Determining the Role of Choline Dehydrogenase in Sperm Cell Function Public Deposited

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  • March 20, 2019
Creator
  • Johnson, Amy R.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
Abstract
  • Approximately 15% of couples suffer from infertility and male factor infertility is the suspected cause in about half of these couples. 40-60% these male factor infertility cases are idiopathic, but genetic aberrations are associated with infertility in as many as 30% of these. Although the relationship between nutrition and reproduction is established, the role of micronutrient metabolism in male fertility is understudied. Choline, an essential nutrient for humans, is important for maintaining a healthy pregnancy and normal fetal development. Choline is necessary for normal mating behavior and male fertility in D. melanogaster but the reason why remains unknown. Choline dehydrogenase (CHDH) catalyzes the conversion of choline into betaine, a methyl group donor and osmolyte. Several single nucleotide polymorphisms (SNPs)within the CHDH gene may alter the function of the CHDH. A choline dehydrogenase knockout mouse (Chdh-/-) was created to model loss-of-function mutations in humans. Mutation of Chdh reduced CHDH activity and decreased betaine concentration in all tissues that normally express this enzyme. Fetal viability, growth and one-year survival rates were not affected. Chdh-/- animals had 59% more plasma homocysteine, but hepatic AdoMet and AdoHcy were unchanged. Chdh-/- males were infertile due to poor sperm motility. Abnormal mitochondrial morphology and function were observed in Chdh-/- sperm. ATP concentration was 55% lower in Chdh-/- sperm. Dietary betaine supplementation resulted in increased Chdh-/- sperm motility, and full restoration of ATP concentration. CHDH SNP rs12676 (G233T; R→L) and IL17βR SNP rs1025689 (G126C; P→P) are associated with changes in mitochondrial function and sperm motility in men. Men who were TT for rs12676 produced sperm with dysmorphic mitochondria. Compared to GG subjects, sperm produced by GT subjects contained 40% less ATP; men who were TT for this SNP had 73% less ATP. Motility characteristics were changed in men with at least one minor allele of either rs12676 or rs1025689. CHDH protein was decreased in primary hepatocytes from individuals who were TT for rs12676, indicating this SNP marks a functional haplotype. We propose that aberrant choline metabolism stemming from decreased CHDH activity may be an underlying cause of idiopathic male factor infertility in men.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition."
Advisor
  • Zeisel, Steven H.
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  • Chapel Hill, NC
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  • Open access
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