A group of large volume, commercially important environmental and industrial toxicants - including the acrylamides, organophosphorus esters and the hexacarbons - selectively injure the nervous system and male reproductive system. Research in this laboratory, supported by ROl ES05033 entitled """"""""Environmental/Industrial Toxicants and Testicular Injury"""""""" and funded through 08/31/93, has focused on the testicular Sertoli cell cytoskeleton as a target for these toxicants. A Research Career Development Award provides an opportunity to expand the scope of research by emphasizing a multifaceted approach to they investigation of these combined neuronal/testicular toxicants. The candidate, Kim Boekelheide, M.D., Ph.D., is Assistant Professor (tenure track} the Department of Pathology and Laboratory Medicine at Brown University. Receipt of a Research Career Development Award will relieve him of non-research-related administrative and teaching burdens which currently occupy 50% of his time. The expectation is that Dr. Boekelheide will continue to take advantage of the fine basic science research available and advance in his research career at Brown University. A manuscript recently accepted for publication in The Journal of Cell biology (M.D. Neely and K. Boekelheide, """"""""Sertoli cell processes have axoplasmic features: an ordered microcubule distribution and an abundance high molecular weight microtubule associated protein (cycoplasmic dynein)""""""""), describes the comparative approach taken to elucidate shared features of neuronal and testicular cytoskeletons. This proposal will continue the basic description of common cytoskeletal features and examine unique neuronal/ testicular cytoskeletal components as targets for toxicant-induced injury. The following specific hypothesis will be tested: 1) intoxication with some toxicants inhibits the function of the cytoplasmic dynein found in Sertoli cells and axons, 2) inhibition of the function of this microtubule motor blocks retrograde transport in the axon and vesicle transport in the Sertoli cell, and 3) failure of retrograde axonal transport results in a localized axonopathy with associated distal degeneration while failure of Sertoli cell vesicle transport leads to germ cell necrosis and sloughing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Modified Research Career Development Award (K04)
Project #
5K04ES000193-04
Application #
3072770
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Brown University
Department
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Redenbach, D M; Hall, E S; Boekelheide, K (1995) Distribution of Sertoli cell microtubules, microtubule-dependent motors, and the Golgi apparatus before and after tight junction formation in developing rat testis. Microsc Res Tech 32:504-19
Hall, E S; Hall, S J; Boekelheide, K (1995) 2,5-Hexanedione exposure alters microtubule motor distribution in adult rat testis. Fundam Appl Toxicol 24:173-82
Redenbach, D M; Boekelheide, K (1994) Microtubules are oriented with their minus-ends directed apically before tight junction formation in rat Sertoli cells. Eur J Cell Biol 65:246-57
Redenbach, D M; Richburg, J H; Boekelheide, K (1994) Microtubules with altered assembly kinetics have a decreased rate of kinesin-based transport. Cell Motil Cytoskeleton 27:79-87
Richburg, J H; Redenbach, D M; Boekelheide, K (1994) Seminiferous tubule fluid secretion is a Sertoli cell microtubule-dependent process inhibited by 2,5-hexanedione exposure. Toxicol Appl Pharmacol 128:302-9
McBurney, M W; Staines, W A; Boekelheide, K et al. (1994) Murine PGK-1 promoter drives widespread but not uniform expression in transgenic mice. Dev Dyn 200:278-93
Johnson, K J; Boekelheide, K (1993) Visualization of Golgi complexes and spermatogonial cohorts of viable, intact seminiferous tubules. J Histochem Cytochem 41:299-306
Allard, E K; Johnson, K J; Boekelheide, K (1993) Colchicine disrupts the cytoskeleton of rat testis seminiferous epithelium in a stage-dependent manner. Biol Reprod 48:143-53
Boekelheide, K; Lee, J W; Hall, S J et al. (1993) A tumorigenic murine Sertoli cell line that is temperature-sensitive for differentiation. Am J Pathol 143:1159-68
Hall, E S; Hall, S J; Boekelheide, K (1992) Sertoli cells isolated from adult 2,5-hexanedione-exposed rats exhibit atypical morphology and actin distribution. Toxicol Appl Pharmacol 117:9-18

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