Developmental Exposure to Low Concentrations of Organophosphate Flame Retardants Causes Life-Long Behavioral Alterations in Zebrafish

Abstract

As the older class of brominated flame retardants (BFRs) are phased out of commercial use because of findings of neurotoxicity with developmental exposure, a newer class of flame retardants have been introduced, the organophosphate flame retardants (OPFRs). Presently, little is known about the potential for developmental neurotoxicity or the behavioral consequences of OPFR exposure. Our aim was to characterize the life-long neurobehavioral effects of 4 widely used OPFRs using the zebrafish model. Zebrafish embryos were exposed to 0.1% DMSO (vehicle control); or one of the following treatments; isopropylated phenyl phosphate (IPP) (0.01, 0.03, 0.1, 0.3 µM); butylphenyl diphenyl phosphate (BPDP) (0.003, 0.03, 0.3, 3 µM); 2-ethylhexyl diphenyl phosphate (EHDP) (0.03, 0.3, 1 µM); isodecyl diphenyl phosphate (IDDP) (0.1, 0.3, 1, 10 µM) from 0- to 5-days postfertilization. On Day 6, the larvae were tested for motility under alternating dark and light conditions. Finally, at 5-7 months of age the exposed fish and controls were tested on a battery of behavioral tests to assess emotional function, sensorimotor response, social interaction and predator evasion. These tests showed chemical-specific short-term effects of altered motility in larvae in all of the tested compounds, and long-term impairment of anxiety-related behavior in adults following IPP, BPDP, or EHDP exposures. Our results show that OPFRs may not be a safe alternative to the phased-out BFRs and may cause behavioral impacts throughout the lifespan. Further research should evaluate the risk to mammalian experimental models and humans.

The zebrafish subcortical social brain as a model for studying social behavior disorders

“…Currently, little is known about the potential developmental neurotoxicity of these chemicals. Six commonly used OPFRs showed no negative effect on shoaling behavior through embryonic exposure (Glazer et al, 2018a; Oliveri et al, 2015). A mixture of BFRs and OPFRs, FM 550 did, however, induce shoaling deficits (Bailey and Levin, 2015).…”

Detection and Prioritization of Developmentally Neurotoxic and/or Neurotoxic Compounds Using Zebrafish

“…In addition, 4 out of 10 active FR (40%) and 5 out of 14 active PAH (36%) also induced a behavioral effect at concentrations where overt toxicity was not detected so they were classified as neurotoxic. Many of these FRs have been studied before and noted to have effects on developmental toxicity and neurotoxicity in other in vitro and alternate animal systems (Behl et al, 2015(Behl et al, , 2016Jarema et al, 2015;Glazer et al, 2018;Shi et al, 2018). In our recently published work with these chemicals (Alzualde et al, 2018), 9 of the 15 FRs were assessed for systems toxicity.…”

Behavioral effects of developmental exposure to JWH-018 in wild type and disrupted in schizophrenia 1 (disc1) mutant zebrafish

“…Larvae were exposed to alternating light dark cycles of 10 min: there was an initial 10 minutes period of dark (baseline), followed by two cycles of 10 minutes of light and 10 minutes of dark. This protocol has been used elsewhere [34]. Distances travelled were recorded using Ethovision XT software (Noldus Information Technology, Wageningen, NL) and data were outputted in one-minute time-bins.…”