title: More than just hormones: H295R cells as predictors of reproductive toxicity.
abstract: Many of the commonly observed reproductive toxicities associated with therapeutic compounds can be traced to a disruption of the steroidogenic pathway. We sought to develop an in vitro assay that would predict reproductive toxicity and be high throughput in nature. H295R cells, previously validated as having an intact and functional steroidogenic pathway, were treated with 83 known-positive and 79 known-negative proprietary and public-domain compounds. The assay measured the expression of the key enzymes STAR, 3βHSD2, CYP17A1, CYP11B2, CYP19A1, CYP21A2, and CYP11A1 and the hormones DHEA, progesterone, testosterone, and cortisol. We found that a Random Forest model yielded a receiver operating characteristic area under the curve (ROC AUC) of 0.845, with sensitivity of 0.724 and specificity of 0.758 for predicting in vivo reproductive toxicity with this in vitro assay system.
authors.affiliation: Compound Safety Prediction, Pfizer Global Research and Development, Pfizer Inc., Cambridge, MA 02420, United States.
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Maglich
authors.affiliation: Non-Clinical Statistics, Pfizer Global Research Development, Pfizer Inc., Groton, CT 06340, United States.
authors.forename: Max
authors.initials: M
authors.lastname: Kuhn
authors.affiliation: Developmental and Reproductive Toxicology Center of Expertise, Pfizer Global Research and Development, Pfizer Inc., Groton, CT 06340, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Chapin
authors.affiliation: Rare Diseases Research Unit, Pfizer Global Research Development, Pfizer Inc., Cambridge, MA 02420, United States. Electronic address: Mathew.Pletcher@pfizer.com.
authors.forename: Mathew T
authors.initials: MT
authors.lastname: Pletcher
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D045744:Cell Line, Tumor; D005576:Colforsin / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007093:Imidazoles / Q000633:toxicity; D008954:Models, Biological; D015233:Models, Statistical; D010750:Phosphoproteins / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D007093:Imidazoles; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D005576:Colforsin; D013739:Testosterone; D003687:Dehydroepiandrosterone; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; C045362:prochloraz; D015096:3-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone
keywords: H295R; Predictive screening; Reproductive toxicology; Steroidogenesis