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. 2006 Apr 5;26(14):3840-4.
doi: 10.1523/JNEUROSCI.4464-05.2006.

The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids

Megan C Holmes  1 , Christian T Abrahamsen, Karen L French, Janice M Paterson, John J Mullins, Jonathan R Seckl
Affiliations

The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids

Megan C Holmes et al. J Neurosci. .

Abstract

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 11beta-hydroxysteroid dehydrogenase type 2 (11beta-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 11beta-HSD2(+/-) mice such that each pregnant female produces +/+, +/-, and -/- offspring and compared them with offspring of homozygous wild-type and -/- matings. We show that 11beta-HSD2(-/-) offspring of either +/- or -/- mothers have lower birth weight and exhibit greater anxiety than 11beta-HSD2(+/+) littermates. This provides clear evidence for the key role of fetoplacental 11beta-HSD2 in prenatal glucocorticoid programming.

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Figures

Figure 1.
Figure 1.
Birth weights of 11β-HSD2+/+ (filled columns), 11β-HSD2+/− (striped columns), and 11β-HSD2−/− (open columns) offspring from 11β-HSD2+/− matings. The columns represent means ± SEM. *p < 0.05 compared with 11β-HSD2+/+ controls.
Figure 2.
Figure 2.
11β-HSD2−/− mice from homozygous matings show increased anxiety in elevated plus maze test. 11β-HSD2−/− mice (open columns) show decreased number of entries and time spent in open arms of EPM compared with 11β-HSD2+/+ mice (filled columns). The columns represent means ± SEM. n = 26. *p < 0.05 compared with 11β-HSD2+/+ control.
Figure 3.
Figure 3.
11β-HSD2−/− mice from heterozygous matings show increased anxiety in the elevated plus maze test. Open arm entries (a) and distance traveled in open arms (b) in 11β-HSD2+/+ (filled columns), 11β-HSD2+/− (striped columns), and HSD−/− (open columns) littermates are shown. The columns represent means ± SEM. *p < 0.05 compared with 11β-HSD2+/+ control.
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