Impact of Neonatal Activation of Nuclear Receptor CAR (Nr1i3) on Cyp2 Gene Expression in Adult Mouse Liver.
Impact of Neonatal Activation of Nuclear Receptor CAR (Nr1i3) on Cyp2 Gene Expression in Adult Mouse Liver.
复制标题
新生儿核受体 CAR (Nr1i3) 激活对成年小鼠肝脏 Cyp2 基因表达的影响。
DOI：
10.1093/toxsci/kfac032
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Waxman,DavidJ
中科院分区：
文献类型：
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作者：
Shin,Aram;Waxman,DavidJ
围产期暴露于环境化学物质被提议重新编程发展和改变疾病的易感性以后的生活。支持这一点，TCPOBOP对核受体组成型雄烷受体（CAR）（Nr 1 i3）的新生儿激活先前报道诱导小鼠hepaticCyp 2基因持续表达至成年，并归因于早期生活暴露的长期表观遗传记忆。在这里，我们证实，相同的高剂量新生儿TCPOBOP暴露研究先前（3毫克/公斤，15倍ED 50）确实诱导延长（12周）增加hepaticCyp 2的表达;然而，我们表明，表达的持久性可以完全解释残留TCPOBOP在肝组织中的持久性。当通过降低新生儿TCPOBOP剂量22倍（0.67× ED 50）消除组织中TCPOBOP的长期存在时，新生儿肝Cyp 2表达仍显著增加，但不会持续到成年期。此外，新生儿ED 50范围TCPOBOP暴露不会使小鼠对随后的低剂量TCPOBOP治疗敏感。相比之下，新生儿治疗苯巴比妥，短半衰期（t1/2= 8小时）的激动剂的CAR和PXR（Nr 1 i2），诱导高水平的新生儿激活的Cyp 2基因，也改变了他们的反应，低剂量苯巴比妥暴露在成年期增加（Cyp 2b 10）或减少（Cyp 2c 55）的表达。因此，新生儿外源性暴露可以重新编程hepaticCyp 2基因，并改变其反应暴露在以后的生活。这些发现强调了在评估生命早期环境化学品暴露的长期影响时，需要仔细考虑异生物质剂量、半衰期和在组织中的持久性。
Perinatal exposure to environmental chemicals is proposed to reprogram development and alter disease susceptibility later in life. Supporting this, neonatal activation of the nuclear receptor constitutive androstane receptor (CAR) (Nr1i3) by TCPOBOP was previously reported to induce persistent expression of mouse hepaticCyp2genes into adulthood, and was attributed to long-term epigenetic memory of the early life exposure. Here, we confirm that the same high-dose neonatal TCPOBOP exposure studied previously (3 mg/kg, 15x ED50) does indeed induce prolonged (12 weeks) increases in hepaticCyp2expression; however, we show that the persistence of expression can be fully explained by the persistence of residual TCPOBOP in liver tissue. When the long-term presence of TCPOBOP in tissue was eliminated by decreasing the neonatal TCPOBOP dose 22-fold (0.67× ED50), strong neonatal increases in hepaticCyp2expression were still obtained but did not persist into adulthood. Furthermore, the neonatal ED50-range TCPOBOP exposure did not sensitize mice to a subsequent, low-dose TCPOBOP treatment. In contrast, neonatal treatment with phenobarbital, a short half-life (t1/2= 8 h) agonist of CAR and PXR (Nr1i2), induced high-level neonatal activation ofCyp2genes and also altered their responsiveness to low-dose phenobarbital exposure at adulthood by either increasing (Cyp2b10) or decreasing (Cyp2c55) expression. Thus, neonatal xenobiotic exposure can reprogram hepaticCyp2genes and alter their responsiveness to exposures later in life. These findings highlight the need to carefully consider xenobiotic dose, half-life, and persistence in tissue when evaluating the long-term effects of early life environmental chemical exposures.