Neonatal endotoxin exposure alters the development of the hypothalamic- pituitary-adrenal axis: early illness and later responsivity to stress

Abstract

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.

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

“…Neonatal effects-In 1995, Shanks et al reported that LPS given during the first week of life was associated with altered levels of glucocorticoid receptors in the rat brain (Shanks et al, 1995) and subsequent studies suggested that LPS pretreated animals were more responsive to adult LPS and exhibited reduced levels of inflammation to adjuvant-induced arthritis (Shanks et al, 2000). With the use of a similar neonatal LPS administration, Walker et al (2006) observed a marked attenuation in febrile response in nLPS (P3-5) treated males exposed to an adult LPS challenge, but no changes in CORT level was observed.…”

Early-Life Immune Challenge: Defining a Critical Window for Effects on Adult Responses to Immune Challenge

“…For example, Shanks et al (1995) and Shanks et al (2000) found differences in adult HPA axis function and responses to a model of experimentally induced arthritis when the rats were given LPS at P3 and P5. Hodgson et al (2001) also found alterations in adult physiology with a series of immune challenges given in the first week of life.…”

“…These investigations all examined somewhat different end points from those looked at here and our present results indicate that this might be an important reason why these studies have found effects on the adult using such different preconditioning time points. In addition, the studies of Hodgson et al (2001), Shanks et al (1995) and Shanks et al (2000) used a multiple injection paradigm perhaps leading to effects on very different mechanisms.…”

“…For example, Shanks et al (2000) found that exposure to LPS at P3 and P5 reduces inflammatory responses to experimental arthritis and alters hypothalamic-pituitary-adrenal (HPA) axis function in the adult (Shanks et al, 1995(Shanks et al, , 2000. Hodgson et al (2001) found changes in resistance to adult tumor colonization, natural killer cell activity and weight gain, as well as corticosterone responses to stress after successive immune challenges administered at P1, 3, 5, and 7.…”

Are There Long-Term Consequences of Pain in Newborn or Very Young Infants?

“…Endotoxin injection on as few as two occasions in the first week of life has been shown to exacerbate responses to stress much later in the mature animal, including HPA axis activation indicators (Hodgson et al, 2000;Shanks, Larocque, & Meaney, 1995), stressinduced suppression of lymphocyte proliferative responses (Shanks et al, 2000), and increased susceptibility to the metastasis of NK-sensitive MADB106 tumor cells (Hodgson et al, 2000). Neonatal endotoxin injection in rats has also been shown to result in delayed wound healing in the mature animal (Hodgson et al, 2000), which reflects the animals' inability to mount an inflammatory response (Padgett, Marucha, & Sheridan, 1998).…”