1 Scientific RepoRts | 6:22965 | DOI: 10.1038/srep22965 www.nature.com/scientificreports the nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms infuencing toxicological outcome philippa H. Harlow 1 , simon J. perry 1 , stephanie Widdison 2 , shannon Daniels 3 , eddie Bondo 3 , Clemens Lamberth 4 , Richard A. Currie 1 & Anthony J. Flemming 1 to determine whether a C. elegans bioassay could predict mammalian developmental activity, we selected diverse compounds known and known not to elicit such activity and measured their efect on C. elegans egg viability. 89% of compounds that reduced C. elegans egg viability also had mammalian developmental activity. Conversely only 25% of compounds found not to reduce egg viability in C. elegans were also inactive in mammals. We conclude that the C. elegans egg viability assay is an accurate positive predictor, but an inaccurate negative predictor, of mammalian developmental activity. We then evaluated C. elegans as a tool to identify mechanisms afecting toxicological outcomes among related compounds. The diference in developmental activity of structurally related fungicides in C. elegans correlated with their rate of metabolism. Knockdown of the cytochrome P450s cyp-35A3 and cyp-35A4 increased the toxicity to C. elegans of the least developmentally active compounds to the level of the most developmentally active. This indicated that these P450s were involved in the greater rate of metabolism of the less toxic of these compounds. We conclude that C. elegans based approaches can predict mammalian developmental activity and can yield plausible hypotheses for factors afecting the biological potency of compounds in mammals. Ensuring the safety to humans of the chemicals they may be exposed to is of critical importance to chemical com- panies, regulatory authorities and the public. It is in the interest of chemical companies researching new active ingredients (AI) to identify adverse toxicological outcomes as soon as possible and avoid wasted investment in unsafe or unregisterable chemical products. One approach is to test new AI earlier in research programmes using the standard, guideline, mammalian toxicological tests required by regulators to determine toxicological out- comes. However, this implies a substantial increase in the number of mammals used which is undesirable for eth- ical and economic reasons. Terefore much research has investigated alternative experimental systems that have fewer of these concerns including in silico modelling 1 , cell-based systems 2 , vertebrate systems of reduced con- cern e.g. Zebrafsh 3 as well as invertebrate model systems 4,5 . Developmental toxicity, where a chemical adversely afects the biological processes of development from egg to adult, is of concern to the agrochemical industry. Developmental biology has been extensively studied in invertebrate model systems making them obvious candi- dates for the study of developmental toxicity. 1 Syngenta Ltd., Jealott’s Hill Research Station, Bracknell, Berkshire, RG42 6EY, UK. 2 General Bioinformatics, Jealott’s Hill Research Station, Bracknell, Berkshire, RG42 6EY, UK. 3 Syngenta, 3054 East Cornwallis Road, Research Triangle Park, NC 27709-2257, USA. 4 Syngenta Crop Protection AG, Chemical Research, Schafauserstrasse 101, 4332 Stein, Switzerland. Correspondence and requests for materials should be addressed to A.J.F. (email: anthony.femming@ syngenta.com) received: 11 December 2015 Accepted: 19 February 2016 Published: 18 March 2016 opeN