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Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries

Early ovary development is considered to be largely hormone independent; yet, there are associations between fetal exposure to endocrine disrupting chemicals and reproductive disorders in women. This can potentially be explained by perturbations to establishment of ovarian endocrine function rather...

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Autores principales: Johansson, Hanna Katarina Lilith, Taxvig, Camilla, Olsen, Gustav Peder Mohr, Svingen, Terje
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285011/
https://www.ncbi.nlm.nih.gov/pubmed/33905526
http://dx.doi.org/10.1093/toxsci/kfab048
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author Johansson, Hanna Katarina Lilith
Taxvig, Camilla
Olsen, Gustav Peder Mohr
Svingen, Terje
author_facet Johansson, Hanna Katarina Lilith
Taxvig, Camilla
Olsen, Gustav Peder Mohr
Svingen, Terje
author_sort Johansson, Hanna Katarina Lilith
collection PubMed
description Early ovary development is considered to be largely hormone independent; yet, there are associations between fetal exposure to endocrine disrupting chemicals and reproductive disorders in women. This can potentially be explained by perturbations to establishment of ovarian endocrine function rather than interference with an already established hormone system. In this study we explore if Hedgehog (HH) signaling, a central pathway for correct ovary development, can be disrupted by exposure to HH-disrupting chemicals, using the antifungal itraconazole as model compound. In the mouse Leydig cell line TM3, used as a proxy for ovarian theca cells, itraconazole exposure had a suppressing effect on genes downstream of HH signaling, such as Gli1. Exposing explanted rat ovaries (gestational day 22 or postnatal day 3) to 30 µM itraconazole for 72 h induced significant suppression of genes in the HH signaling pathway with altered Ihh, Gli1, Ptch1, and Smo expression similar to those previously observed in Ihh/Dhh knock-out mice. Exposing rat dams to 50 mg/kg bw/day in the perinatal period did not induce observable changes in the offspring’s ovaries. Overall, our results suggest that HH signal disruptors may affect ovary development with potential long-term consequences for female reproductive health. However, potent HH inhibitors would likely cause severe teratogenic effects at doses lower than those causing ovarian dysgenesis, so the concern with respect to reproductive disorder is for the presence of HH disruptors at low concentration in combination with other ovary or endocrine disrupting compounds.
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spelling pubmed-82850112021-07-19 Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries Johansson, Hanna Katarina Lilith Taxvig, Camilla Olsen, Gustav Peder Mohr Svingen, Terje Toxicol Sci Developmental and Reproductive Toxicology Early ovary development is considered to be largely hormone independent; yet, there are associations between fetal exposure to endocrine disrupting chemicals and reproductive disorders in women. This can potentially be explained by perturbations to establishment of ovarian endocrine function rather than interference with an already established hormone system. In this study we explore if Hedgehog (HH) signaling, a central pathway for correct ovary development, can be disrupted by exposure to HH-disrupting chemicals, using the antifungal itraconazole as model compound. In the mouse Leydig cell line TM3, used as a proxy for ovarian theca cells, itraconazole exposure had a suppressing effect on genes downstream of HH signaling, such as Gli1. Exposing explanted rat ovaries (gestational day 22 or postnatal day 3) to 30 µM itraconazole for 72 h induced significant suppression of genes in the HH signaling pathway with altered Ihh, Gli1, Ptch1, and Smo expression similar to those previously observed in Ihh/Dhh knock-out mice. Exposing rat dams to 50 mg/kg bw/day in the perinatal period did not induce observable changes in the offspring’s ovaries. Overall, our results suggest that HH signal disruptors may affect ovary development with potential long-term consequences for female reproductive health. However, potent HH inhibitors would likely cause severe teratogenic effects at doses lower than those causing ovarian dysgenesis, so the concern with respect to reproductive disorder is for the presence of HH disruptors at low concentration in combination with other ovary or endocrine disrupting compounds. Oxford University Press 2021-04-27 /pmc/articles/PMC8285011/ /pubmed/33905526 http://dx.doi.org/10.1093/toxsci/kfab048 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Developmental and Reproductive Toxicology
Johansson, Hanna Katarina Lilith
Taxvig, Camilla
Olsen, Gustav Peder Mohr
Svingen, Terje
Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries
title Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries
title_full Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries
title_fullStr Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries
title_full_unstemmed Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries
title_short Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries
title_sort effects of the hedgehog signaling inhibitor itraconazole on developing rat ovaries
topic Developmental and Reproductive Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285011/
https://www.ncbi.nlm.nih.gov/pubmed/33905526
http://dx.doi.org/10.1093/toxsci/kfab048
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