Butyl benzyl phthalate as a key component of phthalate ester in relation to cognitive impairment in NHANES elderly individuals and experimental mice

Phthalates are a group of neurotoxicants with cognitive-disrupting potentials. Given the structural diversity of phthalates, the corresponding neurotoxicity is dramatically altered. To identify the potential contributions of different phthalates on the process of cognitive impairment, data of 836 elders from the NHANES 2011-2014 cycles were used. Survey-weighted logistic regression and principal component analysis-weighted quantile sum regression (PCA-WQSR) models were applied to estimate the independent and combined associations of 11 urinary phthalate metabolites with cognitive deficit [assessed by 4 tests: Immediate Recall (IR), Delayed Recall (DR), Animal Fluency (AF), and Digit Symbol Substitution test (DSST] and to identify the potential phthalate with high weight. Laboratory mice were further used to examine the effect of phthalates on cognitive function and to explore the potential mechanisms. In logistic regression models, MBzP was the only metabolite positively correlated with four tests, with ORs of 2.53 [quartile 3 (Q3)], 2.26 (Q3), 2.89 (Q4) and 2.45 (Q2), 2.82 (Q4) for IR, DR, AF and DSST respectively. In PCA-WQSR co-exposure models, low-molecular-weight (LMW) phthalates were the only PC positively linked to DSST deficit (OR: 1.93), which was further validated in WQSR analysis (WQS OR7-phthalates: 1.56 and WQS OR8-phthalates: 1.55); consistent with the results of logistic regression, MBzP was the dominant phthalate. In mice, butyl benzyl phthalate (BBP), the parent phthalate of MBzP, dose-dependently reduced cognitive function and disrupted hippocampal neurons. Additionally, the hippocampal transcriptome analysis identified 431 differential expression genes, among which most were involved in inhibiting the neuroactive ligand‒receptor interaction pathway and activating the cytokine‒cytokine receptor interaction pathway. Our study indicates the critical role of BBP in the association of phthalates and cognitive deficits among elderly individuals, which might be speculated that BBP could disrupt hippocampal neurons, activate neuroinflammation and inhibit neuroactive receptors. Our findings provide new insight into the cognitive-disrupting potential of BBP.