Challenges and solution approaches for an improved assessment of reproductive toxicity ‐ species differences and in silica predictions

Abstract

Within toxicology, reproductive toxicology is a highly relevant and socially particularly sensitive field. It encompasses all toxicological processes within the reproductive cycle and therefore includes many effects and modes of action. This makes the assessment of reproductive toxicity very challenging despite the established in vivo studies. In addition, the in vivo studies are very demanding both in terms of their conduct and interpretation, and there is scope for decision‐making on both aspects. As a result, the interpretation of study results may vary from laboratory to laboratory. For the final classification, the assessment of relevance for men is decisive. The problem here is that relatively little is known about the species differences between men and the usual test animals (rat and rabbit). The rabbit in particular has hardly been researched in molecular biology. The aim of the dissertation was to develop approaches for a better assessment of reproductive toxicity, with two different foci:The first aim was to investigate species differences, focusing on the expression of xenobiotic transporters during ontogeny. Xenobiotic transporters, of the superfamily of ATP‐binding cassette transporters (ABC) or solute carriers (SLC), are known to transport exogenous substances in addition to their endogenous substrates and therefore play an important role in the absorption, distribution and excretion of xenobiotics. Species differences in kinetics can in turn have a major impact on toxic effects. In the study, the expression of 20 xenobiotic transporters during ontogeny was investigated at the mRNA level in the liver, kidney and placenta of rats and rabbits and compared with that of men. This revealed major differences in the expression of the transporters between the species. However, further studies on the functionality and activity of the xenobiotic transporters are needed to fully assess the kinetic impact of the observed species differences. Overall, the study provides a valid starting point for further systematic investigations of species differences at the protein level. Furthermore, it provides previously unavailable data on the expression of xenobiotic transporters during ontogeny in rabbits, which is an important step in the molecular biological study of this species. The second part focused on investigating the predictive power of in silico models for reproductive toxicology in relation to pesticides. Both the commercial and the freely available models did not perform adequately in the evaluation. Three reasons could be identified for this: 1. many pesticides are outside the chemical space of the models, 2. different definition/assessment of reproductive toxicity and 3. problems in detecting similarity between molecules. To solve these problems, an extension of the databases on reproductive toxicity in relation to pesticides, respecting a uniform nomenclature, is needed. Furthermore, endpoint‐specific models should be developed which, in addition to the usual structure‐based fingerprints, use descriptors for, for example, biological activity. Overall, the dissertation shows how essential it is to further research the modes of action of reproductive toxicity. This knowledge is necessary to correctly assess in vivo studies and their relevance to men, as well as to improve the predictive power of in silico models by incorporating this information.