title: High-throughput characterization of chemical-associated embryonic behavioral changes predicts teratogenic outcomes.
abstract: New strategies are needed to address the data gap between the bioactivity of chemicals in the environment versus existing hazard information. We address whether a high-throughput screening (HTS) system using a vertebrate organism (embryonic zebrafish) can characterize chemical-elicited behavioral responses at an early, 24 hours post-fertilization (hpf) stage that predict teratogenic consequences at a later developmental stage. The system was used to generate full concentration-response behavioral profiles at 24 hpf across 1060 ToxCast™ chemicals. Detailed, morphological evaluation of all individuals was performed as experimental follow-up at 5 days post-fertilization (dpf). Chemicals eliciting behavioral responses were also mapped against external HTS in vitro results to identify specific molecular targets and neurosignalling pathways. We found that, as an integrative measure of normal development, significant alterations in movement highlighted active chemicals representing several modes of action. These early behavioral responses were predictive for 17 specific developmental abnormalities and mortality measured at 5 dpf, often at lower (i.e., more potent) concentrations than those at which morphological effects were observed. Therefore, this system can provide rapid characterization of chemical-elicited behavioral responses at an early developmental stage that are predictive of observable adverse effects later in life.
authors.affiliation: Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
authors.forename: David M
authors.identifier: http://orcid.org/0000-0001-7815-6767
authors.initials: DM
authors.lastname: Reif
authors.affiliation: Sinnhuber Aquatic Research Laboratory, Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, 28645 East Highway 34, Corvallis, OR, 97333, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Truong
authors.affiliation: Sinnhuber Aquatic Research Laboratory, Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, 28645 East Highway 34, Corvallis, OR, 97333, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mandrell
authors.affiliation: Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
authors.forename: Skylar
authors.initials: S
authors.lastname: Marvel
authors.affiliation: Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
authors.forename: Guozhu
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Sinnhuber Aquatic Research Laboratory, Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, 28645 East Highway 34, Corvallis, OR, 97333, USA. robert.tanguay@oregonstate.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Tanguay
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000002:abnormalities* / Q000187:drug effects* / Q000503:physiopathology; D015386:Hazardous Substances / Q000633:toxicity*; D057166:High-Throughput Screening Assays; D011237:Predictive Value of Tests; D013723:Teratogens / Q000633:toxicity*; D015027:Zebrafish / Q000002:abnormalities / Q000196:embryology*
chemical_list: D015386:Hazardous Substances; D013723:Teratogens
keywords: Alternative testing; Behavior; Bioactivity; Bioinformatics; Chemical biology; Data integration; Developmental neurotoxicology; High-throughput screening; ToxCast; Zebrafish