Most attempts to study developmental neurotoxicology have focused on the anatomy or functions of brain regions known to control specific behaviors. From such studies, we know that many behavioral abnormalities seen in brain-damaged humans can be reproduced in laboratory animals. However, many parts of the brain control functions not assessed by behavioral testing. For example, neuroendocrine systems of the hypothalamus control growth, basal metabolism, sexual differentiation, etc. by their actions on the anterior pituitary. We propose to test the hypothesis that neuron groups involved in regulatory functions are subject to injury during development, just as are other neurons and that malfunctions of regulation can occur as birth defects in individuals with no obvious external malformations, just as abnormalities of behavioral function occur in the absence of gross malformations. Special techniques are required to visualize the cells of interest. By combining immunocytochemistry with autoradiography, we have determined the time of proliferation of one cell type in the growth-controlling system, and by exposing these cells to a toxic agent we have produced preliminary evidence that the system can be damaged. We have experience in staining the three major cell types of this system. Therefore, we propose to 1) define the birthdates of somatotropes (growth hormone-producing cells) and growth hormone releasing factor cells (excitatory to somatotropes), as has already been done for the somatostatin cells (inhibitory to somatotropes); 2) reduce the numbers of these cells by exposing rats to methylazoxymethanol or x-ray at the period of development when each cell type forms; 3) evaluate growth from birth to 60 days by body weight and long bone length; 4) measure growth hormone levels at 7, 14, 21, 35, and 60 days and growth hormone response to a known stimulant, morphine sulphate, at 60 days. The results will tell us whether neuroendocrine anomalies can be induced by general teratogens, or whether neuroendocrine systems differ from other CNS regions in their susceptability to early injury. At the completion of these experiments, the data will indicate whether abnormalities of neuroendocrine growth regulation are likely to arise as birth defects. Further, the data will identify the stages of development when such injuries can occur and the pattern of neuroanatomy, pituitary anatomy, growth hormone levels and growth which characterize these defects of the hypothalamic-pituitary axis.
