Distinct transcriptional profiles of the female, male and finasteride-induced feminized male anogenital region in rat fetuses

Camilla Victoria Lindgren Schwartz, Anne Marie Vinggaard, Sofie Christiansen, Thomas Alain Darde, Frederic Chalmel, Terje Svingen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

A short anogenital distance (AGD) in males is a marker for incomplete masculinization and a predictor of adverse effects on male reproductive health. For this reason, AGD is used to assess the endocrine disrupting potential of chemicals for risk assessment purposes. The molecular mechanisms underpinning this chemically induced shortening of the AGD, however, remains unclear. Although it is clear that AR-mediated signaling is essential, evidence also suggest the involvement of other signaling pathways. This study presents the first global transcriptional profile of the anogenital tissue in male rat fetuses with chemically induced short AGD, also including comparison to normal male and female control animals. The anti-androgenic drug finasteride (10mg/kg bw/day) was used to induce short AGD by exposing time-mated Sprague Dawley rats at gestation days (GD) 7-21. The AGD was 37% shorter in exposed male fetuses compared to control males at GD21. Transcriptomics analysis on anogenital tissues revealed a sexually dimorphic transcriptional profile. More than 350 genes were found to be differentially expressed between the three groups. The expression pattern of four genes of particular interest (Esr1, Padi2, Wnt2 and Sfrp4) was also tested by RT-qPCR analyses, indicating that estrogen and Wnt2 signaling play a role in the sexually dimorphic development of the anogenital region. Our transcriptomics profiles provide a stepping-stone for future studies aimed at characterizing the molecular events governing development of the anogenital tissues, as well as describing the detailed Adverse Outcome Pathways for short AGD; an accepted biomarker of endocrine effects for chemical risk assessment.
Original languageEnglish
JournalToxicological Sciences
Volume169
Issue number1
Pages (from-to)303-311
ISSN1096-6080
DOIs
Publication statusPublished - 2019

Keywords

  • Anogenital distance
  • endocrine disruptors
  • gene array
  • reproduction
  • risk assessment
  • transcriptome

Cite this

@article{76044897ac3e412187340bb17ab59bd0,
title = "Distinct transcriptional profiles of the female, male and finasteride-induced feminized male anogenital region in rat fetuses",
abstract = "A short anogenital distance (AGD) in males is a marker for incomplete masculinization and a predictor of adverse effects on male reproductive health. For this reason, AGD is used to assess the endocrine disrupting potential of chemicals for risk assessment purposes. The molecular mechanisms underpinning this chemically induced shortening of the AGD, however, remains unclear. Although it is clear that AR-mediated signaling is essential, evidence also suggest the involvement of other signaling pathways. This study presents the first global transcriptional profile of the anogenital tissue in male rat fetuses with chemically induced short AGD, also including comparison to normal male and female control animals. The anti-androgenic drug finasteride (10mg/kg bw/day) was used to induce short AGD by exposing time-mated Sprague Dawley rats at gestation days (GD) 7-21. The AGD was 37{\%} shorter in exposed male fetuses compared to control males at GD21. Transcriptomics analysis on anogenital tissues revealed a sexually dimorphic transcriptional profile. More than 350 genes were found to be differentially expressed between the three groups. The expression pattern of four genes of particular interest (Esr1, Padi2, Wnt2 and Sfrp4) was also tested by RT-qPCR analyses, indicating that estrogen and Wnt2 signaling play a role in the sexually dimorphic development of the anogenital region. Our transcriptomics profiles provide a stepping-stone for future studies aimed at characterizing the molecular events governing development of the anogenital tissues, as well as describing the detailed Adverse Outcome Pathways for short AGD; an accepted biomarker of endocrine effects for chemical risk assessment.",
keywords = "Anogenital distance, endocrine disruptors, gene array, reproduction, risk assessment, transcriptome",
author = "{Lindgren Schwartz}, {Camilla Victoria} and Vinggaard, {Anne Marie} and Sofie Christiansen and Darde, {Thomas Alain} and Frederic Chalmel and Terje Svingen",
year = "2019",
doi = "10.1093/toxsci/kfz046",
language = "English",
volume = "169",
pages = "303--311",
journal = "Toxicological Sciences",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "1",

}

Distinct transcriptional profiles of the female, male and finasteride-induced feminized male anogenital region in rat fetuses. / Lindgren Schwartz, Camilla Victoria; Vinggaard, Anne Marie; Christiansen, Sofie; Darde, Thomas Alain; Chalmel, Frederic; Svingen, Terje.

