Quantitative in vitro to in vivo extrapolation (IVIVE) predict adverse male reproductive health disorders caused by pesticides

Camilla Taxvig, M. Scholze, A. Kortenkamp, Julie Boberg, Terje Svingen, Karin Lauschke, Sofie Christiansen, S. Ermler, S. Strange Hermann, M. Pedersen, H. Frandsen, Anne Kruse Lykkeberg, A. M. Vinggard

Research output: Contribution to journalConference abstract in journalResearchpeer-review

Abstract

There are currently around 350 pesticides that are approved in the EU, many of which we lack knowledge concerning sensitive endocrine effects related to male reproduction. Thus, there is an urgent need to develop new testing strategies that can predict in vivo exposure levels that could result in adverse effects on male reproductive health.
The development of the male reproductive system strongly depends on androgens produced by the fetal testes. Compounds capable of interfering with the synthesis of androgens or by antagonizing the androgen receptor is therefore of great concern for the developing male fetus.
Our strategy combines androgen‑related activity of pesticides on human cells with physiologically-based kinetic (PBK) modeling. In vitro effect data on AR antagonism and androgen synthesis alert us to compounds with a potential in vivo activity by identifying their critical internal exposure, while the kinetic models simulate the maternal doses necessary to reach these critical levels in the fetus (reverse dosimetry). Using selected pesticides and male anogenital distance as an effect biomarker, we show, as proof-of-principle, that our IVIVE method can translate in vitro toxicity results to adverse in vivo exposures. From a pool of eleven analysed pesticides, six compounds – fludioxonil, cyprodinil, dimethomorph, procymidone, vinclozolin and linuron – were selected for an assessment of their in vivo kinetics and effects. Simulated exposure levels in fetal rats were within a factor of 3 from measured concentrations, and all compounds induced shorter male AGD in vivo at dose ranges as predicted by IVIVE.
In conclusion, we have obtained evidence that our IVIVE approach is viable and has huge potential as an efficient and economical in vitro safety testing method of pesticide-induced male reproductive disorders in animal and humans. Notably, the tool may have the potential in the long term to reduce unnecessary animal testing in risk assessment of chemically-induced male reproductive disorders.
Original languageEnglish
Article number#1005
JournalToxicology Letters
Volume314
Issue numberSI
Pages (from-to)S38-S38
ISSN0378-4274
Publication statusPublished - 2019
Event55th Congress of the European-Societies-of-Toxicology (EUROTOX) - Helsinki, Finland
Duration: 8 Sep 201911 Sep 2019
Conference number: 55

Conference

Conference55th Congress of the European-Societies-of-Toxicology (EUROTOX)
Number55
CountryFinland
CityHelsinki
Period08/09/201911/09/2019

Keywords

  • Male reproduction
  • Pesticides
  • PBK modelling
  • In vitro assays
  • Anogenital distance

Cite this

Taxvig, Camilla ; Scholze, M. ; Kortenkamp, A. ; Boberg, Julie ; Svingen, Terje ; Lauschke, Karin ; Christiansen, Sofie ; Ermler, S. ; Hermann, S. Strange ; Pedersen, M. ; Frandsen, H. ; Kruse Lykkeberg, Anne ; Vinggard, A. M. / Quantitative in vitro to in vivo extrapolation (IVIVE) predict adverse male reproductive health disorders caused by pesticides. In: Toxicology Letters. 2019 ; Vol. 314, No. SI. pp. S38-S38.
@article{93c7ca2b2d014126af8960a5bd2baaee,
title = "Quantitative in vitro to in vivo extrapolation (IVIVE) predict adverse male reproductive health disorders caused by pesticides",
abstract = "There are currently around 350 pesticides that are approved in the EU, many of which we lack knowledge concerning sensitive endocrine effects related to male reproduction. Thus, there is an urgent need to develop new testing strategies that can predict in vivo exposure levels that could result in adverse effects on male reproductive health.The development of the male reproductive system strongly depends on androgens produced by the fetal testes. Compounds capable of interfering with the synthesis of androgens or by antagonizing the androgen receptor is therefore of great concern for the developing male fetus.Our strategy combines androgen‑related activity of pesticides on human cells with physiologically-based kinetic (PBK) modeling. In vitro effect data on AR antagonism and androgen synthesis alert us to compounds with a potential in vivo activity by identifying their critical internal exposure, while the kinetic models simulate the maternal doses necessary to reach these critical levels in the fetus (reverse dosimetry). Using selected pesticides and male anogenital distance as an effect biomarker, we show, as proof-of-principle, that our IVIVE method can translate in vitro toxicity results to adverse in vivo exposures. From a pool of eleven analysed pesticides, six compounds – fludioxonil, cyprodinil, dimethomorph, procymidone, vinclozolin and linuron – were selected for an assessment of their in vivo kinetics and effects. Simulated exposure levels in fetal rats were within a factor of 3 from measured concentrations, and all compounds induced shorter male AGD in vivo at dose ranges as predicted by IVIVE.In conclusion, we have obtained evidence that our IVIVE approach is viable and has huge potential as an efficient and economical in vitro safety testing method of pesticide-induced male reproductive disorders in animal and humans. Notably, the tool may have the potential in the long term to reduce unnecessary animal testing in risk assessment of chemically-induced male reproductive disorders.",
keywords = "Male reproduction, Pesticides, PBK modelling, In vitro assays, Anogenital distance",
author = "Camilla Taxvig and M. Scholze and A. Kortenkamp and Julie Boberg and Terje Svingen and Karin Lauschke and Sofie Christiansen and S. Ermler and Hermann, {S. Strange} and M. Pedersen and H. Frandsen and {Kruse Lykkeberg}, Anne and Vinggard, {A. M.}",
year = "2019",
language = "English",
volume = "314",
pages = "S38--S38",
journal = "Toxicology Letters",
issn = "0378-4274",
publisher = "Elsevier",
number = "SI",

