1. Sponsor Organization: NIH/NIEHS

2. Project Title: 03749-12 THE EFFECTS OF LEAD ON HYPOTHALAMIC/PITUITARY/GONADAL AXIS

3. Project Focus:

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

4. Description:

Environmental exposure to toxic levels of lead occurs in a number of industries with potential adverse effects on reproduction. We have demonstrated using an animal model, that Pb exposure suppresses serum testosterone (T) and spermatogenesis. However, no compensatory increase in circulating gonadotropins occurs and LH levels in Pb exposed castrated male rats do not increase to levels commensurate to those seen in non-Pb treated castrate rats. Recent data demonstrate an increase in hypothalamic levels of GnRH mRNA; and an increase in pituitary levels of luteinizing hormone (LH) mRNA and pituitary stores of LH in Pb-dosed animals. These collective data indicate that Pb disrupts the reproductive axis by interfering with feedback mechanisms at the hypothalamic and pituitary levels. We hypothesize that this disruption occurs either via Pb's inhibition of secretion of GnRH from the hypothalamus and LH from the pituitary; and/or secondary to disruption of production of these hormones at the molecular level via Pb's competition with zinc finger regions within the estradiol (E2) receptor. We will: 1) Determine the mechanisms by which Pb interferes with the secretion of GnRH from the hypothalamus and LH from the pituitary. 2) Determine if Pb disrupts transcription by competing with Zn finger regions within the E2 receptor. 3) Determine the mechanism(s) by which animals chronically exposed to Pb adapt to Pb's toxic effects. 4) Determine if the female reproductive system is disrupted in a fashion similar and analogues to males. 5) Determine if Pb exposure alters methylation patterns in the genes regulating reproductive hormone synthesis and determine if these changes are inherited. From the results of these experiments we will develop a general model which accounts for the disruption by Pb of biologic function at specific metal dependent sites.

5. References:

6. Inventory Category:

• Primary: Models
• Secondary:

7. Inventory Subcategory:

• Primary: Exposure and Risk Models
• Secondary:
  • Basic Research

8. Keywords for Experimental System/Species:

• Species:
  • mammal
  • In Utero,Rat
• Study Type:
  • Laboratory Study
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
  • Reproductive
• Hormonal Measures:
  • Hormone Receptors
  • Moleclur
• Level Of Study:
• Chemistry Metabolism:
  • Toxicokinetics
  • Exposure Monitoring
• Life Stage:
  • Female
  • Male
• Risk Assessment:

10. Chemical Agents:

• Lead

11. Performing Institution:

• HEALTH RESEARCH ASSOCIATION, INC.

12. Contact:

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