Angiotensin-converting enzyme and male fertility

Angiotensin-converting enzyme and male fertility

^*Department of Pathology and Laboratory Medicine, ^§Departments of Cell Biology and Anatomy and Pediatrics, and ^‖Department of Internal Medicine, University of North Carolina, Chapel Hill, NC 27599-7525; ^‡College de France, Laboratoire de Medecine Experimentale, Paris, France; and ^¶Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Contributed by Oliver Smithies

Abstract

The angiotensin-converting enzyme (ACE; EC 3.4.15.1) gene (Ace) encodes both a somatic isozyme found in blood and several other tissues, including the epididymis, and a testis-specific isozyme (testis ACE) found only in developing spermatids and mature sperm. We recently used gene targeting to disrupt the gene coding for both ACE isozymes in mice and reported that male homozygous mutants mate normally but have reduced fertility; the mutant females are fertile. Here we explore the male fertility defect. We demonstrate that ACE is important for achieving in vivo fertilization and that sperm from mice lacking both ACE isozymes show defects in transport within the oviducts and in binding to zonae pellucidae. Males generated by gene targeting that lack somatic ACE but retain testis ACE are normally fertile, establishing that somatic ACE in males is not essential for their fertility. Furthermore, male and female mice lacking angiotensinogen have normal fertility, indicating that angiotensin I is not a necessary substrate for testis ACE. Males heterozygous for the mutation inactivating both ACE isozymes sire wild-type and heterozygous offspring at an indistinguishable frequency, indicating no selection against sperm carrying the mutation.

Footnotes

↵ † To whom reprint requests should be addressed at: 701 B.B.B., CB#7525, University of North Carolina, Chapel Hill, NC 27599-7525. e-mail: hage{at}med.unc.edu.
ABBREVIATIONS:

ACE,

angiotensin-converting enzyme;

ACE,

human ACE gene;

Ace,

mouse ACE gene;

ST,

Ace allele encoding wild-type somatic and testis ACE isozymes;

st,

Ace allele encoding neither isozyme;

sT,

Ace allele encoding only the testis ACE isozyme