Teratological and Behavioral Screening of the National Toxicology Program 91-Compound Library in Zebrafish (Danio rerio)

Abstract

To screen the tens of thousands of chemicals for which no toxicity data currently exists, it is necessary to move from in vivo rodent models to alternative models, such as zebrafish. Here, we used dechorionated Tropical 5D wild-type zebrafish embryos to screen a 91-compound library provided by the National Toxicology Program (NTP) for developmental toxicity. This library contained 86 unique chemicals that included negative controls, flame retardants, polycyclic aromatic hydrocarbons (PAHs), drugs, industrial chemicals, and pesticides. Fish were exposed to 5 concentrations of each chemical or an equal amount of vehicle (0.5% DMSO) in embryo medium from 6 h post-fertilization (hpf) to 5 days post-fertilization (dpf). Fish were examined daily for mortality and teratogenic effects and photomotor behavior was assessed at 4 and 5 dpf. Of the 5 negative control compounds in the library, none caused mortality/teratogenesis, but two altered behavior. Chemicals provided in duplicate produced similar outcomes. Overall, 13 compounds caused mortality/teratology but not behavioral abnormalities, 24 only affected behavior, and 18 altered both endpoints, with behavior affected at concentrations that did not cause mortality/teratology (55/86 hits). Of the compounds that affected behavior, 52% caused behavioral abnormalities at either 4 or 5 dpf. Compounds within the same functional group caused different behavioral abnormalities, while similar behavioral patterns were caused by compounds from different groups. Our data suggest that behavior is a sensitive endpoint for developmental toxicity screening that integrates multiple modes of toxic action and is influenced by the age of the larval fish at the time of testing.

Absence of neurotoxicity and lack of neurobehavioral consequences due to exposure to tetrabromobisphenol A (TBBPA) exposure in humans, animals and zebrafish

“…Godfrey et al (2017) found no significant alterations in locomotor activity in zebrafish larva exposed to 13 µL TBBPA. Similarly, an absence of behavioral changes in zebrafish embryos or larvae exposed to TBBPA was reported by several other investigators (Noyes et al 2015;Dach et al 2019;Jarema et al 2015;Truong et al 2014). In contrast, Chen et al (2016) found that zebrafish embryos exposure to 5 µM TBBPA altered larval behavior as evidenced by diminished activity bursts, lower speed of movement, motor deficits, delayed cranial motor neuron development, and inhibited primary motor neuron development.…”

A non-hallucinogenic psychedelic analogue with therapeutic potential

“…Finally, we compared the morphological effects of ibogaine, IBG, and TBG using a well-established zebrafish developmental toxicity assay. 24 Ibogaine (100 μM) significantly increased malformations and mortality at 2 and 5 days post-fertilization (dpf), respectively ( Fig. 2d – e ).…”

Multigenerational consequences of early-life cannabinoid exposure in zebrafish

“…In this study, we use zebrafish, a well-established model for assessing teratology and developmental neurotoxicity (Dach et al, 2018;Hagstrom et al, 2018;Noyes et al, 2015, Levin andCerutti 2009). Embryos/larvae were exposed to 0.024, 0.12, 0.6 mg/L (0.08, 0.4, 2 μM) THC, 0.006, 0.03, 0.15 mg/L (0.02, 0.1, 0.5 μM) CBD, or 0.05% DMSO control.…”