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Maternal antioxidant blocks programmed cardiovascular and behavioural stress responses in adult mice. Clin Sci (Lond) 2011 Nov;121(10):427-36

Date

05/28/2011

Pubmed ID

21615331

Pubmed Central ID

PMC3677964

DOI

10.1042/CS20110153

Scopus ID

2-s2.0-80052368572   19 Citations

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.

Author List

Roghair RD, Wemmie JA, Volk KA, Scholz TD, Lamb FS, Segar JL

Author

Jeffrey L. Segar MD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

11-beta-Hydroxysteroid Dehydrogenases
Animals
Antioxidants
Anxiety Disorders
Aorta
Carbenoxolone
Conditioning (Psychology)
Cyclic N-Oxides
Enzyme Inhibitors
Fear
Female
Hypertension
Male
Maternal-Fetal Exchange
Mice
Mice, Inbred C57BL
Oxidative Stress
Pregnancy
Pregnancy, Animal
Prenatal Exposure Delayed Effects
Sex Factors
Spin Labels
Stress, Psychological
Telemetry
jenkins-FCD Prod-406 0f9a74600e4e79798f8fa6f545ea115f3dd948b2