We have established and investigated a model of prenatal damage to hypothalamic neurons which leads to normal birthweight, followed by a postnatal growth deficiency or growth acceleration which is symmetrical. The results indicate that part of the growth effect of early injury to the brain may be mediated by a subsequent alteration of the development of the pituitary. We propose to refine the model by increasing the rate of growth abnormalities, to determine the mechanism by which the pituitary is altered, and to evaluate the effects of early hypothalamic injury on the endocrine control of the reproductive system. Rats treated with methylazoxymethanol (NUM) on day 12, day 14, or day 15 1/2 of gestation will be compared to controls for: a) Growth (body weight and bone length) and sexual development. b) The number of immunocytochemically-identified neurons containing growth hormone releasing factor (GRF), somatotropin release inhibiting factor (SRIF), or luteinizing hormone releasing hormone (LHRH). c) The proportion of somatotropes, lactotropes, and gonadotropes in the anterior pituitary. d) The size and composition of the pituitary from birth to adulthood. e) The pituitary content of growth hormone (GH), and luteinizing hormone (LH) by RIA. f) The structure of the suprachiasmatic nucleus (cell counts of vasopressin (VP) and vasointestinal peptide (VIP)-positive cells). g) The growth hormone response to GRF in dwarf and giant animals, and the LH response to LHRH in animals treated with MAM on day 12. These will be measured in freely-moving animals with indwelling catheters. The control of mitosis of pituitary cells will be investigated in vivo in controls by treating neonates with anti-GH, anti-GRF, anti-SRIF, or GH. The effect of each on body growth is well-known, but our goal is to determine the effects of each on pituitary growth. While many teratogens have been suspected to alter endocrine function, virtually all the evidence has come from studies of target tissues. This is the first model in which the effects of an initial defect in the hypothalamus will be traced through the pituitary to somatic targets. The overall goal of these studies is to relate endocrine abnormalities to teratologic injury, suggesting a toxicologic etiology for endocrine syndromes of unknown origin.
