Lack of Functional Pregnancy-Associated Plasma Protein-A (PAPPA) Compromises Mouse Ovarian Steroidogenesis and Female Fertility1

Abstract

The insulin-like growth factor (IGF) system plays an important role in regulating ovarian follicular development and steroidogenesis. IGF binding proteins (IGFBP) mostly inhibit IGF actions, and IGFBP proteolysis is a major mechanism for regulating IGF bioavailability. Pregnancy-associated plasma protein-A (PAPPA) is a secreted metalloprotease responsible for cleavage of IGFBP4 in the ovary. The aim of this study was to investigate whether PAPPA plays a role in regulating ovarian functions and female fertility by comparing the reproductive phenotype of wild-type (WT) mice with mice heterozygous or homozygous for a targeted Pappa gene deletion (heterozygous and PAPP-A knockout [KO] mice, respectively). When mated with WT males, PAPP-A KO females demonstrated an overall reduction in average litter size. PAPP-A KO mice had a reduced number of ovulated oocytes, lower serum estradiol levels following equine chorionic gonadotropin administration, lower serum progesterone levels after human chorionic gonadotropin injection, and reduced expression of ovarian steroidogenic enzyme genes, compared to WT controls. In PAPP-A KO mice, inhibitory IGFBP2, IGFBP3, and IGFBP4 ovarian gene expression was reduced postgonadotropin stimulation, suggesting some compensation within the ovarian IGF system. Expression levels of follicle-stimulating hormone receptor, luteinizing hormone receptor, and genes required for cumulus expansion were not affected. Analysis of preovulatory follicular fluid showed complete loss of IGFBP4 proteolytic activity in PAPP-A KO mice, demonstrating no compensation for loss of PAPPA proteolytic activity by other IGFBP proteases in vivo in the mouse ovary. Taken together, these data demonstrate an important role of PAPPA in modulating ovarian function and female fertility by control of the bioavailability of ovarian IGF.

Identification of Single Nucleotide Polymorphism from Indian <i>Bubalus bubalis</i> through Targeted Sequence Capture

“…The gene mediates its action via peptide hormones (like progesterone and growth hormone) and cytokines in target cells and found to be associated with fertilization and embryonic survival rate 27 . Additionally, fibroblast growth factor 2 (FGF2) and progesterone receptor (PGR) were found to be involved in fertilization, development and survival of fertilized embryo [28][29][30] , while growth hormone receptor (GHR), follicle stimulating hormone receptor (FSHR), Leptin (LEP) and pregnancyassociated plasma protein A2 (PAPPA2) were found to be associated with ovulation, calving interval, survival and growth rate of cattle, and perinatal mortality [31][32][33][34][35] . Further, all these proteins, except FGF2, FSHR and PAAPPA2 have direct interaction with each other.…”

Extracellular Signal-regulated Kinase (ERK)-dependent Phosphorylation of Y-Box-binding Protein 1 (YB-1) Enhances Gene Expression in Granulosa Cells in Response to Follicle-stimulating Hormone (FSH)

“…Lhcgr encodes the LH receptor that is required for ovulation, cumulus cell expansion, and the resumption of meiosis (67); Cyp11a1 encodes cytochrome P450 side chain cleavage, the rate-limiting enzyme for progesterone biosynthesis (18,68); the EGFR contributes to LH-stimulated expansion of cumulus granulosa cells, resumption of meiosis, and ovulation (27,69,70); Cyp19a1 encodes aromatase, the rate-limiting enzyme in estrogen biosynthesis (71); Inha encodes for the inhibin hormone subunit inhibin-␣ that inhibits FSH expression by the anterior pituitary (72); Hsd17b1 encodes the enzyme that converts androstenedione and estrone to testosterone and estradiol-17␤, respectively, and is required for normal ovulation and corpus luteum formation (73); and Pappa encodes a secreted metalloproteinase that cleaves IGF-binding proteins and contributes to estrogen and progesterone biosynthesis and to ovulation (74).…”

TPP and TCEP induce oxidative stress and alter steroidogenesis in TM3 Leydig cells

“…by the co-treatment of hCG with 10 −8 M or greater concentration of zearalenone or ␣-zearalenol. Nyegaard et al [53] reported that Pregnancy-Associated Plasma Protein-A (PAPPA), a chemical could cause the reduction of progesterone content, could significantly reduce the P450-17˛1 and 17ˇ-HSD mRNA levels induced by hCG stimuli in mouse ovarian. Thus, the ability to affect hCG inducible steroidogenesis provided a unique functional feature for screening environmental endocrine disruption that may occur during exposure.…”