Shi Haiqun, Zhang Zehua, Shen Anna, Ding Tong, Zhao Rui, Shi Yan, Zhao Jianyuan, Cai Ke, Wang Feng
Pediatric Heart Center, NHC Key Laboratory of Neonatal Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China.
Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
Pediatr Res. 2025 Mar 15. doi: 10.1038/s41390-025-03997-z.
BACKGROUD: Epidemiological data suggest that maternal occupational exposure to mixed phthalates comprising di(2-ethylhexyl) phthalate (DEHP) increases the risk of congenital heart disease (CHD). In this study, we used mice as an animal model to validate impact of first-trimester DEHP exposure on the risk of CHD in offspring, to elucidate the possible mechanisms and to provide a potential feasible intervention.
Eight-week-old C57BL/6J pregnant mice were randomly divided into standard and DEHP diet groups. The incidence of CHD in DEHP diet group offspring was up to 14.41% observed via Hematoxylin-eosin (HE) staining. Quantitative PCR analysis revealed that expression of key genes involved in cardiogenesis were suppressed at the transcriptional level, which may be due to decreased nuclear translocation of p65. The inhibition of DEHP on key genes was rescued to some extent by choline through driving p65 into nuclear. In the mice, supplementation of choline during DEHP exposure reduced the incidence of CHD in offspring from 14.41% to 4.63%.
Our study demonstrates that mice first-trimester DEHP exposure significantly increases the risk of CHD in the offspring via inhibiting mRNA levels of key genes in cardiogenesis, and choline could protect against the pathogenesis.
Our study provides key mechanistic insights into the risk of CHD by DEHP exposure during early pregnancy, and provides choline as a potentially effective intervention. DEHP suppressed the expression of key genes involved in embryonic cardiac septum development at the transcriptional level via inhibiting nuclear translocation of p65. Choline can play a role in rescuing the inhibition of DEHP on cardiogenesis genes via driving p65 translocate into the nuclear.
背景：流行病学数据表明，孕妇职业性接触包括邻苯二甲酸二（2-乙基己基）酯（DEHP）在内的混合邻苯二甲酸盐会增加先天性心脏病（CHD）的风险。在本研究中，我们以小鼠为动物模型，验证孕早期DEHP暴露对后代患CHD风险的影响，阐明可能的机制，并提供一种潜在可行的干预措施。
将8周龄的C57BL/6J怀孕小鼠随机分为标准饮食组和DEHP饮食组。通过苏木精-伊红（HE）染色观察到，DEHP饮食组后代的CHD发病率高达14.41%。定量PCR分析显示，参与心脏发生的关键基因的表达在转录水平受到抑制，这可能是由于p65的核转位减少所致。胆碱通过驱动p65进入细胞核，在一定程度上挽救了DEHP对关键基因的抑制作用。在小鼠中，DEHP暴露期间补充胆碱可使后代CHD的发病率从14.41%降至4.63%。
我们的研究表明，小鼠孕早期DEHP暴露通过抑制心脏发生关键基因的mRNA水平，显著增加后代患CHD的风险，而胆碱可以预防这种发病机制。
我们的研究为孕早期DEHP暴露导致CHD风险提供了关键的机制见解，并提供胆碱作为一种潜在有效的干预措施。DEHP通过抑制p65的核转位，在转录水平抑制参与胚胎心脏隔膜发育的关键基因的表达。胆碱可以通过驱动p65转位进入细胞核，在挽救DEHP对心脏发生基因的抑制作用中发挥作用。
