title: ALDH Enzyme Expression Is Independent of the Spermatogenic Cycle, and Their Inhibition Causes Misregulation of Murine Spermatogenic Processes.
abstract: Perturbations in the vitamin A metabolism pathway could be a significant cause of male infertility, as well as a target toward the development of a male contraceptive, necessitating the need for a better understanding of how testicular retinoic acid (RA) concentrations are regulated. Quantitative analyses have recently demonstrated that RA is present in a pulsatile manner along testis tubules. However, it is unclear if the aldehyde dehydrogenase (ALDH) enzymes, which are responsible for RA synthesis, contribute to the regulation of these RA concentration gradients. Previous studies have alluded to fluctuations in ALDH enzymes across the spermatogenic cycle, but these inferences have been based primarily on qualitative transcript localization experiments. Here, we show via various quantitative methods that the three well-known ALDH enzymes (ALDH1A1, ALDH1A2, and ALDH1A3), and an ALDH enzyme previously unreported in the murine testis (ALDH8A1), are not expressed in a stage-specific manner in the adult testis, but do fluctuate throughout juvenile development in perfect agreement with the first appearance of each advancing germ cell type. We also show, via treatments with a known ALDH inhibitor, that lowered testicular RA levels result in an increase in blood-testis barrier permeability, meiotic recombination, and meiotic defects. Taken together, these data further our understanding of the complex regulatory actions of RA on various spermatogenic events and, in contrast with previous studies, also suggest that the ALDH enzymes are not responsible for regulating the recently measured RA pulse.
authors.affiliation: School of Molecular Biosciences and the Center for Reproductive Biology, Washington State University, Pullman, Washington.
authors.forename: Travis
authors.initials: T
authors.lastname: Kent
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington.
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Arnold
authors.affiliation: School of Molecular Biosciences and the Center for Reproductive Biology, Washington State University, Pullman, Washington.
authors.forename: Rachael
authors.initials: R
authors.lastname: Fasnacht
authors.affiliation: School of Molecular Biosciences and the Center for Reproductive Biology, Washington State University, Pullman, Washington.
authors.forename: Ross
authors.initials: R
authors.lastname: Rowsey
authors.affiliation: School of Molecular Biosciences and the Center for Reproductive Biology, Washington State University, Pullman, Washington.
authors.forename: Debra
authors.initials: D
authors.lastname: Mitchell
authors.affiliation: School of Molecular Biosciences and the Center for Reproductive Biology, Washington State University, Pullman, Washington.
authors.forename: Cathryn A
authors.initials: CA
authors.lastname: Hogarth
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington.
authors.forename: Nina
authors.initials: N
authors.lastname: Isoherranen
authors.affiliation: School of Molecular Biosciences and the Center for Reproductive Biology, Washington State University, Pullman, Washington mgriswold@vetmed.wsu.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Griswold
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001710:Biotin / Q000378:metabolism; D001814:Blood-Testis Barrier / Q000187:drug effects; D023902:Chromosome Pairing / Q000187:drug effects; D003959:Diamines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008540:Meiosis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D013091:Spermatogenesis / Q000187:drug effects / Q000235:genetics*; D013737:Testis / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism
chemical_list: D003959:Diamines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C002491:N,N'-bis(dichloroacetyl)-1,8-octamethylenediamine; D014212:Tretinoin; D001710:Biotin; D000444:Aldehyde Dehydrogenase
keywords: ALDH; blood-testis barrier; meiosis; retinoic acid; testis