Research

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

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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.