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  3. Mechanistic insight into plasticizer di-(2-ethylhexyl) phthalate as an environmental hazard for abdominal aortic aneurysm: Evidence from in vitro and in vivo studies

Mechanistic insight into plasticizer di-(2-ethylhexyl) phthalate as an environmental hazard for abdominal aortic aneurysm: Evidence from in vitro and in vivo studies

  • Ecotoxicol Environ Saf. 2025 Sep 1:302:118689. doi: 10.1016/j.ecoenv.2025.118689.
Yicheng Wang 1,  Miaoyun Qiu 1,  Bixuan Yue 1,  Mingliang Wang 2,  Luoxing Xia 3,  Fengfeng Li 3,  Chaobo Yang 3,  Zhigao Song 4,  Yushan Liao 5,  Wei Liu 6,  Zhi Zeng 7
Affiliations

Affiliations

  • 1 School of Public Health, Southern Medical University; Department of Cardiovascular Medicine, ZhuJiang Hospital, Southern Medical University, Guangdong, Guangzhou 510515, China.
  • 2 Department of Cardiovascular Surgery, Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences, Southern Medical University, Guangdong, Guangzhou 510810, China.
  • 3 Department of Cardiology, Laboratory of Heart Center, Heart Center, ZhuJiang Hospital, Southern Medical University, Guangdong, Guangzhou 510280, China.
  • 4 Department of Cardiovascular Surgery, ZhuJiang Hospital, Southern Medical University, Guangdong, Guangzhou 510280, China.
  • 5 Department of Cardiovascular Medicine, Hospital of NanHai Economic Development Zone, Guangdong, Foshan 528200, China. Electronic address: liaoyushan1981@163.com.
  • 6 Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, China. Electronic address: liuw327@mail.sysu.edu.cn.
  • 7 School of Public Health, Southern Medical University; Department of Cardiovascular Medicine, ZhuJiang Hospital, Southern Medical University, Guangdong, Guangzhou 510515, China; Department of Cardiology, Laboratory of Heart Center, Heart Center, ZhuJiang Hospital, Southern Medical University, Guangdong, Guangzhou 510280, China. Electronic address: zengzhi86@smu.edu.cn.
PMID: 40680446 DOI: 10.1016/j.ecoenv.2025.118689
Abstract

Di-(2-ethylhexyl) phthalate (DEHP), a widely utilized plasticizer, has been increasingly associated with cardiovascular risks. However, the involvement of DEHP in abdominal aortic aneurysm (AAA) remains unclear. To address this gap, C57BL/6 J mice were intragastrically administered with DEHP for 4 weeks in a CaCl₂-induced AAA model. We found that DEHP exacerbated AAA progression, as evidenced by a notable enlargement in the maximal diameter of the abdominal aorta, enhanced vascular inflammation, and accelerated elastin degradation. In vitro experiments confirmed that DEHP, along with its primary metabolite mono-(2-ethylhexyl) phthalate (MEHP), induced M1 macrophage polarization, leading to increased secretion of inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP9), and pro-inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β). Mechanistically, we demonstrated that DEHP and MEHP triggered the activation of the nuclear factor-kappa B (NF-κB) pathway by upregulating phosphorylated p65 and inducing p65 nuclear translocation, which drove M1 macrophage polarization. These findings were further confirmed using a mouse AAA model in vivo. Additionally, DEHP and MEHP promoted the proliferation and migration of primary human aortic vascular smooth muscle cells (VSMCs). Phenotypic switching of VSMCs was markedly accelerated following DEHP and MEHP treatment, potentially through the PI3K-AKT pathway, as characterized by reducing contractile markers (ACTA2 and CNN1) and enhancing proliferative markers (PCNA and SPP1). Overall, our study underscores the pivotal role that DEHP plays in exacerbating AAA by promoting M1 macrophage polarization and VSMCs phenotypic switching, which provides new insights into the adverse health effects of environmental pollution-relevant Cardiovascular Disease progression.

Keywords

Abdominal aortic aneurysm; Di-(2-ethylhexyl) phthalate; Macrophage; NF-κB signaling pathway; Smooth muscle cell.

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