Thakur Vijay S, Liang Yanhong W, Lingappan Krithika, Jiang Weiwu, Wang Lihua, Barrios Roberto, Zhou Guodong, Guntupalli Bharath, Shivanna Binoy, Maturu Paramahamsa, Welty Stephen E, Moorthy Bhagavatula, Couroucli Xanthi I
Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030, USA.
Department of Pathology and Genomic Medicine, The Methodist Hospital Physician Organization, 6565 Fannin Street, Suite M227, Houston, TX 77030, USA.
Toxicol Lett. 2014 Oct 15;230(2):322-32. doi: 10.1016/j.toxlet.2014.03.006. Epub 2014 Mar 19.
Maternal smoking is one of the risk factors for preterm birth and for the development of bronchopulmonary dysplasia (BPD). In this study, we tested the hypothesis that prenatal exposure of rats to benzo[a]pyrene (BP), a component of cigarette smoke, will result in increased susceptibility of newborns to oxygen-mediated lung injury and alveolar simplification, and that cytochrome P450 (CYP)1A and 1B1 enzymes and oxidative stress mechanistically contribute to this phenomenon. Timed pregnant Fisher 344 rats were administered BP (25 mg/kg) or the vehicle corn oil (CO) on gestational days 18, 19 and 20, and newborn rats were either maintained in room air or exposed to hyperoxia (85% O2) for 7 or 14 days. Hyperoxic newborn rats prenatally exposed to the vehicle CO showed lung injury and alveolar simplification, and inflammation, and these effects were potentiated in rats that were prenatally exposed to BP. Prenatal exposure to BP, followed by hyperoxia, also resulted in significant modulation of hepatic and pulmonary cytochrome P450 (CYP)1A and 1B1 enzymes at PND 7-14. These rats displayed significant oxidative stress in lungs at postnatal day (PND) 14, as evidenced by increased levels of the F2-isoprostane 8-iso-PGF2α. Furthermore, these animals showed BP-derived DNA adducts and oxidative DNA adducts in the lung. In conclusion, our results show increased susceptibility of newborns to oxygen-mediated lung injury and alveolar simplification following maternal exposure to BP, and our results suggest that modulation of CYP1A/1B1 enzymes, increases in oxidative stress, and BP-DNA adducts contributed to this phenomenon.
孕妇吸烟是早产和支气管肺发育不良（BPD）发生的危险因素之一。在本研究中，我们验证了以下假设：孕期大鼠暴露于香烟烟雾成分苯并[a]芘（BP）会导致新生儿对氧介导的肺损伤和肺泡简化更敏感，并且细胞色素P450（CYP）1A和1B1酶以及氧化应激在机制上促成了这一现象。在妊娠第18、19和20天，对定时受孕的Fisher 344大鼠给予BP（25 mg/kg）或赋形剂玉米油（CO），新生大鼠要么置于室内空气中，要么暴露于高氧（85% O2）环境中7天或14天。产前暴露于赋形剂CO的高氧新生大鼠出现了肺损伤、肺泡简化和炎症，而产前暴露于BP的大鼠这些影响更为明显。产前暴露于BP后再进行高氧处理，在出生后第7 - 14天也导致肝脏和肺细胞色素P450（CYP）1A和1B1酶发生显著变化。这些大鼠在出生后第14天（PND 14）肺中显示出明显的氧化应激，F2 - 异前列腺素8 - 异 - PGF2α水平升高证明了这一点。此外，这些动物的肺中显示出BP衍生的DNA加合物和氧化性DNA加合物。总之，我们的结果表明，母体暴露于BP后，新生儿对氧介导的肺损伤和肺泡简化更敏感，我们的结果表明CYP1A/1B1酶的变化、氧化应激增加和BP - DNA加合物促成了这一现象。
