1. Sponsor Organization: NIH/NIEHS

2. Project Title: 06265-05 MECHANISMS OF TOXICITY IN TESTES

3. Project Focus:

• Project Primary Focus: Human Health Effects
• Project Secondary Focus:

4. Description:

The long-term objective of this project is to understand the cellular mechanism of reproductive toxicants, particularly toxicants that also induce the stress response. Cadmium or ethanol, both inducers of the stress or heat-shock response, result in failure of spermatid release in vivo. Inducers of the stress response also cause disruption of microfilaments and loss of tight junctions in cells in vivo and in vitro. Cadmium, heat-shock, and many other toxicants induce the synthesis of the low molecular weight heat-shock protein, hsp27. Hsp27 co-purifies with vinculin, a protein involved in linking microfilaments to cell plasma membranes. Hsp27 also inhibits actin polymerization in vitro. We hypothesize hsp27 is involved in regulation of microfilaments, possibly their attachment to membranes. We further hypothesize that many toxicants affect hsp27 synthesis in vivo and thereby affect abnormally the function of microfilaments and microfilament-dependent structures which may include tight junctions and tubulobulbar complexes in SC and other cell types. As a result, the blood-testis barrier is compromised and spermatid maturation is adversely affected causing failure of spermatid release by SC. To investigate this hypothesis, hsp27, actin microfilament structure, tight junctions and tubulobulbar complexes in SC will be studied. Light and electron microscopy, and immunological methods will be used to study hsp27 distribution and the structure of microfilaments, tight junctions, and tubulobulbar complexes in SC in normal rats and in animals exposed to the stress-inducer cadmium. Immunoprecipitation, affinity chromatography, and gel overlays and blots will be used to investigate interactions of hsp27 with junctional and microfilament-associated proteins. The effect of hsp2 phosphorylation on the ability of hsp27 to affect actin polymerization will be examined.

5. References:

6. Inventory Category:

• Primary: Models
• Secondary:

7. Inventory Subcategory:

• Primary: Basic Research
• Secondary:

8. Keywords for Experimental System/Species:

• Species:
  • Mammal
• Study Type:
  • In Vitro
  • In Vivo
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
  • Reproductive
• Hormonal Measures:
• Level Of Study:
  • Molecular
• Chemistry Metabolism:
  • Stress Response
• Life Stage:
  • Male
• Risk Assessment:

10. Chemical Agents:

• Metals
• Cadmium

11. Performing Institution:

• UNIVERSITY OF MICHIGAN AT ANN ARBOR

12. Contact:

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