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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS024287-01A1
Application #
3408706
Study Section
Toxicology Study Section (TOX)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
School of Medicine & Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Rodier, P M; Ingram, J L; Tisdale, B et al. (1996) Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol 370:247-61
Rodier, P M (1995) Developing brain as a target of toxicity. Environ Health Perspect 103 Suppl 6:73-6
Gavin, C E; Kates, B; Hoffman, G E et al. (1994) Changes in the reproductive system following acute prenatal exposure to ethanol or methylazoxymethanol in the rat: I. Effects on immunoreactive LHRH cell number. Teratology 49:13-9
Rodier, P M; Kates, B; White, W A et al. (1991) The relationship of rat brain weight and pituitary weight to postnatal growth after prenatal exposure to methylazoxymethanol. Neurotoxicol Teratol 13:583-90
Rodier, P M; Kates, B; White, A L (1991) A comparison of hypothalamic cell numbers in dwarf and normal weight rats exposed prenatally to methylazoxymethanol (MAM). Neurotoxicol Teratol 13:591-7
Rodier, P M; Kates, B; White, W A et al. (1991) Effects of prenatal exposure to methylazoxymethanol (MAM) on brain weight, hypothalamic cell number, pituitary structure, and postnatal growth in the rat. Teratology 43:241-51
Rodier, P M (1990) Developmental neurotoxicology. Toxicol Pathol 18:89-95
Rodier, P M; Kates, B; White, W A et al. (1990) Birthdates of the growth hormone releasing factor cells of the rat hypothalamus: an autoradiographic study of immunocytochemically identified neurons. J Comp Neurol 291:363-72
Rodier, P M (1988) Structural--functional relationships in experimentally induced brain damage. Prog Brain Res 73:335-48