Gong Wei, Zhu Hongyan, Sun Xinran, Zhang Jinxiu, Lin Meiyun, Sun Peng
Public Health School, Ningxia Medical University, 750004, Yinchuan, China; Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, 750004, Yinchuan, China; School of Medical Information and Engineering, Ningxia Medical University, 750004, Yinchuan, China.
School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China.
Chem Biol Interact. 2025 Jul 11;420:111651. doi: 10.1016/j.cbi.2025.111651.
Phthalates are widely recognized endocrine-disrupting chemicals. This study investigates the association between phthalate exposure and cardiovascular disease (CVD), with a particular focus on elucidating the underlying molecular mechanisms. First, an epidemiological analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES) spanning 2005-2018 to assess the relationship between phthalate metabolites and CVD. Generalized linear models (GLM) and weighted quantile sum (WQS) regression were employed to evaluate the impact of phthalate exposure. Among 12,127 participants, 1301 were diagnosed with CVD. The results showed a significant positive association between phthalate mixtures and CVD prevalence. GLM analysis identified MECPP, MEHHP, MEOHP, and MBzP as independent predictors of CVD (P < 0.05). WQS regression further demonstrated that the phthalate metabolite mixture exposure index was associated with CVD (OR = 1.21, 95 % CI: 1.07-1.37, P = 0.002), highlighting MEOHP, MECPP, MBzP, and MnBP as key contributors. Subgroup analysis revealed that these associations were strongest among individuals aged ≥60 years, females, and during the 2013-2014 NHANES cycle. To further explore the potential molecular mechanisms, we conducted a network toxicology analysis. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape 3.9.1 to identify key molecular targets associated with phthalate-induced CVD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that phthalate-induced CVD is linked to neuroactive ligand-receptor interactions, GABAergic synapses, the PI3K-Akt and JAK-STAT signaling pathways, and calcium signaling. Among 29 identified CVD-related targets, seven core targets (GABRA3, GABRG2, GABRA5, GABRA2, BCL2, CCND2, and PIK3CA) were strongly implicated in phthalate-induced cardiovascular toxicity. Molecular docking analysis further confirmed strong binding affinities between phthalate metabolites and key targets, particularly GABRA5, PIK3CA, and BCL2. This study provided robust evidence linking phthalate exposure to CVD and suggests that phthalate-induced cardiovascular toxicity may involve neuroactive signaling, apoptosis, and inflammation-related mechanisms. These findings offered valuable insights for future research and potential therapeutic strategies in environmental health and CVD prevention.
邻苯二甲酸盐是广泛认可的内分泌干扰化学物质。本研究调查了邻苯二甲酸盐暴露与心血管疾病（CVD）之间的关联，尤其着重于阐明其潜在的分子机制。首先，利用2005 - 2018年国家健康与营养检查调查（NHANES）的数据进行了一项流行病学分析，以评估邻苯二甲酸酯代谢物与CVD之间的关系。采用广义线性模型（GLM）和加权分位数和（WQS）回归来评估邻苯二甲酸盐暴露的影响。在12127名参与者中，有1301人被诊断患有CVD。结果显示邻苯二甲酸酯混合物与CVD患病率之间存在显著正相关。GLM分析确定MECPP、MEHHP、MEOHP和MBzP为CVD的独立预测因子（P < 0.05）。WQS回归进一步表明邻苯二甲酸酯代谢物混合物暴露指数与CVD相关（OR = 1.21，95% CI：1.07 - 1.37，P = 0.002），突出了MEOHP、MECPP、MBzP和MnBP为关键贡献因素。亚组分析显示，这些关联在年龄≥60岁的个体、女性以及2013 - 2014年NHANES周期中最为明显。为了进一步探索潜在的分子机制，我们进行了网络毒理学分析。使用STRING和Cytoscape 3.9.1构建了蛋白质 - 蛋白质相互作用（PPI）网络，以识别与邻苯二甲酸盐诱导的CVD相关的关键分子靶点。基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析表明，邻苯二甲酸盐诱导的CVD与神经活性配体 - 受体相互作用、GABA能突触、PI3K - Akt和JAK - STAT信号通路以及钙信号传导有关。在鉴定出的29个与CVD相关的靶点中，七个核心靶点（GABRA3、GABRG2、GABRA5、GABRA2、BCL2、CCND2和PIK3CA）与邻苯二甲酸盐诱导的心血管毒性密切相关。分子对接分析进一步证实了邻苯二甲酸酯代谢物与关键靶点之间具有很强的结合亲和力，特别是GABRA5、PI3KCA和BCL2。本研究提供了有力证据，将邻苯二甲酸盐暴露与CVD联系起来，并表明邻苯二甲酸盐诱导的心血管毒性可能涉及神经活性信号传导、细胞凋亡和炎症相关机制。这些发现为环境健康和CVD预防的未来研究及潜在治疗策略提供了有价值的见解。
