Molecular interactions of paraben family of pollutants with embryonic neuronal proteins of Danio rerio: A step ahead in computational toxicity towards adverse outcome pathway

Abstract

The paraben family of endocrine disruptors exhibit persistent behaviours in aquatic matrices, having bio-accumulative effects and necessitating toxicity analysis and safe use, as well as prevention of food web penetration. In this study, the toxicity effects of 9 different parabens (Methyl, Ethyl, Propyl, Butyl, Heptyl, Isopropyl, Isobutyl, benzyl parabens and p-hydroxybenzoic acid) were studied against 17 neuronal proteins (Neurog1, Ascl1a, DLA, Syn2a, Ntn1a, Pitx2, and SoxB1, Her/Hes, Zic family) expressed during the early embryonic developmental stage of Danio rerio. The neuronal genes were selected as a biomarker to study the inhibitory effects on the cascade of genes expressed in the early developmental stage. The study uses trRossetta software to predict protein structures of neuronal genes, followed by structural refinement, energy minimisation, and active site prediction, evaluated using energy value, RC plot and ERRAT scores of PROCHECK and ERRAT programs. Compared to raw structures, highly confident predicted structures and quality scores were observed for refined protein with few exceptions. Based on the polarity and charge of the aminoacids, the probable pockets were identified using active site prediction, which were then used for molecular docking analysis. Further, the ADMET analysis, ligand likeliness and toxicological test revealed the paraben family of compounds as one of the most susceptible toxic and mutagenic compounds. The molecular docking results showed an interesting pattern of increasing binding affinity with increase in the carbon chains of paraben molecules. Benzyl Paraben showed higher binding affinities across all 17 neuronal proteins. Finally, gene co-occurrence/co-expression and protein-protein interaction studies using the STRING database depict that all proteins are functionally related and play essential roles in standard biological processes or pathways, conserved and expressed in diverse organisms. The interaction between paraben compounds and neuronal genes indicates high risks of inhibiting reactions in embryonic stages, emphasising the need for effective treatment measures and strict regulations.