The long-term consequences of neonatal endotoxin exposure on hypothalamic-pituitary-adrenal axis (HPA) function were assessed in adult female and male Long-Evans rats. At 3 and 5 d of age, pups were administered endotoxin (Salmonella enteritidis, 0.05 mg/kg, i.p.) at a dose that provokes a rapid and sustained physiological response, but with no mortality. As adults, neonatally endotoxin-treated animals exhibited significantly greater adrenocorticotrophic hormone (ACTH) and corticosterone responses to restraint stress than controls. In addition, dexamethasone pretreatment was less effective in suppressing ACTH responses to restraint stress in endotoxin-treated animals than in controls, suggesting decreased negative-feedback sensitivity to glucocorticoids. Neonatal endotoxin treatment elevated resting-state median eminence levels of corticotropin-releasing hormone (CRH) and arginine vasopressin in adult male animals, and arginine vasopressin in both adult males and females. Neonatal exposure to endotoxin also increased CRH mRNA expression in the paraventricular nucleus of the hypothalamus of adult males, with no difference in females. Finally, glucocorticoid receptor density was reduced across a wide range of brain regions in the neonatal endotoxin-treated, adult animals. These data illustrate the interactive nature of immune and endocrine systems during development. It appears that endotoxin exposure during critical stages of development decreases glucocorticoid negative-feedback inhibition of ACTH secretagogue synthesis, thus increasing HPA responsiveness to stress. The implication of these findings is that exposure to gram-negative LPS in early life can alter the development of neural systems which govern endocrine responses to stress and may thereby predispose individuals to stress-related pathology.

1. Several years ago, investigators described the effects of infantile handling on the development of hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Rat pups exposed to brief periods of innocuous handling early in life showed reduced HPA responses to a wide variety of stressors, and the effect persists throughout the life of the animal. These effects are robust and provide an excellent model for understanding how early environmental stimuli, which are external to the organism, alter neural differentiation and, thus, neuroendocrine responsivity to stress. 2. This paper reviews the endocrine mechanisms affected by early handling and our current understanding of the neural transduction of environmental events and their effects at the level of the target neurons (in the hippocampus and frontal cortex). 3. In brief, handling serves to increase glucocorticoid receptor gene transcription, increasing sensitivity to glucocorticoid negative feedback regulation and, thus, altering the activity within hypothalamic corticotropin-releasing factor/vasopressin neurons. Together these changes serve to determine neuroendocrine responsivity to stress.

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