin-like growth factor I mRNA were reduced in ventral prostates PND 16. These results indicate that reduced activity of P450c17 may be a primary cause of the disrupted fetal steroidogenesis and that an altered androgen metabolism may play a role as well. In vitro studies on human adrenocortical carcinoma cells supported the findings in vivo as reduced testosterone and increased progesterone levels were observed. Overall, these results together indicate that prochloraz acts directly on the fetal testis to inhibit steroidogenesis and that this effect is exhibited at protein, and not at genomic, level. (c) 2005 Elsevier Inc. All rights reserved.
Original languageEnglish
JournalToxicology and Applied Pharmacology
Volume213
Issue number2
Pages (from-to)160-171
ISSN0041-008X
DOIs
Publication statusPublished - 2006

Cite this

Laier, Peter ; Metzdorff, Stine Broeng ; Boberg, Julie ; Hagen, Marie ; Hass, Ulla ; Christiansen, Sofie ; Petersen, Marta Axelstad ; Kledal, Thuri ; Dalgaard, Majken ; McKinnell, C. ; Brokken, L. J. S. ; Vinggaard, Anne. / Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz. In: Toxicology and Applied Pharmacology. 2006 ; Vol. 213, No. 2. pp. 160-171.
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abstract = "The fungicide prochloraz has got multiple mechanisms of action that may influence the demasculinizing and reproductive toxic effects of the compound. In the present study, Wistar rats were dosed perinatally with prochloraz (50 and 150 mg/kg/day) from gestational day (GD) 7 to postnatal day (PND) 16. Caesarian sections were performed on selected dams at GD 21, while others were allowed to give birth to pups that were followed until PND 16. Prochloraz caused mild dysgenesis of the male external genitalia as well as reduced anogenital distance and retention of nipples in male pups. An increased anogenital distance indicated virilization of female pups. Effects on steroidogenesis in male fetuses became evident as decreased testicular and plasma levels of testosterone and increased levels of progesterone. Ex vivo synthesis of both steroid hormones was qualitatively similarly affected by prochloraz. Immunohistochemistry of fetal testes showed increased expression of 17 alpha-hydroxylase/17,20-lyase (P450c17) and a reduction in 17 beta-hydroxysteroid dehydrogenase (type 10) expression, whereas no changes in expression of genes involved in testicular steroidogenesis were observed. Increased expression of P450c17 mRNA was observed in fetal male adrenals, and the androgen-regulated genes ornithine decarboxylase, prostatic binding protein C3 as well as insulin-like growth factor I mRNA were reduced in ventral prostates PND 16. These results indicate that reduced activity of P450c17 may be a primary cause of the disrupted fetal steroidogenesis and that an altered androgen metabolism may play a role as well. In vitro studies on human adrenocortical carcinoma cells supported the findings in vivo as reduced testosterone and increased progesterone levels were observed. Overall, these results together indicate that prochloraz acts directly on the fetal testis to inhibit steroidogenesis and that this effect is exhibited at protein, and not at genomic, level. (c) 2005 Elsevier Inc. All rights reserved.",
author = "Peter Laier and Metzdorff, {Stine Broeng} and Julie Boberg and Marie Hagen and Ulla Hass and Sofie Christiansen and Petersen, {Marta Axelstad} and Thuri Kledal and Majken Dalgaard and C. McKinnell and Brokken, {L. J. S.} and Anne Vinggaard",
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Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz. / Laier, Peter; Metzdorff, Stine Broeng; Boberg, Julie; Hagen, Marie; Hass, Ulla; Christiansen, Sofie; Petersen, Marta Axelstad; Kledal, Thuri; Dalgaard, Majken; McKinnell, C.; Brokken, L. J. S.; Vinggaard, Anne.

In: Toxicology and Applied Pharmacology, Vol. 213, No. 2, 2006, p. 160-171.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz

AU - Laier, Peter

AU - Metzdorff, Stine Broeng

AU - Boberg, Julie

AU - Hagen, Marie

AU - Hass, Ulla

AU - Christiansen, Sofie

AU - Petersen, Marta Axelstad

AU - Kledal, Thuri

AU - Dalgaard, Majken

AU - McKinnell, C.

