Development of an animal model for ototoxicity using 4-vinylcyclohexene

A case study

Patricia B Hoyer, I. Glenn Sipes

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

BACKGROUND: The occupational chemical 4-vinylcyclohexene (VCH) has been shown to cause destruction of small pre-antral follicles in ovaries of mice. Further, its monoepoxide metabolites, 1,2-VCH epoxide, 7,8-VCH epoxide, and the diepoxide, VCD, have been shown to cause pre-antral follicle loss in rats as well as mice. Chemicals that destroy small pre-antral follicles are of concern to women because exposure can result in premature ovarian failure (early menopause). METHODS: Studies working with these chemicals over the past decade have determined a number of aspects of the mechanism(s) of small pre-antral destruction, and a variety of questions have been answered. RESULTS: Specifically, it has been determined that the diepoxide (VCD) is the bioactive form and it directly targets the ovary in mice and rats. Mice are more susceptible to VCH than rats because they are capable of its metabolic bioactivation. Follicle destruction by VCD is selective for primordial and primary follicles. Mechanistic studies in rats have determined that VCD causes ovotoxicity by accelerating the natural process of atresia (apoptosis) and this requires repeated exposures. Pro-apoptotic signaling events in the Bcl-2 and mitogen activated protein kinase families have been shown to be selectively activated in fractions of small pre-antral follicles (targets for VCD). Finally, a whole ovarian culture system using neonatal mouse and rat ovaries has been developed to expand the potential for more in depth investigations into ovotoxicity caused by VCD. CONCLUSIONS: This article provides an overview of the questions asked and the approaches taken in studying VCH and VCD to support these conclusions.

Original languageEnglish (US)
Pages (from-to)113-125
Number of pages13
JournalBirth Defects Research Part B - Developmental and Reproductive Toxicology
Volume80
Issue number2
DOIs
StatePublished - Apr 2007

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Rats
Animals
Animal Models
Ovary
Epoxy Compounds
Primary Ovarian Insufficiency
Mitogen-Activated Protein Kinase 1
Menopause
Metabolites
4-vinylcyclohexene
Antral
Apoptosis

Keywords

  • 4-Vinylcyclohexene (VCH)
  • Animal model
  • Ovotoxicity

ASJC Scopus subject areas

  • Genetics
  • Toxicology
  • Cancer Research

Cite this

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title = "Development of an animal model for ototoxicity using 4-vinylcyclohexene: A case study",
abstract = "BACKGROUND: The occupational chemical 4-vinylcyclohexene (VCH) has been shown to cause destruction of small pre-antral follicles in ovaries of mice. Further, its monoepoxide metabolites, 1,2-VCH epoxide, 7,8-VCH epoxide, and the diepoxide, VCD, have been shown to cause pre-antral follicle loss in rats as well as mice. Chemicals that destroy small pre-antral follicles are of concern to women because exposure can result in premature ovarian failure (early menopause). METHODS: Studies working with these chemicals over the past decade have determined a number of aspects of the mechanism(s) of small pre-antral destruction, and a variety of questions have been answered. RESULTS: Specifically, it has been determined that the diepoxide (VCD) is the bioactive form and it directly targets the ovary in mice and rats. Mice are more susceptible to VCH than rats because they are capable of its metabolic bioactivation. Follicle destruction by VCD is selective for primordial and primary follicles. Mechanistic studies in rats have determined that VCD causes ovotoxicity by accelerating the natural process of atresia (apoptosis) and this requires repeated exposures. Pro-apoptotic signaling events in the Bcl-2 and mitogen activated protein kinase families have been shown to be selectively activated in fractions of small pre-antral follicles (targets for VCD). Finally, a whole ovarian culture system using neonatal mouse and rat ovaries has been developed to expand the potential for more in depth investigations into ovotoxicity caused by VCD. CONCLUSIONS: This article provides an overview of the questions asked and the approaches taken in studying VCH and VCD to support these conclusions.",
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