Flame Retardant TDCIPP Reduces Heart Rate Variability Through Potential Direct Inhibition of Choline...

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used halogen-containing organophosphate flame retardant with potential neurotoxicity, but its effects on cardiac autonomic function remain largely unexplored. This study investigated TDCIPP's impact on heart rate variability (HRV) and the underlying molecular mechanisms. Young adult male rats were treated with TDCIPP (0, 13.3, 40, 120, or 360 mg/kg/day) by gavage for 114 days. TDCIPP exposure significantly reduced multiple HRV parameters including SDRR (by 58%-62%, p < 0.005), CVRR (by 57%-64%, p < 0.01), RMSSD (by 55%-63%, p < 0.05), and SD₂ (by 59%-65%, p < 0.01) across all dose groups, indicating impaired cardiac autonomic function with a possible threshold-like pattern instead of a typical dose-dependent response. Further analyses revealed that TDCIPP decreased choline acetyltransferase (ChAT) activity (by 28%-53%, p < 0.001) and mRNA expression (by 22%-48%, p < 0.05 to p < 0.001) dose-dependently without affecting protein levels, while acetylcholinesterase (AChE) activity remained unchanged. Acetylcholine levels were significantly reduced in the 40 and 360 mg/kg/day groups (by 31% and 42%, respectively, p < 0.05). Molecular docking analysis demonstrated that TDCIPP binds to the choline binding site of ChAT, forming a hydrogen bond with His334, the same residue critical for choline binding. This suggests TDCIPP impairs cardiac autonomic function by disrupting cholinergic neurotransmission through putative competitive inhibition of ChAT activity. This novel mechanism differs from that of chlorpyrifos and provides new insights into how environmental flame retardants may impact cardiovascular health.