title: A high throughput screening system for predicting chemically-induced reproductive organ deformities.
abstract: There is a great need for alternative testing methods for reproductive toxicants that are practical, fast, cost-effective and easy to interpret. Previously we followed a pragmatic approach using readily available tests, which was successful in predicting reproductive toxicity of chemicals [13]. This initial battery still contained apical tests and is fairly complex and low in its throughput. The current study aimed to simplify this screening battery using a mechanistic approach and a panel of high throughput CALUX reporter gene assays. A mechanistic approach was taken to validate this high throughput test battery. To this end it was challenged with two preselected sets of chemicals addressing two major apical effect classes relevant in reproductive toxicity. We found selectivity in this battery in that 82% of the compounds inducing reproductive organ deformities were predicted correctly, while for compounds inducing neural tube defects this was the case in 47% only. This is consistent with the mechanisms of toxicity covered in the battery. The most informative assays in the battery were ERalpha CALUX to measure estrogenicity and the AR-anti CALUX assay to measure androgen receptor antagonism.
authors.affiliation: BioDetection Systems BV, Amsterdam, The Netherlands. Electronic address: bart.van.der.burg@bds.nl.
authors.forename: Bart
authors.initials: B
authors.lastname: van der Burg
authors.affiliation: BioDetection Systems BV, Amsterdam, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Pieterse
authors.affiliation: TNO, Zeist, The Netherlands.
authors.forename: Harrie
authors.initials: H
authors.lastname: Buist
authors.affiliation: Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
authors.forename: Geertje
authors.initials: G
authors.lastname: Lewin
authors.affiliation: BioDetection Systems BV, Amsterdam, The Netherlands.
authors.forename: Sander C
authors.initials: SC
authors.lastname: van der Linden
authors.affiliation: BioDetection Systems BV, Amsterdam, The Netherlands.
authors.forename: Hai-yen
authors.initials: HY
authors.lastname: Man
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Emiel
authors.initials: E
authors.lastname: Rorije
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
authors.affiliation: Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
authors.forename: Inge
authors.initials: I
authors.lastname: Mangelsdorf
authors.affiliation: TNO, Zeist, The Netherlands.
authors.forename: Andre P M
authors.initials: AP
authors.lastname: Wolterbeek
authors.affiliation: TNO, Zeist, The Netherlands.
authors.forename: E Dinant
authors.initials: ED
authors.lastname: Kroese
authors.affiliation: BioDetection Systems BV, Amsterdam, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: van Vugt-Lussenburg
mesh_terms: D059002:Androgen Receptor Antagonists / Q000633:toxicity; D002460:Cell Line; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000633:toxicity; D005835:Genitalia / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D009436:Neural Tube Defects / Q000139:chemically induced; D011944:Receptors, Androgen / Q000378:metabolism; D013723:Teratogens / Q000633:toxicity*
chemical_list: D059002:Androgen Receptor Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011944:Receptors, Androgen; D013723:Teratogens
keywords: Estrogen–androgen reporter gene assay; High throughput screening; Mechanistic validation; Reproductive organ deformities