Tri-n-butyl phosphate inhibits neurogenesis and motor functions during embryonic development in zebrafish

Abstract

Tri-n-butyl phosphate (TBP), an organophosphate ester (OPE), is heavily used as a solvent in synthetic resins, inks, and adhesives and as an antifoaming agent in detergents and emulsion products. Further, it is used as a flame retardant and plasticizer in the fabric and electronics industry. Further, TBP is used to extract uranium, plutonium, and thorium. Thus, widespread uses of TBP in industrialized countries led to the release of TBP and its metabolites, dibutyl phosphate (DBP) and monobutyl phosphate (MBP), in the environment, including air, soil, and water, and get detected in human samples. Accumulating these OPEs over time in humans and other animals may develop toxicological effects. The reports also say OPEs contaminants pass through the mother-fetal transmission route and may affect embryonic development. However, the impact of TBP and its metabolites on vertebrate development has been poorly studied. Ex-Utero development, short generation time, high fecundity, optical transparency, and genetic and physiological similarity to humans make the zebrafish a preferred model for studying vertebrate development, organogenesis, small molecule screening, toxicological evaluation, etc. Thus, we aim to explore the toxic effects of TBP, DBP, and MBP on vertebrate organogenesis and overall embryonic development using zebrafish as a model organism. Our study found that TBP inhibits neural growth resulting in decreased spontaneous movements frequency at 22 and 28 hpf without altering the somite and overall embryonic growth in lower doses. In contrast, in lower concentrations, DBP-treated embryos showed normal neuronal and embryonic development and increased spontaneous movement frequency at 22 and 28 hpf. Further, we found that in higher concentrations, TBP is teratogenic, DBP is lethal to the embryos, and MBP did not show detectable toxic effects in the developing embryos. Altogether, we found that TBP inhibits neurogenesis, and its metabolite DBP is neuroexcitatory during embryonic development. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/564317v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1855d5corg.highwire.dtl.DTLVardef@b470eeorg.highwire.dtl.DTLVardef@623b78org.highwire.dtl.DTLVardef@12e6e8f_HPS_FORMAT_FIGEXP M_FIG C_FIG