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Programming Neuroendocrine Stress Axis Activity by Exposure to Glucocorticoids during Postembryonic Development of the Frog, Xenopus laevis

Departments of Molecular, Cellular, and Developmental Biology (F.H., R.J.D.) and Ecology and Evolutionary Biology (R.J.D.), The University of Michigan, Ann Arbor, Michigan 48109; and Department of Biology (E.J.C.), Vassar College, Poughkeepsie, New York 12604

Address all correspondence and requests for reprints to: Dr. Robert J. Denver, Departments of Molecular, Cellular, and Developmental Biology and Ecology and Evolutionary Biology, The University of Michigan, Ann Arbor, Michigan 48109. E-mail: rdenver{at}umich.edu.

Exposure to elevated glucocorticoids during early mammalian development can have profound, long-term consequences for health and disease. However, it is not known whether such actions occur in nonmammalian species, and if they do, whether the molecular physiological mechanisms are evolutionarily conserved. We investigated the effects of dietary restriction, which elevates endogenous corticosterone (CORT), or exposure to exogenous CORT added to the aquarium water of Xenopus laevis tadpoles on later-life measures of growth, feeding behavior, and neuroendocrine stress axis activity. Dietary restriction of prometamorphic tadpoles reduced body size at metamorphosis, but juvenile frogs increased food intake, showed catch-up growth through 21 d after metamorphosis, and had elevated whole-body CORT content compared with controls. Dietary restriction causes increased CORT in tadpoles, so to mimic this increase, we treated tadpoles with 100 nM CORT or vehicle for 5 or 10 d and then reared juvenile frogs to 2 months after metamorphosis. Treatment with CORT decreased body weight at metamorphosis, but juvenile frogs showed catch-up growth and had elevated basal plasma (CORT). Immunohistochemical analysis showed that CORT exposure as a tadpole led to decreased glucocorticoid receptor immunoreactivity in brain regions involved with stress axis regulation and in the anterior pituitary gland of juvenile frogs. The elevated CORT in juvenile frogs, which could result from decreased negative feedback owing to down-regulation of glucocorticoid receptor, may drive the hyperphagic response. Taken together, our findings suggest that long-term, stable phenotypic changes in response to elevated glucocorticoids early in life are an ancient and conserved feature of the vertebrate lineage.