Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity

Jill A. Madden, Patricia B Hoyer, Patrick J. Devine, Aileen F. Keating

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The finite ovarian follicle reserve can be negatively impacted by exposure to chemicals including the anti-neoplastic agent, cyclophosphamide (CPA). CPA requires bioactivation to phosphoramide mustard (PM) to elicit its therapeutic effects however; in addition to being the tumor-targeting metabolite, PM is also ovotoxic. In addition, PM can break down to a cytotoxic, volatile metabolite, chloroethylaziridine (CEZ). The aim of this study was initially to characterize PM-induced ovotoxicity in growing follicles. Using PND4 Fisher 344 rats, ovaries were cultured for 4. days before being exposed once to PM (10 or 30. μM). Following eight additional days in culture, relative to control (1% DMSO), PM had no impact on primordial, small primary or large primary follicle number, but both PM concentrations induced secondary follicle depletion (P<. 0.05). Interestingly, a reduction in follicle number in the control-treated ovaries was observed. Thus, the involvement of a volatile, cytotoxic PM metabolite (VC) in PM-induced ovotoxicity was explored in cultured rat ovaries, with control ovaries physically separated from PM-treated ovaries during culture. Direct PM (60. μM) exposure destroyed all stage follicles after 4. days (P<. 0.05). VC from nearby wells depleted primordial follicles after 4. days (P<. 0.05), temporarily reduced secondary follicle number after 2. days, and did not impact other stage follicles at any other time point. VC was determined to spontaneously liberate from PM, which could contribute to degradation of PM during storage. Taken together, this study demonstrates that PM and VC are ovotoxicants, with different follicular targets, and that the VC may be a major player during PM-induced ovotoxicity observed in cancer survivors.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalToxicology and Applied Pharmacology
Volume277
Issue number1
DOIs
StatePublished - May 15 2014

Fingerprint

Metabolites
Ovary
phosphoramide mustard
Cyclophosphamide
Rats
Ovarian Follicle
Therapeutic Uses
Dimethyl Sulfoxide
Tumors
Neoplasms

Keywords

  • Chloroethylaziridine
  • Ovotoxicity
  • Phosphoramide mustard

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity. / Madden, Jill A.; Hoyer, Patricia B; Devine, Patrick J.; Keating, Aileen F.

In: Toxicology and Applied Pharmacology, Vol. 277, No. 1, 15.05.2014, p. 1-7.

Research output: Contribution to journalArticle

Madden, Jill A. ; Hoyer, Patricia B ; Devine, Patrick J. ; Keating, Aileen F. / Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity. In: Toxicology and Applied Pharmacology. 2014 ; Vol. 277, No. 1. pp. 1-7.
@article{66a134df6a7b4090801e9cf77c894057,
title = "Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity",
abstract = "The finite ovarian follicle reserve can be negatively impacted by exposure to chemicals including the anti-neoplastic agent, cyclophosphamide (CPA). CPA requires bioactivation to phosphoramide mustard (PM) to elicit its therapeutic effects however; in addition to being the tumor-targeting metabolite, PM is also ovotoxic. In addition, PM can break down to a cytotoxic, volatile metabolite, chloroethylaziridine (CEZ). The aim of this study was initially to characterize PM-induced ovotoxicity in growing follicles. Using PND4 Fisher 344 rats, ovaries were cultured for 4. days before being exposed once to PM (10 or 30. μM). Following eight additional days in culture, relative to control (1{\%} DMSO), PM had no impact on primordial, small primary or large primary follicle number, but both PM concentrations induced secondary follicle depletion (P<. 0.05). Interestingly, a reduction in follicle number in the control-treated ovaries was observed. Thus, the involvement of a volatile, cytotoxic PM metabolite (VC) in PM-induced ovotoxicity was explored in cultured rat ovaries, with control ovaries physically separated from PM-treated ovaries during culture. Direct PM (60. μM) exposure destroyed all stage follicles after 4. days (P<. 0.05). VC from nearby wells depleted primordial follicles after 4. days (P<. 0.05), temporarily reduced secondary follicle number after 2. days, and did not impact other stage follicles at any other time point. VC was determined to spontaneously liberate from PM, which could contribute to degradation of PM during storage. Taken together, this study demonstrates that PM and VC are ovotoxicants, with different follicular targets, and that the VC may be a major player during PM-induced ovotoxicity observed in cancer survivors.",
keywords = "Chloroethylaziridine, Ovotoxicity, Phosphoramide mustard",
author = "Madden, {Jill A.} and Hoyer, {Patricia B} and Devine, {Patrick J.} and Keating, {Aileen F.}",
year = "2014",
month = "5",
day = "15",
doi = "10.1016/j.taap.2014.03.006",
language = "English (US)",
volume = "277",
pages = "1--7",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity

AU - Madden, Jill A.

