title: The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcome.
abstract: 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 effect 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 affecting toxicological outcomes among related compounds. The difference 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 affecting the biological potency of compounds in mammals.
authors.affiliation: Syngenta Ltd., Jealott's Hill Research Station, Bracknell, Berkshire, RG42 6EY, UK.
authors.forename: Philippa H
authors.initials: PH
authors.lastname: Harlow
authors.affiliation: Syngenta Ltd., Jealott's Hill Research Station, Bracknell, Berkshire, RG42 6EY, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Perry
authors.affiliation: General Bioinformatics, Jealott's Hill Research Station, Bracknell, Berkshire, RG42 6EY, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Widdison
authors.affiliation: Syngenta, 3054 East Cornwallis Road, Research Triangle Park, NC 27709-2257, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Daniels
authors.affiliation: Syngenta, 3054 East Cornwallis Road, Research Triangle Park, NC 27709-2257, USA.
authors.forename: Eddie
authors.initials: E
authors.lastname: Bondo
authors.affiliation: Syngenta Crop Protection AG, Chemical Research, Schaffhauserstrasse 101, 4332 Stein, Switzerland.
authors.forename: Clemens
authors.initials: C
authors.lastname: Lamberth
authors.affiliation: Syngenta Ltd., Jealott's Hill Research Station, Bracknell, Berkshire, RG42 6EY, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Currie
authors.affiliation: Syngenta Ltd., Jealott's Hill Research Station, Bracknell, Berkshire, RG42 6EY, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Flemming
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D008322:Mammals / Q000254:growth & development* / Q000378:metabolism; D023421:Models, Animal; D010575:Pesticides / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
chemical_list: D029742:Caenorhabditis elegans Proteins; D010575:Pesticides; D003577:Cytochrome P-450 Enzyme System