Mechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis

Steroid production in Leydig cells is stimulated mainly by the pituitary luteinizing hormone, which leads to increased expression of genes involved in steroidogenesis, including the gene encoding the steroidogenic acute regulatory (STAR) protein. Mono(2-ethylhexyl)phthalate (MEHP), the active metabo...

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Autores principales:	Annick N. Enangue Njembele, Jacques J. Tremblay
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	testis Leydig cells steroidogenesis Star environmental toxicology endocrine disrupters Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/2187ad38e49b4bdb939333e252134841
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spelling	oai:doaj.org-article:2187ad38e49b4bdb939333e2521348412021-11-11T16:55:08ZMechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis10.3390/ijms2221114561422-00671661-6596https://doaj.org/article/2187ad38e49b4bdb939333e2521348412021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11456https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Steroid production in Leydig cells is stimulated mainly by the pituitary luteinizing hormone, which leads to increased expression of genes involved in steroidogenesis, including the gene encoding the steroidogenic acute regulatory (STAR) protein. Mono(2-ethylhexyl)phthalate (MEHP), the active metabolite of the widely used plasticizer DEHP, is known to disrupt Leydig steroidogenesis but its mechanisms of action remain poorly understood. We found that MEHP caused a significant reduction in hormone-induced steroid hormone production in two Leydig cell lines, MA-10 and MLTC-1. Consistent with disrupted cholesterol transport, we found that MEHP represses cAMP-induced <i>Star</i> promoter activity. MEHP responsiveness was mapped to the proximal <i>Star</i> promoter, which contains multiple binding sites for several transcription factors. In addition to STAR, we found that MEHP also reduced the levels of ferredoxin reductase, a protein essential for electron transport during steroidogenesis. Finally, we tested new plasticizers as alternatives to phthalates. Two plasticizers, dioctyl succinate and 1,6-hexanediol dibenzoate, had no significant effect on hormone-induced steroidogenesis. Our current findings reveal that MEHP represses steroidogenesis by affecting cholesterol transport and its conversion into pregnenolone. We also found that two novel molecules with desirable plasticizer properties have no impact on Leydig cell steroidogenesis and could be suitable phthalate replacements.Annick N. Enangue NjembeleJacques J. TremblayMDPI AGarticletestisLeydig cellssteroidogenesisStarenvironmental toxicologyendocrine disruptersBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11456, p 11456 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	testis Leydig cells steroidogenesis Star environmental toxicology endocrine disrupters Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	testis Leydig cells steroidogenesis Star environmental toxicology endocrine disrupters Biology (General) QH301-705.5 Chemistry QD1-999 Annick N. Enangue Njembele Jacques J. Tremblay Mechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis
description	Steroid production in Leydig cells is stimulated mainly by the pituitary luteinizing hormone, which leads to increased expression of genes involved in steroidogenesis, including the gene encoding the steroidogenic acute regulatory (STAR) protein. Mono(2-ethylhexyl)phthalate (MEHP), the active metabolite of the widely used plasticizer DEHP, is known to disrupt Leydig steroidogenesis but its mechanisms of action remain poorly understood. We found that MEHP caused a significant reduction in hormone-induced steroid hormone production in two Leydig cell lines, MA-10 and MLTC-1. Consistent with disrupted cholesterol transport, we found that MEHP represses cAMP-induced <i>Star</i> promoter activity. MEHP responsiveness was mapped to the proximal <i>Star</i> promoter, which contains multiple binding sites for several transcription factors. In addition to STAR, we found that MEHP also reduced the levels of ferredoxin reductase, a protein essential for electron transport during steroidogenesis. Finally, we tested new plasticizers as alternatives to phthalates. Two plasticizers, dioctyl succinate and 1,6-hexanediol dibenzoate, had no significant effect on hormone-induced steroidogenesis. Our current findings reveal that MEHP represses steroidogenesis by affecting cholesterol transport and its conversion into pregnenolone. We also found that two novel molecules with desirable plasticizer properties have no impact on Leydig cell steroidogenesis and could be suitable phthalate replacements.
format	article
author	Annick N. Enangue Njembele Jacques J. Tremblay
author_facet	Annick N. Enangue Njembele Jacques J. Tremblay
author_sort	Annick N. Enangue Njembele
title	Mechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis
title_short	Mechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis
title_full	Mechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis
title_fullStr	Mechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis
title_full_unstemmed	Mechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis
title_sort	mechanisms of mehp inhibitory action and analysis of potential replacement plasticizers on leydig cell steroidogenesis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2187ad38e49b4bdb939333e252134841
work_keys_str_mv	AT annicknenanguenjembele mechanismsofmehpinhibitoryactionandanalysisofpotentialreplacementplasticizersonleydigcellsteroidogenesis AT jacquesjtremblay mechanismsofmehpinhibitoryactionandanalysisofpotentialreplacementplasticizersonleydigcellsteroidogenesis
_version_	1718432164288135168

Mechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis

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