In: Toxicological Sciences, Vol. 169, No. 1, 2019, p. 303-311.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Distinct transcriptional profiles of the female, male and finasteride-induced feminized male anogenital region in rat fetuses

AU - Lindgren Schwartz, Camilla Victoria

AU - Vinggaard, Anne Marie

AU - Christiansen, Sofie

AU - Darde, Thomas Alain

AU - Chalmel, Frederic

AU - Svingen, Terje

PY - 2019

Y1 - 2019

N2 - A short anogenital distance (AGD) in males is a marker for incomplete masculinization and a predictor of adverse effects on male reproductive health. For this reason, AGD is used to assess the endocrine disrupting potential of chemicals for risk assessment purposes. The molecular mechanisms underpinning this chemically induced shortening of the AGD, however, remains unclear. Although it is clear that AR-mediated signaling is essential, evidence also suggest the involvement of other signaling pathways. This study presents the first global transcriptional profile of the anogenital tissue in male rat fetuses with chemically induced short AGD, also including comparison to normal male and female control animals. The anti-androgenic drug finasteride (10mg/kg bw/day) was used to induce short AGD by exposing time-mated Sprague Dawley rats at gestation days (GD) 7-21. The AGD was 37% shorter in exposed male fetuses compared to control males at GD21. Transcriptomics analysis on anogenital tissues revealed a sexually dimorphic transcriptional profile. More than 350 genes were found to be differentially expressed between the three groups. The expression pattern of four genes of particular interest (Esr1, Padi2, Wnt2 and Sfrp4) was also tested by RT-qPCR analyses, indicating that estrogen and Wnt2 signaling play a role in the sexually dimorphic development of the anogenital region. Our transcriptomics profiles provide a stepping-stone for future studies aimed at characterizing the molecular events governing development of the anogenital tissues, as well as describing the detailed Adverse Outcome Pathways for short AGD; an accepted biomarker of endocrine effects for chemical risk assessment.

AB - A short anogenital distance (AGD) in males is a marker for incomplete masculinization and a predictor of adverse effects on male reproductive health. For this reason, AGD is used to assess the endocrine disrupting potential of chemicals for risk assessment purposes. The molecular mechanisms underpinning this chemically induced shortening of the AGD, however, remains unclear. Although it is clear that AR-mediated signaling is essential, evidence also suggest the involvement of other signaling pathways. This study presents the first global transcriptional profile of the anogenital tissue in male rat fetuses with chemically induced short AGD, also including comparison to normal male and female control animals. The anti-androgenic drug finasteride (10mg/kg bw/day) was used to induce short AGD by exposing time-mated Sprague Dawley rats at gestation days (GD) 7-21. The AGD was 37% shorter in exposed male fetuses compared to control males at GD21. Transcriptomics analysis on anogenital tissues revealed a sexually dimorphic transcriptional profile. More than 350 genes were found to be differentially expressed between the three groups. The expression pattern of four genes of particular interest (Esr1, Padi2, Wnt2 and Sfrp4) was also tested by RT-qPCR analyses, indicating that estrogen and Wnt2 signaling play a role in the sexually dimorphic development of the anogenital region. Our transcriptomics profiles provide a stepping-stone for future studies aimed at characterizing the molecular events governing development of the anogenital tissues, as well as describing the detailed Adverse Outcome Pathways for short AGD; an accepted biomarker of endocrine effects for chemical risk assessment.

KW - Anogenital distance

KW - endocrine disruptors

KW - gene array

KW - reproduction

KW - risk assessment

KW - transcriptome

U2 - 10.1093/toxsci/kfz046

DO - 10.1093/toxsci/kfz046

M3 - Journal article

VL - 169

SP - 303

EP - 311

JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

IS - 1

ER -