title: Maternal antioxidant blocks programmed cardiovascular and behavioural stress responses in adult mice.
abstract: Intra-uterine growth restriction is an independent risk factor for adult psychiatric and cardiovascular diseases. In humans, intra-uterine growth restriction is associated with increased placental and fetal oxidative stress, as well as down-regulation of placental 11β-HSD (11β-hydroxysteroid dehydrogenase). Decreased placental 11β-HSD activity increases fetal exposure to maternal glucocorticoids, further increasing fetal oxidative stress. To explore the developmental origins of co-morbid hypertension and anxiety disorders, we increased fetal glucocorticoid exposure by administering the 11β-HSD inhibitor CBX (carbenoxolone; 12 mg·kg-1 of body weight·day-1) during the final week of murine gestation. We hypothesized that maternal antioxidant (tempol throughout pregnancy) would block glucocorticoid-programmed anxiety, vascular dysfunction and hypertension. Anxiety-related behaviour (conditioned fear) and the haemodynamic response to stress were measured in adult mice. Maternal CBX administration significantly increased conditioned fear responses of adult females. Among the offspring of CBX-injected dams, maternal tempol markedly attenuated the behavioural and cardiovascular responses to psychological stress. Compared with offspring of undisturbed dams, male offspring of dams that received daily third trimester saline injections had increased stress-evoked pressure responses that were blocked by maternal tempol. In contrast, tempol did not block CBX-induced aortic dysfunction in female mice (measured by myography and lucigenin-enhanced chemiluminescence). We conclude that maternal stress and exaggerated fetal glucocorticoid exposure enhance sex-specific stress responses, as well as alterations in aortic reactivity. Because concurrent tempol attenuated conditioned fear and stress reactivity even among the offspring of saline-injected dams, we speculate that antenatal stressors programme offspring stress reactivity in a cycle that may be broken by antenatal antioxidant therapy.
authors: Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA. robert-roghair@uiowa.edu
authors: Robert D
authors: RD
authors: Roghair
authors: John A
authors: JA
authors: Wemmie
authors: Kenneth A
authors: KA
authors: Volk
authors: Thomas D
authors: TD
authors: Scholz
authors: Fred S
authors: FS
authors: Lamb
authors: Jeffrey L
authors: JL
authors: Segar
references: Pediatrics. 2009 Feb;123(2):731-4
references: 19171645
references: Brain Res Rev. 2008 Mar;57(2):571-85
references: 18164765
references: J Endocrinol. 2008 Feb;196(2):343-52
references: 18252958
references: J Clin Endocrinol Metab. 2006 May;91(5):1868-71
references: 16464950
references: Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E863-70
references: 15238353
references: Neurochem Res. 2009 Apr;34(4):739-45
references: 18802752
references: Eur J Neurosci. 2000 Mar;12(3):1047-54
references: 10762336
references: Behav Med. 2009 Winter;34(4):125-32
references: 19064371
references: Pediatr Res. 2009 Jul;66(1):53-8
references: 19342983
references: Am J Physiol Regul Integr Comp Physiol. 2009 Mar;296(3):R651-62
references: 19144750
references: PLoS One. 2010 Feb 16;5(2):e9237
references: 20169056
references: Neurosci Lett. 2008 Sep 19;442(3):262-6
references: 18625285
references: Cardiovasc Res. 1998 Dec;40(3):600-6
references: 10070502
references: Kidney Int. 2005 Nov;68(5):2180-8
references: 16221217
references: PLoS One. 2010 Feb 17;5(2):e9250
references: 20174656
references: Pediatr Res. 2006 Jun;59(6):784-9
references: 16641213
references: Free Radic Biol Med. 2002 Mar 1;32(5):446-53
references: 11864784
references: Endothelium. 2000;7(4):265-78
references: 11201524
references: Eur J Obstet Gynecol Reprod Biol. 2008 Dec;141(2):95-9
references: 18760523
references: Am J Physiol Regul Integr Comp Physiol. 2007 Mar;292(3):R1236-45
references: 17138729
references: Life Sci. 2007 Jan 30;80(8):709-15
references: 17157880
references: Hypertension. 1998 Jul;32(1):108-14
references: 9674646
references: J Cardiovasc Pharmacol. 2002 Oct;40(4):501-9
references: 12352311
references: Placenta. 2006 Feb-Mar;27(2-3):171-80
references: 16338462
references: Placenta. 1996 Mar-Apr;17(2-3):169-72
references: 8730887
references: J Neurosci. 2003 Jul 2;23(13):5496-502
references: 12843249
references: Physiol Res. 2009;58(1):69-75
references: 18198987
references: J Clin Invest. 2007 Apr;117(4):1058-67
references: 17380204
references: Psychoneuroendocrinology. 2010 Jun;35(5):686-93
references: 19931984
references: Brain Res. 1998 Jun 1;794(2):199-210
references: 9622630
references: Hypertension. 1996 Jun;27(6):1200-4
references: 8641724
references: J Comp Neurol. 1991 Nov 15;313(3):486-93
references: 1770172
references: Circulation. 2001 Mar 6;103(9):1264-8
references: 11238271
references: Arch Gen Psychiatry. 2005 Jun;62(6):593-602
references: 15939837
references: Hypertension. 2007 Oct;50(4):679-85
references: 17724277
references: Neuroendocrinology. 1996 Dec;64(6):412-8
references: 8990073
references: J Physiol. 2001 Jan 1;530(Pt 1):141-52
references: 11136866
references: J Psychiatr Res. 2008 Oct;42(13):1104-11
references: 18281061
references: Placenta. 2008 Feb;29(2):193-200
references: 18061258
references: Circ Res. 2003 Jan 10;92(1):81-7
references: 12522124
references: Ann N Y Acad Sci. 2006 Jul;1071:351-78
references: 16891583
references: Nat Neurosci. 2002 Nov;5(11):1242-7
references: 12379862
references: Redox Rep. 2008;13(1):11-6
references: 18284846
references: Gynecol Obstet Invest. 2007;64(4):187-92
references: 17664879
references: Lancet. 1993 Feb 6;341(8841):339-41
references: 8094115
references: Circulation. 2000 Nov 28;102(22):2739-44
references: 11094041