Maternal antioxidant blocks programmed cardiovascular and behavioural stress responses in adult mice. Clin Sci (Lond) 2011 Nov;121(10):427-36
Date
05/28/2011Pubmed ID
21615331Pubmed Central ID
PMC3677964DOI
10.1042/CS20110153Scopus ID
2-s2.0-80052368572 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
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 JLAuthor
Jeffrey L. Segar MD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
11-beta-Hydroxysteroid DehydrogenasesAnimals
Antioxidants
Anxiety Disorders
Aorta
Carbenoxolone
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
