Department of Toxicology, School for Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
Mutagenesis. 2012 Jul;27(4):445-51. doi: 10.1093/mutage/ges002. Epub 2012 Feb 14.
Variation in xenobiotic metabolism cannot entirely be explained by genetic diversity in metabolic enzymes. We suggest that maternal diet during gestation can contribute to variation in metabolism by creating an in utero environment that shapes the offspring's defence against chemical carcinogens. Therefore, pregnant mice were supplemented with the natural aryl hydrocarbon receptor (AhR) agonist quercetin (1 mmol quercetin/kg feed) until delivery. Next, it was investigated whether the adult offspring at the age of 12 weeks had altered biotransformation of the environmental pollutant benzo[a]pyrene (B[a]P). In utero quercetin exposure resulted in significantly enhanced gene expression of Cyp1a1, Cyp1b1, Nqo1 and Ugt1a6 in liver of foetuses at Day 14.5 of gestation. Despite cessation of supplementation after delivery, altered gene expression persisted into adulthood, but in a tissue- and gender-dependent manner. Expression of Phase I enzymes (Cyp1a1 and Cyp1b1) was up-regulated in the liver of adult female mice in utero exposed to quercetin, whereas expression of Phase II enzymes (Gstp1, Nqo1 and Ugt1a6) was predominantly enhanced in the lung tissue of female mice. Epigenetic mechanisms may contribute to this adapted gene expression, as the repetitive elements (SINEB1) were hypomethylated in liver of female mice prenatally exposed to quercetin. Studies on ex vivo metabolism of B[a]P by lung and liver microsomes showed that the amount of B[a]P-9,10-dehydrodiol, B[a]P-7,8-dihydrodiol and 3-hydroxy-B[a]P did not change, but the amount of unmetabolised B[a]P was significantly lower after incubation with lung microsomes from offspring that received quercetin during gestation. Moreover, ex vivo B[a]P-induced DNA adduct formation was significantly lower for liver microsomes of offspring that were exposed to quercetin during gestation. These results suggest that prenatal diet leads to persistent alterations in Phase I and II enzymes of adult mice and may affect cancer risk.
外源性物质代谢的变化不能完全用代谢酶的遗传多样性来解释。我们认为，妊娠期母体饮食可以通过创造一种宫内环境来促进代谢的变化，这种环境塑造了后代对化学致癌物的防御能力。因此，怀孕的老鼠在整个孕期都被补充天然芳香烃受体 (AhR) 激动剂槲皮素（1mmol 槲皮素/公斤饲料）。接着，研究了 12 周龄的成年后代的环境污染物苯并[a]芘（B[a]P）的生物转化是否发生了变化。在妊娠第 14.5 天，槲皮素暴露导致胎儿肝脏中 Cyp1a1、Cyp1b1、Nqo1 和 Ugt1a6 的基因表达显著增强。尽管分娩后停止了补充，但改变的基因表达持续到成年期，但具有组织和性别依赖性。在母体暴露于槲皮素的成年雌性小鼠的肝脏中，I 相酶（Cyp1a1 和 Cyp1b1）的表达上调，而 II 相酶（Gstp1、Nqo1 和 Ugt1a6）的表达主要在雌性小鼠的肺组织中增强。表观遗传机制可能有助于这种适应的基因表达，因为在母体暴露于槲皮素的雌性小鼠的肝脏中，重复元件（SINEB1）被低甲基化。体外 B[a]P 代谢研究表明，B[a]P-9,10-二羟基二醇、B[a]P-7,8-二羟基二醇和 3-羟基-B[a]P 的量没有变化，但在与妊娠期接受槲皮素的后代的肺微粒体孵育后，未代谢的 B[a]P 量显著降低。此外，妊娠期暴露于槲皮素的后代的肝微粒体体外 B[a]P 诱导的 DNA 加合物形成显著降低。这些结果表明，产前饮食会导致成年小鼠的 I 相和 II 相酶持续改变，并可能影响癌症风险。
