The lactate dehydrogenase (LDH) protein family members characteristically are distributed in tissue- and cell type-specific patterns and serve as the

Lactate dehydrogenase C (LDHC) was, to the best of our knowledge, the first testis‐specific isozyme discovered in male germ cells. In fact, this was accomplished shortly before “isozymes or isoenzymes” became a field of study. LDHC was detected initially in human spermatozoa and spermatogenic cells of the testes by gel electrophoresis. Immunohistochemistry was used to localize LDHC first in early‐pachytene primary spermatocytes, with an apparent increase in quantity after meiosis, to its final localization in and on the principal piece of the sperm tail. After several decades of biologic, biochemical, and genetic investigations, we now know that the lactate dehydrogenase isozymes are ubiquitous in vertebrates, developmentally regulated, tissue and cell specific, and multifunctional. Here, we will review the history of LDHC and the work that demonstrates clearly that it is required for sperm to accomplish their ultimate goal, fertilization.

Autoimmune responses to meiotic germ cell antigens (MGCA) that are expressed on sperm and testis occur in human infertility and after vasectomy. Many MGCA are also expressed as cancer/testis antigens (CTA) in human cancers, but the tolerance status of MGCA has not been investigated. MGCA are considered to be uniformly immunogenic and nontolerogenic, and the prevailing view posits that MGCA are sequestered behind the Sertoli cell barrier in seminiferous tubules. Here, we have shown that only some murine MGCA are sequestered. Nonsequestered MCGA (NS-MGCA) egressed from normal tubules, as evidenced by their ability to interact with systemically injected antibodies and form localized immune complexes outside the Sertoli cell barrier. NS-MGCA derived from cell fragments that were discarded by spermatids during spermiation. They egressed as cargo in residual bodies and maintained Treg-dependent physiological tolerance. In contrast, sequestered MGCA (S-MGCA) were undetectable in residual bodies and were nontolerogenic. Unlike postvasectomy autoantibodies, which have been shown to mainly target S-MGCA, autoantibodies produced by normal mice with transient Treg depletion that developed autoimmune orchitis exclusively targeted NS-MGCA. We conclude that spermiation, a physiological checkpoint in spermatogenesis, determines the egress and tolerogenicity of MGCA. Our findings will affect target antigen selection in testis and sperm autoimmunity and the immune responses to CTA in male cancer patients.

LDH‐C₄ (Ldh3) is a member of the lactate dehydrogenase family of isozymes that catalyze the terminal reaction in the glycolytic pathway. In mammals, 3 genes, ldha, ldhb, and Ldhc, encode the subunits that assemble into catalytically active homo‐ and heterotetramers. Differential expression of these genes determines the lactate dehydrogenase (LDH) isozyme composition of tissues, and, as is well known, A subunits predominate in skeletal muscle and B subunits are abundantly produced in brain and heart, with the Ldh2 isozyme the most abundant form in oocytes. The C peptide can be detected first in pachytene spermatocytes and constitutes the primary LDH of spermatozoa. Originally the Ldhc gene (Ldh3 in terminology applied to murine cells) was considered to be testis specific on the basis of immunochemical, enzymatic, and molecular analyses. Here we report the detection of this isozyme in the murine oocyte and early embryo. Our results indicate that Ldh3 mRNA is transcribed in oocytes and cannot be detected in fertilized eggs. Ldh3 protein, however, persists to the blastocyst stage of embryonic development localizing mainly to the cortex region of oocytes, eggs, zygotes, and embryonic blastomeres.

By targeted disruption of the lactate dehydrogenase c (Ldhc) gene, we demonstrated that spermatozoa require Ldhc for capacitation, motility, and fert

There has been a recent upsurge in interest about contraceptive development, evidenced by the Contraceptive Special Issue of Biology of Reproduction [1], with research funding from the Male Contraceptive Initiative (MCI), and the Bill and Melinda Gates Foundation. Support from the Contraceptive Research Branch of the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD) continues with a marked change in focus in the funding announcements. This has motivated me to reflect on research, mostly from my laboratory starting in the 1960’s to the present, on the development of a male contraceptive based on the sperm specific glycolytic enzyme, Lactate Dehydrogenase C (LDHC₄). This review considers the rationale behind this research, the development paths pursued, obstacles encountered and the renewed interest in going forward toward development of a male contraceptive mediated by inhibition of the sperm specific form of Lactate dehydrogenase (LDHC). I will address how some papers published many years ago are relevant to present goals of non-hormonal contraception and will mention innovative technology now available that can advance this project. This review presumably will serve as an instructive guide for a research program with a focused program related to contraception. As an aside, many of the citations in this review are to most of the 26 publications in Biology of Reproduction co-authored by this investigator and collaborators from 1974 through 2020 not long after the first issue of BOR which was published in April 1969.