AU - Brokken, L. J. S.

AU - Vinggaard, Anne

PY - 2006

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N2 - The fungicide prochloraz has got multiple mechanisms of action that may influence the demasculinizing and reproductive toxic effects of the compound. In the present study, Wistar rats were dosed perinatally with prochloraz (50 and 150 mg/kg/day) from gestational day (GD) 7 to postnatal day (PND) 16. Caesarian sections were performed on selected dams at GD 21, while others were allowed to give birth to pups that were followed until PND 16. Prochloraz caused mild dysgenesis of the male external genitalia as well as reduced anogenital distance and retention of nipples in male pups. An increased anogenital distance indicated virilization of female pups. Effects on steroidogenesis in male fetuses became evident as decreased testicular and plasma levels of testosterone and increased levels of progesterone. Ex vivo synthesis of both steroid hormones was qualitatively similarly affected by prochloraz. Immunohistochemistry of fetal testes showed increased expression of 17 alpha-hydroxylase/17,20-lyase (P450c17) and a reduction in 17 beta-hydroxysteroid dehydrogenase (type 10) expression, whereas no changes in expression of genes involved in testicular steroidogenesis were observed. Increased expression of P450c17 mRNA was observed in fetal male adrenals, and the androgen-regulated genes ornithine decarboxylase, prostatic binding protein C3 as well as insulin-like growth factor I mRNA were reduced in ventral prostates PND 16. These results indicate that reduced activity of P450c17 may be a primary cause of the disrupted fetal steroidogenesis and that an altered androgen metabolism may play a role as well. In vitro studies on human adrenocortical carcinoma cells supported the findings in vivo as reduced testosterone and increased progesterone levels were observed. Overall, these results together indicate that prochloraz acts directly on the fetal testis to inhibit steroidogenesis and that this effect is exhibited at protein, and not at genomic, level. (c) 2005 Elsevier Inc. All rights reserved.

AB - The fungicide prochloraz has got multiple mechanisms of action that may influence the demasculinizing and reproductive toxic effects of the compound. In the present study, Wistar rats were dosed perinatally with prochloraz (50 and 150 mg/kg/day) from gestational day (GD) 7 to postnatal day (PND) 16. Caesarian sections were performed on selected dams at GD 21, while others were allowed to give birth to pups that were followed until PND 16. Prochloraz caused mild dysgenesis of the male external genitalia as well as reduced anogenital distance and retention of nipples in male pups. An increased anogenital distance indicated virilization of female pups. Effects on steroidogenesis in male fetuses became evident as decreased testicular and plasma levels of testosterone and increased levels of progesterone. Ex vivo synthesis of both steroid hormones was qualitatively similarly affected by prochloraz. Immunohistochemistry of fetal testes showed increased expression of 17 alpha-hydroxylase/17,20-lyase (P450c17) and a reduction in 17 beta-hydroxysteroid dehydrogenase (type 10) expression, whereas no changes in expression of genes involved in testicular steroidogenesis were observed. Increased expression of P450c17 mRNA was observed in fetal male adrenals, and the androgen-regulated genes ornithine decarboxylase, prostatic binding protein C3 as well as insulin-like growth factor I mRNA were reduced in ventral prostates PND 16. These results indicate that reduced activity of P450c17 may be a primary cause of the disrupted fetal steroidogenesis and that an altered androgen metabolism may play a role as well. In vitro studies on human adrenocortical carcinoma cells supported the findings in vivo as reduced testosterone and increased progesterone levels were observed. Overall, these results together indicate that prochloraz acts directly on the fetal testis to inhibit steroidogenesis and that this effect is exhibited at protein, and not at genomic, level. (c) 2005 Elsevier Inc. All rights reserved.

U2 - 10.1016/j.taap.2005.10.013

DO - 10.1016/j.taap.2005.10.013

M3 - Journal article

VL - 213

SP - 160

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JO - Toxicology and Applied Pharmacology

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SN - 0041-008X

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