Outline

  • Abstract
  • Graphical Abstract
  • Highlights
  • Abbreviations
  • Keywords
  • 1. Introduction
  • 2. Materials and Methods
  • 2.1. Mice
  • 2.1.1. Diets
  • 2.1.2. Colony Founders
  • 2.1.3. F0
  • 2.1.4. F1
  • 2.2. Red Blood Cell Folate Concentrations
  • 2.3. Cauda Epididymal Sperm Counts
  • 2.4. Sperm Chromatin Structure Assay
  • 2.5. Isolation of Dna for Mutation Analysis
  • 2.6. Single Molecule Pcr for Detection of Mutants
  • 2.7. Statistical Analysis
  • 3. Results
  • 3.1. Red Blood Cell Folate Concentrations
  • 3.2. Cauda Epididymal Sperm Counts
  • 3.3. Sperm Chromatin Structure Assay
  • 3.4. Tandem Repeat Mutations
  • 4. Discussion
  • 5. Conclusions
  • Conflict of Interest Statement
  • Role of the Funding Source
  • Acknowledgements
  • References

رئوس مطالب

  • چکیده
  • کلید واژه ها
  • 1.مقدمه
  • 2.مواد و روش ها
  • 2.1. موش ها
  • 2.1.1. رژیم ها
  • 2.1.2. فروریختگی کلونی
  • 2.1.3. F0
  • 2.1.3. F1
  • 2.2. غلظت های فولات سلول قرمز خون
  • 2.3. شمارش اسپرم های اپیدرمال کودا
  • 2.6. PCR تک مولکولی برای یافتن موتانت ها
  • 2.7. آنالیزهای آماری
  • 3. نتایج
  • 3.1. غلظت های سلولی فولات قرمز خون
  • 3.2. شمارش اسپرم کودای اپیدرمال
  • 3.3. آزمایش ساختار کروماتین اسپرم
  • 3.4. موتاسیون های پشت سر‌هم
  • 4. بحث
  • 5. نتیجه گیری
  • نقش منابع مالی

Abstract

To date, fewer than 50 mutagens have been studied for their ability to cause heritable mutations. The majority of those studied are classical mutagens like radiation and anti-cancer drugs. Very little is known about the dietary variables influencing germline mutation rates. Folate is essential for DNA synthesis and methylation and can impact chromatin structure. We therefore determined the effects of folic acid-deficient (0 mg/kg), control (2 mg/kg) and supplemented (6 mg/kg) diets in early development and during lactation or post-weaning on mutation rates and chromatin quality in sperm of adult male Balb/c mice. The sperm chromatin structure assay and mutation frequencies at expanded simple tandem repeats (ESTRs) were used to evaluate germline DNA integrity. Treatment of a subset of mice fed the control diet with the mutagen ethylnitrosourea (ENU) at 8 weeks of age was included as a positive control. ENU treated mice exhibited decreased cauda sperm counts, increased DNA fragmentation and increased ESTR mutation frequencies relative to non-ENU treated mice fed the control diet. Male mice weaned to the folic acid deficient diet had decreased cauda sperm numbers, increased DNA fragmentation index, and increased ESTR mutation frequency. Folic acid deficiency in early development did not lead to changes in sperm counts or chromatin integrity in adult mice. Folic acid supplementation in early development or post-weaning did not affect germ cell measures. Therefore, adequate folic acid intake in adulthood is important for preventing chromatin damage and mutation in the male germline. Folic acid supplementation at the level achieved in this study does not improve nor is it detrimental to male germline chromatin integrity.

Keywords: - - - -

Conclusions

Funding for this project provided by Health Canada A-base and the Canadian Regulatory Systems for Biotechnology. Financial support for B.S. provided by the Canadian Institute of Health Research training program in Reproduction, Early Development and the Impact on Health. The funding sources had no involvement in study design; collection, analysis and interpretation of the data; in the writing of the report or in the decision to submit the article for publication.

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