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J Clin Invest. Jun 1994; 93(6): 2600–2607.
PMCID: PMC294494

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


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 10(8) human red blood cells (HRBC) or gram-negative bacterial endotoxin (Escherichia coli LPS: 30 micrograms/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 ACTH 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-1 beta 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.

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  • Coid CR, Sandison H, Slavin S, Altman DG. Escherichia coli infection in mice and impaired fetal development. Br J Exp Pathol. 1978 Jun;59(3):292–297. [PMC free article] [PubMed]
  • Guilbert L, Robertson SA, Wegmann TG. The trophoblast as an integral component of a macrophage-cytokine network. Immunol Cell Biol. 1993 Feb;71(Pt 1):49–57. [PubMed]
  • Silen ML, Firpo A, Morgello S, Lowry SF, Francus T. Interleukin-1 alpha and tumor necrosis factor alpha cause placental injury in the rat. Am J Pathol. 1989 Aug;135(2):239–244. [PMC free article] [PubMed]
  • Dinarello CA. Interleukin-1. Rev Infect Dis. 1984 Jan-Feb;6(1):51–95. [PubMed]
  • Dinarello CA. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed]
  • Kluger MJ. Fever: role of pyrogens and cryogens. Physiol Rev. 1991 Jan;71(1):93–127. [PubMed]
  • Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA. Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest. 1988 Apr;81(4):1162–1172. [PMC free article] [PubMed]
  • Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci. 1982;389:39–48. [PubMed]
  • Rivier C, Vale W. In the rat, interleukin-1 alpha acts at the level of the brain and the gonads to interfere with gonadotropin and sex steroid secretion. Endocrinology. 1989 May;124(5):2105–2109. [PubMed]
  • Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev. 1988 Summer;12(2):123–137. [PubMed]
  • Kent S, Bluthe RM, Dantzer R, Hardwick AJ, Kelley KW, Rothwell NJ, Vannice JL. Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9117–9120. [PMC free article] [PubMed]
  • Besedovsky H, del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science. 1986 Aug 8;233(4764):652–654. [PubMed]
  • Bateman A, Singh A, Kral T, Solomon S. The immune-hypothalamic-pituitary-adrenal axis. Endocr Rev. 1989 Feb;10(1):92–112. [PubMed]
  • Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev. 1984 Winter;5(1):25–44. [PubMed]
  • Besedovsky HO, del Rey A. Immune-neuroendocrine circuits: integrative role of cytokines. Front Neuroendocrinol. 1992 Jan;13(1):61–94. [PubMed]
  • Reul JM, de Kloet ER. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology. 1985 Dec;117(6):2505–2511. [PubMed]
  • Reul JM, de Kloet ER. Anatomical resolution of two types of corticosterone receptor sites in rat brain with in vitro autoradiography and computerized image analysis. J Steroid Biochem. 1986 Jan;24(1):269–272. [PubMed]
  • Van Eekelen JA, Jiang W, De Kloet ER, Bohn MC. Distribution of the mineralocorticoid and the glucocorticoid receptor mRNAs in the rat hippocampus. J Neurosci Res. 1988 Sep;21(1):88–94. [PubMed]
  • De Kloet ER, Reul JM. Feedback action and tonic influence of corticosteroids on brain function: a concept arising from the heterogeneity of brain receptor systems. Psychoneuroendocrinology. 1987;12(2):83–105. [PubMed]
