title: The Hydroxysteroid (17β) Dehydrogenase Family Gene HSD17B12 Is Involved in the Prostaglandin Synthesis Pathway, the Ovarian Function, and Regulation of Fertility.
abstract: The hydroxysteroid (17beta) dehydrogenase (HSD17B)12 gene belongs to the hydroxysteroid (17β) dehydrogenase superfamily, and it has been implicated in the conversion of estrone to estradiol as well as in the synthesis of arachidonic acid (AA). AA is a precursor of prostaglandins, which are involved in the regulation of female reproduction, prompting us to study the role of HSD17B12 enzyme in the ovarian function. We found a broad expression of HSD17B12 enzyme in both human and mouse ovaries. The enzyme was localized in the theca interna, corpus luteum, granulosa cells, oocytes, and surface epithelium. Interestingly, haploinsufficiency of the HSD17B12 gene in female mice resulted in subfertility, indicating an important role for HSD17B12 enzyme in the ovarian function. In line with significantly increased length of the diestrous phase, the HSD17B+/-females gave birth less frequently than wild-type females, and the litter size of HSD17B12+/-females was significantly reduced. Interestingly, we observed meiotic spindle formation in immature follicles, suggesting defective meiotic arrest in HSD17B12+/-ovaries. The finding was further supported by transcriptome analysis showing differential expression of several genes related to the meiosis. In addition, polyovular follicles and oocytes trapped inside the corpus luteum were observed, indicating a failure in the oogenesis and ovulation, respectively. Intraovarian concentrations of steroid hormones were normal in HSD17B12+/-females, whereas the levels of AA and its metabolites (6-keto prostaglandin F1alpha, prostaglandin D2, prostaglandin E2, prostaglandin F2α, and thromboxane B2) were decreased. In conclusion, our study demonstrates that HSD17B12 enzyme plays an important role in female fertility through its role in AA metabolism.
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Heidi
authors.initials: H
authors.lastname: Kemiläinen
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Marion
authors.initials: M
authors.lastname: Adam
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Jenni
authors.initials: J
authors.lastname: Mäki-Jouppila
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Pauliina
authors.initials: P
authors.lastname: Damdimopoulou
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Anastasios E
authors.initials: AE
authors.lastname: Damdimopoulos
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Outi
authors.initials: O
authors.lastname: Hovatta
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Teemu D
authors.initials: TD
authors.lastname: Laajala
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Tero
authors.initials: T
authors.lastname: Aittokallio
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ryberg
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Leena
authors.initials: L
authors.lastname: Strauss
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling (H.K., M.A., J.M.-J., T.D.L., L.S., M.P.), Institute of Biomedicine, University of Turku, FI-20540 Turku, Finland; Department of Clinical Science, Intervention and Technology (P.D., O.H.), Karolinska Institute, 141 52 Huddinge, Sweden; Swedish Toxicology Sciences Research Center (P.D.), Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Biosciences and Nutrition (A.E.D., J.K.), Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Mathematics and Statistics (T.D.L., T.A.), University of Turku, FI-20014 Turku, Finland; Institute for Molecular Medicine Finland (T.A.), University of Helsinki, FI-00014 Helsinki, Finland; Experimental Genetics (J.A.), Center of Life and Food Sciences, Weihenstephan, 85354 Freising, Germany; Institute of experimental Genetics (J.A.), Helmholtz Zentrum, 81377 München, Germany; Genome Analysis Center (J.A.), German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Neuroscience and Physiology (H.R.), Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; Institute of Medicine (C.O., M.P.), The Sahlgrenska Academy, University of Gothenburg, SE-413 46 Gothenburg, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D030762:Estrous Cycle; D005260:Female; D005298:Fertility; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D008297:Male; D008540:Meiosis; D008810:Mice, Inbred C57BL; D009866:Oogenesis; D010053:Ovary / Q000502:physiology*; D010060:Ovulation; D011453:Prostaglandins / Q000096:biosynthesis*; D011897:Random Allocation
chemical_list: D012739:Gonadal Steroid Hormones; D011453:Prostaglandins; D016718:Arachidonic Acid; D015067:17-Hydroxysteroid Dehydrogenases; C000619440:HSD17B12 protein, mouse