The development of the male reproductive system strongly depends on androgens produced by the fetal testes, and hence the fetus is a target for compounds capable of interfering with the synthesis of these hormones or by antagonizing the androgen receptor.
Our strategy combines androgen-related activity of pesticides on human cells with physiologically-based kinetic modeling. Here, in vitro data pinpoints to compounds with a potential in vivo activity by identifying their critical internal exposure, while the kinetic model simulates the maternal doses necessary to reach critical levels in the fetus. We have developed a proof of principle showing that adverse effects on anogenital distance in male offspring, which is a unique and non-invasive marker for male reproductive health effects in animals and humans, can be predicted for selected pesticides.
We investigated this strategy on 9 pesticides and selected 3 compounds – fludioxonil, cyprodinil and dimethomorph – for in vivo ‘validation’ of the alternative approach in rats. Predicted fetal levels were within a factor of 2 from measured concentrations, and all three compounds showed a shorthened AGD in vivo.
In conclusion, our approach can be used to avoid unnecessary animal testing and focus on compounds that most likely will produce in vivo activity.