  • Rothuizen J, Reul JM, van Sluijs FJ, Mol JA, Rijnberk A, de Kloet ER. Increased neuroendocrine reactivity and decreased brain mineralocorticoid receptor-binding capacity in aged dogs. Endocrinology. 1993 Jan;132(1):161–168. [PubMed]
  • Besedovsky H, Sorkin E, Keller M, Müller J. Changes in blood hormone levels during the immune response. Proc Soc Exp Biol Med. 1975 Nov;150(2):466–470. [PubMed]
  • Yasuda N, Greer MA. Evidence that the hypothalamus mediates endotoxin stimulation of adrenocorticotropic hormone secretion. Endocrinology. 1978 Mar;102(3):947–953. [PubMed]
  • Dunn AJ. Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: comparison with interleukin-1. J Pharmacol Exp Ther. 1992 Jun;261(3):964–969. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Reul JM, Stec I, Söder M, Holsboer F. Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology. 1993 Jul;133(1):312–320. [PubMed]
  • Reul JM, de Kloet ER, van Sluijs FJ, Rijnberk A, Rothuizen J. Binding characteristics of mineralocorticoid and glucocorticoid receptors in dog brain and pituitary. Endocrinology. 1990 Aug;127(2):907–915. [PubMed]
  • Spencer RL, McEwen BS. Adaptation of the hypothalamic-pituitary-adrenal axis to chronic ethanol stress. Neuroendocrinology. 1990 Nov;52(5):481–489. [PubMed]
  • Spencer RL, Young EA, Choo PH, McEwen BS. Adrenal steroid type I and type II receptor binding: estimates of in vivo receptor number, occupancy, and activation with varying level of steroid. Brain Res. 1990 Apr 23;514(1):37–48. [PubMed]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed]
  • Mosmann TR, Coffman RL. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol. 1989;46:111–147. [PubMed]
  • Cher DJ, Mosmann TR. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol. 1987 Jun 1;138(11):3688–3694. [PubMed]
  • Chaouat G, Menu E, Clark DA, Dy M, Minkowski M, Wegmann TG. Control of fetal survival in CBA x DBA/2 mice by lymphokine therapy. J Reprod Fertil. 1990 Jul;89(2):447–458. [PubMed]
  • Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. [PMC free article] [PubMed]
  • Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993 Jul;14(7):353–356. [PubMed]
  • Balkwill FR, Burke F. The cytokine network. Immunol Today. 1989 Sep;10(9):299–304. [PubMed]
  • di Giovine FS, Duff GW. Interleukin 1: the first interleukin. Immunol Today. 1990 Jan;11(1):13–20. [PubMed]
  • Dahl GM, Telemo E, Weström BR, Jakobsson I, Lindberg T, Karlsson BW. The passage of orally fed proteins from mother to foetus in the rat. Comp Biochem Physiol A Comp Physiol. 1984;77(2):199–201. [PubMed]
  • Ornoy A, Altshuler G. Maternal endotoxemia, fetal anomalies, and central nervous system damage: a rat model of a human problem. Am J Obstet Gynecol. 1976 Jan 15;124(2):196–204. [PubMed]
  • Hall GA, Jones PW. An experimental study of Salmonella dublin abortion in cattle. Br Vet J. 1976 Jan-Feb;132(1):60–65. [PubMed]
  • Haesaert B, Ornoy A. Transplacental effects of endotoxemia on fetal mouse brain, bone, and placental tissue. Pediatr Pathol. 1986;5(2):167–181. [PubMed]
  • Altshuler G. Some placental considerations related to neurodevelopmental and other disorders. J Child Neurol. 1993 Jan;8(1):78–94. [PubMed]
  • Beckmann I, Meisel-Mikołajczyk F, Leszczynski P, Brooijmans M, Wallenburg HC. Endotoxin-induced fetal growth retardation in the pregnant guinea pig. Am J Obstet Gynecol. 1993 Feb;168(2):714–718. [PubMed]
  • TEDESCHI CG, INGALLS TH. Vascular anomalies of mouse fetuses exposed to anoxia during pregnancy. Am J Obstet Gynecol. 1956 Jan;71(1):16–28. [PubMed]
