National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America.
PLoS One. 2011;6(9):e24381. doi: 10.1371/journal.pone.0024381. Epub 2011 Sep 8.
Differences in responses to environmental chemicals and drugs between life stages are likely due in part to differences in the expression of xenobiotic metabolizing enzymes and transporters (XMETs). No comprehensive analysis of the mRNA expression of XMETs has been carried out through life stages in any species.
Using full-genome arrays, the mRNA expression of all XMETs and their regulatory proteins was examined during fetal (gestation day (GD) 19), neonatal (postnatal day (PND) 7), prepubescent (PND32), middle age (12 months), and old age (18 and 24 months) in the C57BL/6J (C57) mouse liver and compared to adults. Fetal and neonatal life stages exhibited dramatic differences in XMET mRNA expression compared to the relatively minor effects of old age. The total number of XMET probe sets that differed from adults was 636, 500, 84, 5, 43, and 102 for GD19, PND7, PND32, 12 months, 18 months and 24 months, respectively. At all life stages except PND32, under-expressed genes outnumbered over-expressed genes. The altered XMETs included those in all of the major metabolic and transport phases including introduction of reactive or polar groups (Phase I), conjugation (Phase II) and excretion (Phase III). In the fetus and neonate, parallel increases in expression were noted in the dioxin receptor, Nrf2 components and their regulated genes while nuclear receptors and regulated genes were generally down-regulated. Suppression of male-specific XMETs was observed at early (GD19, PND7) and to a lesser extent, later life stages (18 and 24 months). A number of female-specific XMETs exhibited a spike in expression centered at PND7.
The analysis revealed dramatic differences in the expression of the XMETs, especially in the fetus and neonate that are partially dependent on gender-dependent factors. XMET expression can be used to predict life stage-specific responses to environmental chemicals and drugs.
生命阶段对环境化学物质和药物的反应存在差异，部分原因可能是外源性代谢酶和转运体（XMET）的表达存在差异。在任何物种中，都没有针对整个生命阶段对 XMET 的 mRNA 表达进行全面分析。
使用全基因组芯片，检测了 C57BL/6J（C57）小鼠肝脏中所有 XMET 及其调节蛋白在胎儿（妊娠第 19 天（GD19））、新生（出生后第 7 天（PND7））、青春期前（PND32）、中年（12 个月）和老年（18 和 24 个月）的 mRNA 表达，并与成年期进行了比较。与老年期相比，胎儿和新生期的 XMET mRNA 表达差异较大，而老年期的影响相对较小。与成年期相比，GD19、PND7、PND32、12 个月、18 个月和 24 个月的 XMET 探针集分别有 636、500、84、5、43 和 102 个不同。除 PND32 外，在所有生命阶段，表达下调的基因数量都超过了表达上调的基因。改变的 XMET 包括所有主要的代谢和转运阶段，包括引入反应性或极性基团（I 期）、结合（II 期）和排泄（III 期）。在胎儿和新生儿中，二恶英受体、Nrf2 成分及其调节基因的表达平行增加，而核受体和调节基因通常下调。在早期（GD19、PND7）和程度较轻的后期生命阶段（18 和 24 个月）观察到雄性特异性 XMET 的抑制。一些雌性特异性 XMET 的表达在 PND7 时出现高峰。
该分析揭示了 XMET 的表达存在显著差异，尤其是在胎儿和新生儿中，部分依赖于性别相关因素。XMET 的表达可用于预测生命阶段特异性对环境化学物质和药物的反应。
