Institute of Clinical Medicine, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Shuaifuyuan, Dongcheng Dist., Beijing, 100730, China.
College of Animal Science and Technology, Beijing University of Agriculture, Beijing, China.
Sci Rep. 2024 Jul 24;14(1):17002. doi: 10.1038/s41598-024-68029-y.
Prenatal exposure to Benzo[a]pyrene (BaP) has been suggested to increase the risk of adverse pregnancy outcomes. However, the role of placental apoptosis on BaP reproductive toxicity is poorly understood. We conducted a maternal animal model of C57BL/6 wild-type (WT) and transformation-related protein 53 (Trp53) heterozygous knockout (p53KO) mice, as well as a nested case-control study involving 83 women with PB and 82 term birth from a birth cohort on prenatal exposure to BaP and preterm birth (PB). Pregnant WT and p53KO mice were randomly allocated to BaP treatment and control groups, intraperitoneally injected of low (7.8 mg/kg), medium (35 mg/kg), and high (78 mg/kg) doses of 3,4-BaP per day and equal volume of vegetable oil, from gestational day 10.5 until delivery. Results show that high-dose BaP treatment increased the incidence of preterm birth in WT mice. The number of fetal deaths and resorptions increased with increasing doses of BaP exposure in mice. Notably, significant reductions in maternal and birth weights, increases in placental weights, and decrease in the number of livebirths were observed in higher-dose BaP groups in dose-dependent manner. We additionally observed elevated p53-mediated placental apoptosis in higher BaP exposure groups, with altered expression levels of p53 and Bax/Bcl-2. In case-control study, the expression level of MMP2 was increased among women with high BaP exposure and associated with the increased risk of all PB and moderate PB. Our study provides the first evidence of BaP-induced reproductive toxicity and its adverse effects on maternal-fetal outcomes in both animal and population studies.
产前接触苯并[a]芘（BaP）已被认为会增加不良妊娠结局的风险。然而，胎盘细胞凋亡在 BaP 生殖毒性中的作用尚未完全阐明。我们进行了一项 C57BL/6 野生型（WT）和转化相关蛋白 53（Trp53）杂合子敲除（p53KO）小鼠的母体动物模型研究，以及一项巢式病例对照研究，该研究纳入了 83 名产前接触 BaP 并早产（PB）和 82 名足月分娩的妇女。将怀孕的 WT 和 p53KO 小鼠随机分配到 BaP 处理组和对照组，每天腹腔注射低（7.8mg/kg）、中（35mg/kg）和高（78mg/kg）剂量的 3,4-BaP 以及等量的植物油，从妊娠第 10.5 天到分娩。结果表明，高剂量 BaP 处理增加了 WT 小鼠早产的发生率。随着 BaP 暴露剂量的增加，胎儿死亡和吸收的数量增加。值得注意的是，在较高剂量 BaP 组中，母鼠和仔鼠体重明显降低，胎盘重量增加，活产数减少，且呈剂量依赖性。我们还观察到在较高 BaP 暴露组中 p53 介导的胎盘细胞凋亡增加，p53 和 Bax/Bcl-2 的表达水平发生改变。在病例对照研究中，高 BaP 暴露组的 MMP2 表达水平升高，与所有 PB 和中度 PB 的风险增加有关。我们的研究在动物和人群研究中首次提供了 BaP 诱导的生殖毒性及其对母婴结局的不良影响的证据。
