Data suggest that the neonatal period is a second critical interval (in addition to the prenatal period) when the nervous system is sensitive to the organizational effects of androgens, and that early postnatal treatment with gonadotropin releasing hormone (GnRH) analogues alters early programming of immune responses in male primates. This proposal seeks to expand the understanding of the importance of neonatal testosterone in sexual and behavioral development and to further assess the impact of neonatal treatment with GnRH analogues on the development of the immune system in male primates. Using animals treated as neonates with a GnRH antagonist, the investigators will further examine the importance of neonatal activation of the pituitary-testicular axis on the timing of puberty, peripubertal endocrine events, skeletal maturation, postpubertal reproductive function (including fertility), and peripubertal and postpubertal sexual and aggressive behavior and laterality. Efforts will continue to define the site(s) (hypothalamus, pituitary or testis) of the physiological defect responsible for abnormal sexual and behavioral function in animals treated as neonates with GnRH analogues. Animals will be tethered and used to assess whether GnRH pulsatility (as measured indirectly by LH assay) is altered by treatment. The tethered animals will also be used to assess the involvement of the endogenous opioid system, CRH and/or subnormal testosterone levels in mediating the reduced gonadotropin response of treated monkeys to excitatory amino acids. The effect of treatment on fertility, Leydig cell ultrastructure, testicular morphology, and spermatogenic efficiency will also be examined. The investigators will also assess the impact of neonatal treatment with a GnRH antagonist or antagonist and androgen on the development of immune function. They will perform experiments designed to identify the effects of neonatal GnRH analogue treatment on: 1) lymphocyte subsets distribution and immunoglobulin production; 2) development of specific immune responses to selected antigens; and 3) selection of the T cell receptor gene products repertoire. The proposed studies will further the understanding of mechanisms governing sexual, skeletal, behavioral and immune system development, and the role that neonatal testosterone plays in this process.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD026423-08
Application #
2392399
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1989-12-01
Project End
1999-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Morehouse School of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30310
Mann, David R; Plant, Tony M (2002) Leptin and pubertal development. Semin Reprod Med 20:93-102
Mann, D R; Akinbami, M A; Gould, K G et al. (2002) Leptin and thyroxine during sexual development in male monkeys: effect of neonatal gonadotropin-releasing hormone antagonist treatment and delayed puberty on the developmental pattern of leptin and thyroxine secretion. Eur J Endocrinol 146:891-8
Mann, D R; Akinbami, M A; Lunn, S F et al. (2000) Endocrine-immune interaction: alteractions in immune function resulting from neonatal treatment with a GnRH antagonist and seasonality in male primates. Am J Reprod Immunol 44:30-40
Mann, D R; Akinbami, M A; Gould, K G et al. (2000) Seasonal variations in cytokine expression and cell-mediated immunity in male rhesus monkeys. Cell Immunol 200:105-15
Herman, R A; Jones, B; Mann, D R et al. (2000) Timing of prenatal androgen exposure: anatomical and endocrine effects on juvenile male and female rhesus monkeys. Horm Behav 38:52-66
Mann, D R; Akinbami, M A; Gould, K G et al. (2000) A longitudinal study of leptin during development in the male rhesus monkey: the effect of body composition and season on circulating leptin levels. Biol Reprod 62:285-91
Mann, D R; Lunn, S F; Akinbami, M A et al. (1999) Effect of neonatal treatment with a GnRH antagonist on development of the cell-mediated immune response in marmosets. Am J Reprod Immunol 42:175-86
Mann, D R; Howie, S; Paulsen, D F et al. (1998) Changes in lymphoid tissue after treatment with a gonadotropin releasing hormone antagonist in the neonatal marmoset (Callithrix jacchus). Am J Reprod Immunol 39:256-65
Prince, F P; Mann, D R; Fraser, H M (1998) Blockade of the hypothalamic-pituitary-testicular axis with a GnRH antagonist in the neonatal marmoset monkey: changes in Leydig cell ultrastructure. Tissue Cell 30:651-61
Gould, K G; Akinbami, M A; Mann, D R (1998) Effect of neonatal treatment with a gonadotropin releasing hormone antagonist on developmental changes in circulating lymphocyte subsets: a longitudinal study in male rhesus monkeys. Dev Comp Immunol 22:457-67

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