Butyl benzyl phthalate as a key component of phthalate ester in relation to cognitive impairment in NHANES elderly individuals and experimental mice
Butyl benzyl phthalate as a key component of phthalate ester in relation to cognitive impairment in NHANES elderly individuals and experimental mice
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DOI：
10.1007/s11356-023-25729-8
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发表时间：
2023-02
影响因子：
5.8
通讯作者：
Yongquan Yu;Yucheng Wang;Yuejie Dong;Shuge Shu;Di Zhang;Jiayi Xu;Ying Zhang;W. Shi;Shou-Lin Wang
中科院分区：
文献类型：
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作者：
Yongquan Yu;Yucheng Wang;Yuejie Dong;Shuge Shu;Di Zhang;Jiayi Xu;Ying Zhang;W. Shi;Shou-Lin Wang
邻苯二甲酸酯是一组具有认知干扰潜力的神经毒物。鉴于邻苯二甲酸酯的结构多样性，相应的神经毒性会发生显著变化。为了确定不同邻苯二甲酸酯对认知障碍过程的潜在贡献，使用了NHANES 2011-2014周期的836名老年人的数据。应用调查加权逻辑回归和主成分分析加权分位数和回归（PCA-WQSR）模型估计11种尿邻苯二甲酸酯代谢物与认知缺陷（通过4项测试评估：即刻回忆（IR）、延迟回忆（DR）、动物流畅性（AF）和数字符号替代测试（DSST））的独立和组合关联，并识别具有高权重的潜在邻苯二甲酸酯。进一步使用实验小鼠来检查邻苯二甲酸酯对认知功能的影响并探索潜在的机制。在logistic回归模型中，MBzP是唯一与四项检验呈正相关的代谢物，IR、DR、AF和DSST的OR分别为2.53（四分位数3（Q3））、2.26（Q3）、2.89（Q4）和2.45（Q2）、2.82（Q4）。在PCA-WQSR联合暴露模型中，低分子量（LMW）邻苯二甲酸酯是唯一与DSST缺陷呈正相关的PC（OR：1.93），这在WQSR分析中得到了进一步验证（WQS OR 7-邻苯二甲酸酯：1.56和WQS OR 8-邻苯二甲酸酯：1.55）;与逻辑回归结果一致，MBzP是主要的邻苯二甲酸酯。在小鼠中，邻苯二甲酸丁基苄酯（BBP），MBzP的母体邻苯二甲酸酯，剂量依赖性地降低认知功能和破坏海马神经元。此外，海马转录组分析确定了431个差异表达基因，其中大多数参与抑制神经活性配体-受体相互作用途径和激活精氨酸-细胞因子受体相互作用途径。我们的研究表明BBP在邻苯二甲酸酯和老年人认知障碍的相关性中起着关键作用，这可能是推测BBP可以破坏海马神经元，激活神经炎症，并抑制神经活性受体。我们的发现为BBP的认知破坏潜力提供了新的见解。
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.