AU - Hoyer, Patricia B

AU - Devine, Patrick J.

AU - Keating, Aileen F.

PY - 2014/5/15

Y1 - 2014/5/15

N2 - The finite ovarian follicle reserve can be negatively impacted by exposure to chemicals including the anti-neoplastic agent, cyclophosphamide (CPA). CPA requires bioactivation to phosphoramide mustard (PM) to elicit its therapeutic effects however; in addition to being the tumor-targeting metabolite, PM is also ovotoxic. In addition, PM can break down to a cytotoxic, volatile metabolite, chloroethylaziridine (CEZ). The aim of this study was initially to characterize PM-induced ovotoxicity in growing follicles. Using PND4 Fisher 344 rats, ovaries were cultured for 4. days before being exposed once to PM (10 or 30. μM). Following eight additional days in culture, relative to control (1% DMSO), PM had no impact on primordial, small primary or large primary follicle number, but both PM concentrations induced secondary follicle depletion (P<. 0.05). Interestingly, a reduction in follicle number in the control-treated ovaries was observed. Thus, the involvement of a volatile, cytotoxic PM metabolite (VC) in PM-induced ovotoxicity was explored in cultured rat ovaries, with control ovaries physically separated from PM-treated ovaries during culture. Direct PM (60. μM) exposure destroyed all stage follicles after 4. days (P<. 0.05). VC from nearby wells depleted primordial follicles after 4. days (P<. 0.05), temporarily reduced secondary follicle number after 2. days, and did not impact other stage follicles at any other time point. VC was determined to spontaneously liberate from PM, which could contribute to degradation of PM during storage. Taken together, this study demonstrates that PM and VC are ovotoxicants, with different follicular targets, and that the VC may be a major player during PM-induced ovotoxicity observed in cancer survivors.

AB - The finite ovarian follicle reserve can be negatively impacted by exposure to chemicals including the anti-neoplastic agent, cyclophosphamide (CPA). CPA requires bioactivation to phosphoramide mustard (PM) to elicit its therapeutic effects however; in addition to being the tumor-targeting metabolite, PM is also ovotoxic. In addition, PM can break down to a cytotoxic, volatile metabolite, chloroethylaziridine (CEZ). The aim of this study was initially to characterize PM-induced ovotoxicity in growing follicles. Using PND4 Fisher 344 rats, ovaries were cultured for 4. days before being exposed once to PM (10 or 30. μM). Following eight additional days in culture, relative to control (1% DMSO), PM had no impact on primordial, small primary or large primary follicle number, but both PM concentrations induced secondary follicle depletion (P<. 0.05). Interestingly, a reduction in follicle number in the control-treated ovaries was observed. Thus, the involvement of a volatile, cytotoxic PM metabolite (VC) in PM-induced ovotoxicity was explored in cultured rat ovaries, with control ovaries physically separated from PM-treated ovaries during culture. Direct PM (60. μM) exposure destroyed all stage follicles after 4. days (P<. 0.05). VC from nearby wells depleted primordial follicles after 4. days (P<. 0.05), temporarily reduced secondary follicle number after 2. days, and did not impact other stage follicles at any other time point. VC was determined to spontaneously liberate from PM, which could contribute to degradation of PM during storage. Taken together, this study demonstrates that PM and VC are ovotoxicants, with different follicular targets, and that the VC may be a major player during PM-induced ovotoxicity observed in cancer survivors.

KW - Chloroethylaziridine

KW - Ovotoxicity

KW - Phosphoramide mustard

UR - http://www.scopus.com/inward/record.url?scp=84897945864&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897945864&partnerID=8YFLogxK

U2 - 10.1016/j.taap.2014.03.006

DO - 10.1016/j.taap.2014.03.006

M3 - Article

C2 - 24642057

AN - SCOPUS:84897945864

VL - 277

SP - 1

EP - 7

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

IS - 1

ER -