  • Edwards MJ, Penny RH, Zevnik I. A brain cell deficit in newborn guinea-pigs following prenatal hyperthermia. Brain Res. 1971 May 7;28(2):341–345. [PubMed]
  • Zarrow MX, Philpott JE, Denenberg VH. Passage of 14C-4-corticosterone from the rat mother to the foetus and neonate. Nature. 1970 Jun 13;226(5250):1058–1059. [PubMed]
  • Takahashi LK, Kalin NH, Barksdale CM, Vanden Burgt JA, Brownfield MS. Stressor controllability during pregnancy influences pituitary-adrenal hormone concentrations and analgesic responsiveness in offspring. Physiol Behav. 1988;42(4):323–329. [PubMed]
  • Moyer JA, Herrenkohl LR, Jacobowitz DM. Stress during pregnancy: effect on catecholamines in discrete brain regions of offspring as adults. Brain Res. 1978 Apr 7;144(1):173–178. [PubMed]
  • Ward IL. Prenatal stress feminizes and demasculinizes the behavior of males. Science. 1972 Jan 7;175(4017):82–84. [PubMed]
  • Wilke DL, Tseu SR, Rhees RW, Fleming DE. Effects of environmental stress or ACTH treatment during pregnancy on maternal and fetal plasma androstenedione in the rat. Horm Behav. 1982 Sep;16(3):293–303. [PubMed]
  • Dussault JH, Ruel J. Thyroid hormones and brain development. Annu Rev Physiol. 1987;49:321–334. [PubMed]
  • Porterfield SP, Hendrich CE. The role of thyroid hormones in prenatal and neonatal neurological development--current perspectives. Endocr Rev. 1993 Feb;14(1):94–106. [PubMed]
  • Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: the "euthyroid sick syndrome". Endocr Rev. 1982 Spring;3(2):164–217. [PubMed]
  • Burger AG, Hughes JN, Saville E. Starvation and thyroid function: effects on thermogenesis and serum thyrotropin. Life Sci. 1981 Apr 13;28(15-16):1737–1744. [PubMed]
  • Dubuis JM, Dayer JM, Siegrist-Kaiser CA, Burger AG. Human recombinant interleukin-1 beta decreases plasma thyroid hormone and thyroid stimulating hormone levels in rats. Endocrinology. 1988 Nov;123(5):2175–2181. [PubMed]
  • Tuomisto J, Männistö P. Neurotransmitter regulation of anterior pituitary hormones. Pharmacol Rev. 1985 Sep;37(3):249–332. [PubMed]
  • Sawchenko PE, Swanson LW, Steinbusch HW, Verhofstad AA. The distribution and cells of origin of serotonergic inputs to the paraventricular and supraoptic nuclei of the rat. Brain Res. 1983 Oct 31;277(2):355–360. [PubMed]
  • Checkley S. Neuroendocrine mechanisms and the precipitation of depression by life events. Br J Psychiatry Suppl. 1992 Feb;(15):7–17. [PubMed]
  • Holsboer F, Liebl R, Hofschuster E. Repeated dexamethasone suppression test during depressive illness. Normalisation of test result compared with clinical improvement. J Affect Disord. 1982 Jun;4(2):93–101. [PubMed]
  • Greden JF, Gardner R, King D, Grunhaus L, Carroll BJ, Kronfol Z. Dexamethasone suppression tests in antidepressant treatment of melancholia. The process of normalization and test-retest reproducibility. Arch Gen Psychiatry. 1983 May;40(5):493–500. [PubMed]
  • Holsboer-Trachsler E, Stohler R, Hatzinger M. Repeated administration of the combined dexamethasone-human corticotropin releasing hormone stimulation test during treatment of depression. Psychiatry Res. 1991 Aug;38(2):163–171. [PubMed]
  • O'Callaghan E, Sham P, Takei N, Glover G, Murray RM. Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet. 1991 May 25;337(8752):1248–1250. [PubMed]
  • Patrick MJ. Influence of maternal renal infection on the foetus and infant. Arch Dis Child. 1967 Apr;42(222):208–213. [PMC free article] [PubMed]

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