Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats.

Abstract

We investigated whether non-abortive maternal infections would compromise fetal brain development and alter hypothalamic-pituitary-adrenocortical (HPA) axis functioning when adult. To study putative teratogenic effects of a T cell-mediated immune response versus an endotoxic challenge, 10-d-pregnant rats received a single intraperitoneal injection of 5 X 10i human red blood cells (HRBC) or gram-negative bacterial endotoxin (Escherichia coli LPS: 30 ag/kg). The adult male progeny (3 mo old) of both experimental groups showed increased basal plasma corticosterone levels. In addition, after novelty stress the HRBC group, but not the LPS group, showed increased AC'H and corticosterone levels. Both groups showed substantial decreases in mineralocorticoid (MR) and glucocorticoid receptor (GR) levels in the hippocampus, a limbic brain structure critical for HPA axis regulation, whereas GR concentrations in the hypothalamus were unchanged and in anterior pituitary were slightly increased. HRBC and LPS indeed stimulated the maternal immune system as revealed by specific anti-HRBC antibody production and enhanced IL-1ft mRNA expression in splenocytes, respectively. This study demonstrates that a T cell-mediated immune response as well as an endotoxic challenge during pregnancy can induce anomalies in HPA axis function in adulthood. Clinically, it may be postulated that disturbed fetal brain development due to prenatal immune challenge increases the vulnerability to develop mental illness involving inadequate responses to stress. (J. Clin. Invest. 1994.

Cerebrospinal Fluid Corticotropin-Releasing Factor and Perceived Early-Life Stress in Depressed Patients and Healthy Control Subjects

“…A pattern of hypoactive HPA responsivity associated with perinatal stress was also suggested by results of a study of 8-14 year olds in whom a history of premature birth was associated with attenuated salivary cortisol and heart rate responses to a standardized psychosocial stressor in comparison to full-term subjects (Buske-Kirschbaum et al, 2000). Similarly, in preclinical work, prenatal immune challenge has been found to diminish HPA axis reactivity in adult rats (Reul et al, 1994). Other preclinical investigations have revealed developmental effects similar to those found in the present study.…”

Mice with an Increased Glucocorticoid Receptor Gene Dosage Show Enhanced Resistance to Stress and Endotoxic Shock

“…Both prenatal and postnatal experiences are known to influence the regulation of the HPA axis and the response to stress (15,25). Prenatal immune challenges were shown to result in increased corticosterone secretion under basal as well as stress conditions, which was correlated with a reduction of GR expression in the hippocampus (25).…”

Molecular and functional evidence for in vitro cytokine enhancement of human and murine target cell sensitivity to glucocorticoids. TNF-alpha priming increases glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis.

“…L-929 cells were processed as described previously (26). The cells were collected by centrifugation and the pellet was homogenized (two pellets, 2 ϫ 10 7 cells/2 ml; 10 strokes at 900 rpm) in ice-cold 5 mM Tris-HCl (pH 7.4) containing 0.5 mM phenylmethylsulfonyl fluoride, 5 g/ml antipain, 5 g/ml leupeptin, 5% glycerol, 10 mM sodium molybdate, 1 mM EDTA, and 2 mM ␤ -mercaptoethanol.…”