Comparison of prostate gene expression and tissue weight changes as monitors of antiandrogen activity in GNRH-inhibited rats

Christine Lydia Nellemann, P. A. Lefevre, J. Ashby

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

BACKGROUND: The Hershberger assay for antiandrogens and modifiers of steroid biosynthesis uses surgically-castrated rats. We described an adaptation of the assay using the GnRH inhibitor Antarelix in place of surgical castration [Ashby J, Lefevre PA, Deghenghi R, Wallis N. Regulatory Toxicology and Pharmacology 34:188-203, 2001], and concomitantly described changes in expression of the androgen-dependent prostatic genes PBP C3, TRPM-2, and ODC as a possible complement to gravimetric analysis of the sex accessory tissues (SAT) [Nellemann C, Vinggaard AM, Dalgaard M, Hossaini A, Larsen J-J. Toxicology 163:29-38, 2001]. METHODS: The present study describes the results of combining these two modifications into a single assay. During the course of these experiments it was shown that SD rats gave similar results to AP rats and that the higher stimulatory dose of testosterone propionate (TP) used in our experiments gave stronger assay responses to FLU than the lower dose of TP used by some earlier investigators. The potent antiandrogen flutamide (FLU) and the weak antiandrogen DDE were used to evaluate this modified assay. RESULTS: For all parameters studied (SAT weights and changes in expression of the 3 prostatic genes) FLU gave the expected positive results. The weak antiandrogen DDE gave variable and mainly non-reproducible responses. Use of DDE as a weak antiandrogen accelerated assessment of the new assay. CONCLUSIONS: Possible reasons for this failure to detect DDE are discussed, and it is concluded that the modified assay is unsuitable for use in its present form. The use of gene expression analyses together with evaluation of SAT weights is a promising tool as an early and sensitive marker of antiandrogen action, but more work is needed on the choice of time frame as well as the selection of genes to monitor.
Original languageEnglish
JournalBirth Defects Research. Part B: Developmental and Reproductive Toxicology
Volume68
Issue number4
Pages (from-to)344-354
ISSN1542-9733
DOIs
Publication statusPublished - 2003

Keywords

  • PBPC3
  • flutamide
  • antiandrogen
  • prostate genes
  • TRPM-2
  • DDE
  • GnRH
  • prostate weight
  • Hershberger assay
  • ODC

Cite this

@article{df9563076d4e4efaa654b69675f58b6c,
title = "Comparison of prostate gene expression and tissue weight changes as monitors of antiandrogen activity in GNRH-inhibited rats",
abstract = "BACKGROUND: The Hershberger assay for antiandrogens and modifiers of steroid biosynthesis uses surgically-castrated rats. We described an adaptation of the assay using the GnRH inhibitor Antarelix in place of surgical castration [Ashby J, Lefevre PA, Deghenghi R, Wallis N. Regulatory Toxicology and Pharmacology 34:188-203, 2001], and concomitantly described changes in expression of the androgen-dependent prostatic genes PBP C3, TRPM-2, and ODC as a possible complement to gravimetric analysis of the sex accessory tissues (SAT) [Nellemann C, Vinggaard AM, Dalgaard M, Hossaini A, Larsen J-J. Toxicology 163:29-38, 2001]. METHODS: The present study describes the results of combining these two modifications into a single assay. During the course of these experiments it was shown that SD rats gave similar results to AP rats and that the higher stimulatory dose of testosterone propionate (TP) used in our experiments gave stronger assay responses to FLU than the lower dose of TP used by some earlier investigators. The potent antiandrogen flutamide (FLU) and the weak antiandrogen DDE were used to evaluate this modified assay. RESULTS: For all parameters studied (SAT weights and changes in expression of the 3 prostatic genes) FLU gave the expected positive results. The weak antiandrogen DDE gave variable and mainly non-reproducible responses. Use of DDE as a weak antiandrogen accelerated assessment of the new assay. CONCLUSIONS: Possible reasons for this failure to detect DDE are discussed, and it is concluded that the modified assay is unsuitable for use in its present form. The use of gene expression analyses together with evaluation of SAT weights is a promising tool as an early and sensitive marker of antiandrogen action, but more work is needed on the choice of time frame as well as the selection of genes to monitor.",
keywords = "PBPC3, flutamide, antiandrogen, prostate genes, TRPM-2, DDE, GnRH, prostate weight, Hershberger assay, ODC",
author = "Nellemann, {Christine Lydia} and Lefevre, {P. A.} and J. Ashby",
year = "2003",
doi = "10.1002/bdrb.10030",
language = "English",
volume = "68",
pages = "344--354",
journal = "Birth Defects Research",
issn = "0040-3709",
publisher = "John Wiley & Sons Ltd",
number = "4",

}

Comparison of prostate gene expression and tissue weight changes as monitors of antiandrogen activity in GNRH-inhibited rats. / Nellemann, Christine Lydia; Lefevre, P. A.; Ashby, J.