}

Quantitative in vitro to in vivo extrapolation (IVIVE) predict adverse male reproductive health disorders caused by pesticides. / Taxvig, Camilla; Scholze, M.; Kortenkamp, A.; Boberg, Julie; Svingen, Terje; Lauschke, Karin; Christiansen, Sofie; Ermler, S.; Hermann, S. Strange; Pedersen, M.; Frandsen, H.; Kruse Lykkeberg, Anne; Vinggard, A. M.

In: Toxicology Letters, Vol. 314, No. SI, #1005, 2019, p. S38-S38.

Research output: Contribution to journalConference abstract in journalResearchpeer-review

TY - ABST

T1 - Quantitative in vitro to in vivo extrapolation (IVIVE) predict adverse male reproductive health disorders caused by pesticides

AU - Taxvig, Camilla

AU - Scholze, M.

AU - Kortenkamp, A.

AU - Boberg, Julie

AU - Svingen, Terje

AU - Lauschke, Karin

AU - Christiansen, Sofie

AU - Ermler, S.

AU - Hermann, S. Strange

AU - Pedersen, M.

AU - Frandsen, H.

AU - Kruse Lykkeberg, Anne

AU - Vinggard, A. M.

PY - 2019

Y1 - 2019

N2 - There are currently around 350 pesticides that are approved in the EU, many of which we lack knowledge concerning sensitive endocrine effects related to male reproduction. Thus, there is an urgent need to develop new testing strategies that can predict in vivo exposure levels that could result in adverse effects on male reproductive health.The development of the male reproductive system strongly depends on androgens produced by the fetal testes. Compounds capable of interfering with the synthesis of androgens or by antagonizing the androgen receptor is therefore of great concern for the developing male fetus.Our strategy combines androgen‑related activity of pesticides on human cells with physiologically-based kinetic (PBK) modeling. In vitro effect data on AR antagonism and androgen synthesis alert us to compounds with a potential in vivo activity by identifying their critical internal exposure, while the kinetic models simulate the maternal doses necessary to reach these critical levels in the fetus (reverse dosimetry). Using selected pesticides and male anogenital distance as an effect biomarker, we show, as proof-of-principle, that our IVIVE method can translate in vitro toxicity results to adverse in vivo exposures. From a pool of eleven analysed pesticides, six compounds – fludioxonil, cyprodinil, dimethomorph, procymidone, vinclozolin and linuron – were selected for an assessment of their in vivo kinetics and effects. Simulated exposure levels in fetal rats were within a factor of 3 from measured concentrations, and all compounds induced shorter male AGD in vivo at dose ranges as predicted by IVIVE.In conclusion, we have obtained evidence that our IVIVE approach is viable and has huge potential as an efficient and economical in vitro safety testing method of pesticide-induced male reproductive disorders in animal and humans. Notably, the tool may have the potential in the long term to reduce unnecessary animal testing in risk assessment of chemically-induced male reproductive disorders.

AB - There are currently around 350 pesticides that are approved in the EU, many of which we lack knowledge concerning sensitive endocrine effects related to male reproduction. Thus, there is an urgent need to develop new testing strategies that can predict in vivo exposure levels that could result in adverse effects on male reproductive health.The development of the male reproductive system strongly depends on androgens produced by the fetal testes. Compounds capable of interfering with the synthesis of androgens or by antagonizing the androgen receptor is therefore of great concern for the developing male fetus.Our strategy combines androgen‑related activity of pesticides on human cells with physiologically-based kinetic (PBK) modeling. In vitro effect data on AR antagonism and androgen synthesis alert us to compounds with a potential in vivo activity by identifying their critical internal exposure, while the kinetic models simulate the maternal doses necessary to reach these critical levels in the fetus (reverse dosimetry). Using selected pesticides and male anogenital distance as an effect biomarker, we show, as proof-of-principle, that our IVIVE method can translate in vitro toxicity results to adverse in vivo exposures. From a pool of eleven analysed pesticides, six compounds – fludioxonil, cyprodinil, dimethomorph, procymidone, vinclozolin and linuron – were selected for an assessment of their in vivo kinetics and effects. Simulated exposure levels in fetal rats were within a factor of 3 from measured concentrations, and all compounds induced shorter male AGD in vivo at dose ranges as predicted by IVIVE.In conclusion, we have obtained evidence that our IVIVE approach is viable and has huge potential as an efficient and economical in vitro safety testing method of pesticide-induced male reproductive disorders in animal and humans. Notably, the tool may have the potential in the long term to reduce unnecessary animal testing in risk assessment of chemically-induced male reproductive disorders.

KW - Male reproduction

KW - Pesticides

KW - PBK modelling

KW - In vitro assays

KW - Anogenital distance

M3 - Conference abstract in journal

VL - 314

SP - S38-S38

JO - Toxicology Letters

JF - Toxicology Letters

SN - 0378-4274

IS - SI

M1 - #1005

ER -