First Evidence on the Penetration Efficiencies of Parent Neonicotinoids and Their Metabolites across the Blood–Cerebrospinal Fluid Barrier

Abstract

The ability of exogenous compounds to cross the blood–cerebrospinal fluid barrier (BCSFB) is a crucial factor in evaluating their potential neurotoxic risks. To date, limited research has reported the presence of parent neonicotinoids (p-NEOs) and metabolite NEOs (m-NEOs) in cerebrospinal fluid (CSF), not to mention their penetration efficiencies across BCSFB. Nine p-NEOs and 5 m-NEOs were measured in 159 paired serum and CSF samples. Seven p-NEOs and 5 m-NEOs were frequently detected in serum (median of 0.030–0.295 ng/mL), while 5 p-NEOs and 5 m-NEOs were commonly found in CSF (median of 0.032–0.283 ng/mL). Notably, concentrations of imidacloprid-olefin and acetamiprid-N-desmethyl exceeded those of imidacloprid (IMI) and acetamiprid (ACE), indicating that IMI and ACE predominantly existed as metabolites. The ratios (R_CSF/serum) of NEO concentrations in CSF to those in paired serum were used to estimate penetration efficiencies across BCSFB. Their R_CSF/serum (median of 0.468–0.992) were positively correlated with log P (r = 0.673, p = 0.033) while negatively correlated with water solubility (r = −0.745, p = 0.013), highlighting lipophilicity as a principal factor influencing BCSFB penetration. Additionally, R_CSF/serum was significantly correlated with white blood cell count in CSF. This study provided a unique delineation of differential behaviors of p-NEOs and m-NEOs in crossing BCSFB, offering a novel perspective on their neurotoxic risks.