The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids.
The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids.
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DOI：
10.1523/jneurosci.4464-05.2006
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发表时间：
2006-04-05
期刊：
影响因子：
--
通讯作者：
Seckl JR
中科院分区：
文献类型：
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作者：
Holmes MC;Abrahamsen CT;French KL;Paterson JM;Mullins JJ;Seckl JR
低出生体重与成人心脏代谢和情感障碍的易感性增加有关，这产生了胎儿“编程”的概念。产前暴露于过量的糖皮质激素可能是因果关系。作为支持，母体压力或在妊娠期间使用地塞米松（穿过胎盘）或胎儿胎盘11β-羟类固醇脱氢酶2（11β-HSD 2）抑制剂（母体糖皮质激素的生理“屏障”）进行治疗，可降低出生体重并导致后代永久性高血压、高血糖和焦虑行为。目前尚不清楚这种影响是通过母体功能的改变间接介导的，还是直接作用于胎儿及其胎盘。为了剖析这一关键问题，我们将11只β-HSD 2 +/-小鼠交配，使每只妊娠雌性产生+/+、+/-和-/-后代，并将它们与纯合子野生型和-/-交配的后代进行比较。我们发现，bHSD 2-/-或-/-母亲的后代具有较低的出生体重，并表现出比β-HSD 2 +/+同窝仔更大的焦虑。这为胎儿胎盘11β-HSD 2在产前糖皮质激素编程中的关键作用提供了明确的证据。
Low birth weight associates with increased susceptibility to adult cardiometabolic and affective disorders spawning the notion of fetal “programming.” Prenatal exposure to excess glucocorticoids may be causal. In support, maternal stress or treatment during pregnancy with dexamethasone (which crosses the placenta) or inhibitors of fetoplacental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the physiological “barrier” to maternal glucocorticoids, reduces birth weight and programs permanent offspring hypertension, hyperglycemia, and anxiety behaviors. It remains uncertain whether such effects are mediated indirectly via altered maternal function or directly on the fetus and its placenta. To dissect this critical issue, we mated 11β-HSD2+/- mice such that each pregnant female produces +/+, +/-, and -/- offspring and compared them with offspring of homozygous wild-type and -/- matings. We show that bHSD2-/- offspring of either +/- or -/- mothers have lower birth weight and exhibit greater anxiety than β-HSD2+/+ littermates. This provides clear evidence for the key role of fetoplacental 11β-HSD2 in prenatal glucocorticoid programming.