Department of Pediatrics , First Affiliated Hospital of Wenzhou Medical University , Zhejiang 325000 , China.
Chem Res Toxicol. 2019 Jun 17;32(6):1070-1081. doi: 10.1021/acs.chemrestox.8b00386. Epub 2019 Apr 5.
Childhood obesity, which is prevalent in developed countries, is a metabolic risk factor for cardiovascular disease. Cadmium (Cd), a ubiquitous environmental toxic metal, also has deleterious effects on the cardiovascular system. However, the combined effects of a high-fat diet (HFD) and lifelong, low-dose Cd exposure on cardiac remodeling remain unclear. This study aims to determine the effects of combined HFD and Cd exposure on cardiac remodeling, as well as gender-specific differences in the response. C57BL/6J mice were exposed to Cd at a low dose (L-Cd, 0.5 ppm) or high dose (H-Cd, 5 ppm) via drinking water from conception to sacrifice. After being weaned, the offspring mice were fed with a HFD (42% kcal from fat) for an additional 10 weeks. H-Cd exposure significantly increased Cd accumulation in the hearts of both parents and their offspring; a HFD showed no added effects on cardiac Cd content. H-Cd exposure increased cardiac metallothionein protein levels only in female mice, regardless of dietary intake. Histological analysis revealed that H-Cd exposure combined with a HFD induced cardiac hypertrophy and fibrosis only in female mice. This was further supported by elevated expression of ANP and COL1A1 protein levels along with COL1A1, COL1A2, and COL3A1 mRNA levels. Profibrotic markers PAI-1, CTGF, and FN were also elevated in HFD/H-Cd-exposed female mice. Levels of the oxidative stress marker 3-NT significantly increased in the hearts of HFD-fed female mice, whereas Cd exposure showed no additional effects. Of all the antioxidant markers examined, levels of CAT significantly increased in mice fed a HFD, regardless of gender and Cd exposure. In summary, a HFD combined with lifelong, low-dose Cd exposure induces cardiac hypertrophy and fibrosis in female but not male mice, a response that is independent of oxidative stress.
儿童肥胖症在发达国家较为普遍，是心血管疾病的代谢危险因素。镉（Cd）是一种普遍存在的环境毒性金属，对心血管系统也有有害影响。然而，高脂肪饮食（HFD）和终生低剂量 Cd 暴露对心脏重构的联合影响尚不清楚。本研究旨在确定 HFD 和 Cd 暴露联合对心脏重构的影响，以及性别特异性反应的差异。C57BL/6J 小鼠从受孕开始至处死通过饮用水暴露于低剂量（L-Cd，0.5ppm）或高剂量（H-Cd，5ppm）Cd。断奶后，后代小鼠继续用 HFD（42%的热量来自脂肪）喂养 10 周。H-Cd 暴露显著增加了亲代及其后代心脏中的 Cd 积累；HFD 对心脏 Cd 含量没有额外影响。H-Cd 暴露仅增加了雌性小鼠的心脏金属硫蛋白蛋白水平，而不论饮食摄入如何。组织学分析显示，H-Cd 暴露与 HFD 联合仅在雌性小鼠中引起心脏肥大和纤维化。这进一步得到了 ANP 和 COL1A1 蛋白水平以及 COL1A1、COL1A2 和 COL3A1 mRNA 水平升高的支持。PAI-1、CTGF 和 FN 等促纤维化标志物在 HFD/H-Cd 暴露的雌性小鼠中也升高。HFD 喂养的雌性小鼠心脏中氧化应激标志物 3-NT 的水平显著升高，而 Cd 暴露没有额外影响。在所检查的所有抗氧化标志物中，CAT 水平在 HFD 喂养的小鼠中显著升高，而与性别和 Cd 暴露无关。总之，终生低剂量 Cd 暴露与 HFD 联合在雌性而非雄性小鼠中引起心脏肥大和纤维化，这种反应与氧化应激无关。
