title: Application of a mathematical model to describe the effects of chlorpyrifos on Caenorhabditis elegans development.
abstract: BACKGROUND
  The nematode Caenorhabditis elegans is being assessed as an alternative model organism as part of an interagency effort to develop better means to test potentially toxic substances. As part of this effort, assays that use the COPAS Biosort flow sorting technology to record optical measurements (time of flight (TOF) and extinction (EXT)) of individual nematodes under various chemical exposure conditions are being developed. A mathematical model has been created that uses Biosort data to quantitatively and qualitatively describe C. elegans growth, and link changes in growth rates to biological events. Chlorpyrifos, an organophosphate pesticide known to cause developmental delays and malformations in mammals, was used as a model toxicant to test the applicability of the growth model for in vivo toxicological testing.
  
  
  RESULTS
  L1 larval nematodes were exposed to a range of sub-lethal chlorpyrifos concentrations (0-75 microM) and measured every 12 h. In the absence of toxicant, C. elegans matured from L1s to gravid adults by 60 h. A mathematical model was used to estimate nematode size distributions at various times. Mathematical modeling of the distributions allowed the number of measured nematodes and log(EXT) and log(TOF) growth rates to be estimated. The model revealed three distinct growth phases. The points at which estimated growth rates changed (change points) were constant across the ten chlorpyrifos concentrations. Concentration response curves with respect to several model-estimated quantities (numbers of measured nematodes, mean log(TOF) and log(EXT), growth rates, and time to reach change points) showed a significant decrease in C. elegans growth with increasing chlorpyrifos concentration.
  
  
  CONCLUSIONS
  Effects of chlorpyrifos on C. elegans growth and development were mathematically modeled. Statistical tests confirmed a significant concentration effect on several model endpoints. This confirmed that chlorpyrifos affects C. elegans development in a concentration dependent manner. The most noticeable effect on growth occurred during early larval stages: L2 and L3. This study supports the utility of the C. elegans growth assay and mathematical modeling in determining the effects of potentially toxic substances in an alternative model organism using high-throughput technologies.
authors.affiliation: Biomoleclular Screening Branch, National Toxicology Program, Research Triangle Park, North Carolina, USA.
authors.forename: Windy A
authors.initials: WA
authors.lastname: Boyd
authors.forename: Marjolein V
authors.initials: MV
authors.lastname: Smith
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kissling
authors.forename: Julie R
authors.initials: JR
authors.lastname: Rice
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Snyder
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Portier
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Freedman
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects*; D004390:Chlorpyrifos / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007306:Insecticides / Q000494:pharmacology* / Q000633:toxicity; D008390:Markov Chains; D015233:Models, Statistical; D008962:Models, Theoretical; D012044:Regression Analysis; D013997:Time Factors
chemical_list: D007306:Insecticides; D004390:Chlorpyrifos