Microplastic derived benzyl butyl phthalate disrupts JAK signalling in mouse hippocamps: a molecular dynamics and transcriptome based study

Janus kinases (JAKs) represent the non-receptor tyrosine kinase family responsible for the regulation of several biological events like neuronal homeostasis and cytokine signalling. Neuroinflammation and other neurological disorders have been known to result from the dysregulation of JAKs. In this study molecular docking and dynamics simulations have been used to evaluate the interactions between benzyl butyl phthalate (BBP) and JAK1, JAK2, JAK3. Ruxolitinib and tofacitinib, FDA approved JAKs inhibitors, were used as reference ligand. Binding stabilities were further assessed using Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations of binding free energy (ΔG). BBP consistently bound to JAK1, JAK2, and JAK3 through van der Waal and hydrophobic forces, whereas ruxolitinib bound to JAK1, JAK2, and JAK3 with stronger electrostatic contacts and a higher binding selectivity for JAK2. The computed binding free energies were found to be −21.08 kJ/moL for JAK1, −15.57 kJ/moL for JAK2, and −21.89 kJ/moL for JAK3 in the case of BBP, indicating favorable binding interactions. In comparison, the binding free energies of ruxolitinib were found to be −18.33 kJ/moL with JAK1 and −17.69 kJ/moL with JAK2, while tofacitinib was found to exhibit a binding free energy of −11.36 kJ/moL with JAK3. Publicly accessible RNA-seq data (SRA project PRJNA884659) from mouse hippocampus tissue treated with 50 mg/kg/day BBP were used to identified transcriptome changes. BBP exposure predominantly modulates JAKs-associated transcriptional changes through altered alternative splicing and the production of novel isoforms, according to transcriptomic profiling. Together, these results show that BBP has potency to interact with JAKs isoforms at atomistic level leading to modulation of transcriptomic profile. This study offers mechanistic understanding of the neurotoxic consequences of BBP.