In: Birth Defects Research. Part B: Developmental and Reproductive Toxicology, Vol. 68, No. 4, 2003, p. 344-354.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Comparison of prostate gene expression and tissue weight changes as monitors of antiandrogen activity in GNRH-inhibited rats

AU - Nellemann, Christine Lydia

AU - Lefevre, P. A.

AU - Ashby, J.

PY - 2003

Y1 - 2003

N2 - BACKGROUND: The Hershberger assay for antiandrogens and modifiers of steroid biosynthesis uses surgically-castrated rats. We described an adaptation of the assay using the GnRH inhibitor Antarelix in place of surgical castration [Ashby J, Lefevre PA, Deghenghi R, Wallis N. Regulatory Toxicology and Pharmacology 34:188-203, 2001], and concomitantly described changes in expression of the androgen-dependent prostatic genes PBP C3, TRPM-2, and ODC as a possible complement to gravimetric analysis of the sex accessory tissues (SAT) [Nellemann C, Vinggaard AM, Dalgaard M, Hossaini A, Larsen J-J. Toxicology 163:29-38, 2001]. METHODS: The present study describes the results of combining these two modifications into a single assay. During the course of these experiments it was shown that SD rats gave similar results to AP rats and that the higher stimulatory dose of testosterone propionate (TP) used in our experiments gave stronger assay responses to FLU than the lower dose of TP used by some earlier investigators. The potent antiandrogen flutamide (FLU) and the weak antiandrogen DDE were used to evaluate this modified assay. RESULTS: For all parameters studied (SAT weights and changes in expression of the 3 prostatic genes) FLU gave the expected positive results. The weak antiandrogen DDE gave variable and mainly non-reproducible responses. Use of DDE as a weak antiandrogen accelerated assessment of the new assay. CONCLUSIONS: Possible reasons for this failure to detect DDE are discussed, and it is concluded that the modified assay is unsuitable for use in its present form. The use of gene expression analyses together with evaluation of SAT weights is a promising tool as an early and sensitive marker of antiandrogen action, but more work is needed on the choice of time frame as well as the selection of genes to monitor.

AB - BACKGROUND: The Hershberger assay for antiandrogens and modifiers of steroid biosynthesis uses surgically-castrated rats. We described an adaptation of the assay using the GnRH inhibitor Antarelix in place of surgical castration [Ashby J, Lefevre PA, Deghenghi R, Wallis N. Regulatory Toxicology and Pharmacology 34:188-203, 2001], and concomitantly described changes in expression of the androgen-dependent prostatic genes PBP C3, TRPM-2, and ODC as a possible complement to gravimetric analysis of the sex accessory tissues (SAT) [Nellemann C, Vinggaard AM, Dalgaard M, Hossaini A, Larsen J-J. Toxicology 163:29-38, 2001]. METHODS: The present study describes the results of combining these two modifications into a single assay. During the course of these experiments it was shown that SD rats gave similar results to AP rats and that the higher stimulatory dose of testosterone propionate (TP) used in our experiments gave stronger assay responses to FLU than the lower dose of TP used by some earlier investigators. The potent antiandrogen flutamide (FLU) and the weak antiandrogen DDE were used to evaluate this modified assay. RESULTS: For all parameters studied (SAT weights and changes in expression of the 3 prostatic genes) FLU gave the expected positive results. The weak antiandrogen DDE gave variable and mainly non-reproducible responses. Use of DDE as a weak antiandrogen accelerated assessment of the new assay. CONCLUSIONS: Possible reasons for this failure to detect DDE are discussed, and it is concluded that the modified assay is unsuitable for use in its present form. The use of gene expression analyses together with evaluation of SAT weights is a promising tool as an early and sensitive marker of antiandrogen action, but more work is needed on the choice of time frame as well as the selection of genes to monitor.

KW - PBPC3

KW - flutamide

KW - antiandrogen

KW - prostate genes

KW - TRPM-2

KW - DDE

KW - GnRH

KW - prostate weight

KW - Hershberger assay

KW - ODC

U2 - 10.1002/bdrb.10030

DO - 10.1002/bdrb.10030

M3 - Journal article

VL - 68

SP - 344

EP - 354

JO - Birth Defects Research

JF - Birth Defects Research

SN - 0040-3709

IS - 4

ER -