Regulation of Folliculogenesis by Growth Factors in Piglet Ovary Exposed Prenatally to β-Hydroxy-β-Methylbutyrate (HMB)

Abstract Β-hydroxy-β-methylbutyrate (HMB) is one of the leucine metabolites with protein anabolic effects which makes it very popular among athletes. Previously, it was shown that HMB administered during the prenatal period reduced the pool of primordial follicles and increased the proportion of developing follicles in newborn piglets. This work is a further step to understand these morphological alterations. Therefore, the aim of this study was to examine the effect of prenatal HMB treatment on the expression of the Kit ligand, BMP-4, bFGF, and the IGF-1/IGF-1R system which are the main growth factors controlling follicular development. Excised ovaries from 12 newborn piglets, originated from the control (n=6) and HMB-treated (n=6) sows were used for immunohistochemical and western-blot analysis. The tested proteins were localized within egg nests and ovarian follicles. Furthermore, the western-blot assay indicated higher BMP-4, Kit ligand, and IGF-1R expression, while the level of bFGF and IGF-1 proteins decreased after HMB dietary treatment. These findings show that HMB included into sow diet can modulate the expression of growth factors and thereby alter ovarian morphology in offspring. Therefore, this study opens a discussion about the benefits and risks of the diet supplemented with HMB and its potential application in medicine and animal husbandry, and further research is necessary in this area.

[1]  P. Dobrowolski,et al.  Maternal β-hydroxy-β-methylbutyrate (HMB) supplementation during pregnancy affects early folliculogenesis in the ovary of newborn piglets. , 2019, Theriogenology.

[2]  B. Nieradko-Iwanicka,et al.  β-Hydroxy β-methylbutyrate (HMB) supplementation during pregnancy and perinatal period in animals studies and possible application in humans , 2018 .

[3]  P. Dobrowolski,et al.  A metabolite of leucine (β-hydroxy-β-methylbutyrate) given to sows during pregnancy alters bone development of their newborn offspring by hormonal modulation , 2017, PloS one.

[4]  J. Passos,et al.  Effects of bone morphogenetic protein 4 (BMP4) on in vitro development and survival of bovine preantral follicles enclosed in fragments ovarian tissue , 2017, Zygote.

[5]  Z. Fang,et al.  Transfer of β-hydroxy-β-methylbutyrate from sows to their offspring and its impact on muscle fiber type transformation and performance in pigs , 2017, Journal of Animal Science and Biotechnology.

[6]  P. Dobrowolski,et al.  Prenatally administered HMB modifies the enamel surface roughness in spiny mice offspring: An atomic force microscopy study. , 2016, Archives of oral biology.

[7]  Yan Liu,et al.  Dietary supplementation with β-hydroxy-β-methylbutyrate calcium during the early postnatal period accelerates skeletal muscle fibre growth and maturity in intra-uterine growth-retarded and normal-birth-weight piglets. , 2016, The British journal of nutrition.

[8]  B. Feng,et al.  Effects of Dietary Supplementation of β-hydroxy-β-methylbutyrate on Sow Performance and mRNA Expression of Myogenic Markers in Skeletal Muscle of Neonatal Piglets. , 2016, Reproduction in domestic animals = Zuchthygiene.

[9]  P. Dobrowolski,et al.  Calretinin expression in hippocampus of mouse offspring from dams treated with β-hydroxy-β-methylbutyrate , 2016 .

[10]  J. Qiao,et al.  Basic fibroblast growth factor promotes macaque follicle development in vitro. , 2015, Reproduction.

[11]  K. Vukojević,et al.  Expression pattern of RAGE and IGF-1 in the human fetal ovary and ovarian serous carcinoma. , 2015, Acta histochemica.

[12]  Yuan Cheng,et al.  Intraovarian control of early folliculogenesis. , 2015, Endocrine reviews.

[13]  D. Sloboda,et al.  Early-life nutritional effects on the female reproductive system. , 2015, The Journal of endocrinology.

[14]  Liying Yan,et al.  Basic fibroblast growth factor promotes the development of human ovarian early follicles during growth in vitro. , 2014, Human reproduction.

[15]  J. Stark,et al.  Role of Insulin-like growth factors in initiation of follicle growth in normal and polycystic human ovaries. , 2013, The Journal of clinical endocrinology and metabolism.

[16]  Jeffrey R Stout,et al.  International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB) , 2013, Journal of the International Society of Sports Nutrition.

[17]  P. Theil,et al.  Body composition of piglets from sows fed the leucine metabolite β-hydroxy β-methyl butyrate in late gestation. , 2012, Journal of animal science.

[18]  C. Junien,et al.  Maternal environment and the reproductive function of the offspring. , 2012, Theriogenology.

[19]  G. Smith,et al.  Effects of maternal environment during gestation on ovarian folliculogenesis and consequences for fertility in bovine offspring. , 2012, Reproduction in domestic animals = Zuchthygiene.

[20]  A. Childs,et al.  BMP Signaling in the Human Fetal Ovary is Developmentally Regulated and Promotes Primordial Germ Cell Apoptosis , 2010, Stem cells.

[21]  M. Matos,et al.  Expression of protein and mRNA encoding Insulin Growth Factor-I (IGF-I) in goat ovarian follicles and the influence of IGF-I on in vitro development and survival of caprine preantral follicles , 2010 .

[22]  C. Tingen,et al.  The primordial pool of follicles and nest breakdown in mammalian ovaries. , 2009, Molecular human reproduction.

[23]  Jacob M. Wilson,et al.  Effects of beta-hydroxy-beta-methylbutyrate (HMB) on exercise performance and body composition across varying levels of age, sex, and training experience: A review , 2008, Nutrition & metabolism.

[24]  W. Krupski,et al.  Prenatal programming of skeletal development in the offspring: effects of maternal treatment with beta-hydroxy-beta-methylbutyrate (HMB) on femur properties in pigs at slaughter age. , 2007, Bone.

[25]  Z. Bielańska-Osuchowska.  Oogenesis in pig ovaries during the prenatal period: ultrastructure and morphometry. , 2006, Reproductive biology.

[26]  E. McLaughlin,et al.  Kit ligand and c-Kit have diverse roles during mammalian oogenesis and folliculogenesis. , 2006, Molecular human reproduction.

[27]  K. Møllgård,et al.  Stem cell factor and c-Kit in human primordial germ cells and fetal ovaries , 2005, Molecular and Cellular Endocrinology.

[28]  Mahmoud R Hussein,et al.  Apoptosis in the ovary: molecular mechanisms. , 2005, Human reproduction update.

[29]  Zhaoyuan Hu,et al.  Anti‐apoptotic action of stem cell factor on oocytes in primordial follicles and its signal transduction , 2005, Molecular reproduction and development.

[30]  Y. Miyake,et al.  Differential expression of bone morphogenetic protein 4-6 (BMP-4, -5, and -6) and growth differentiation factor-9 (GDF-9) during ovarian development in neonatal pigs. , 2004, Domestic animal endocrinology.

[31]  J. L. Stanton,et al.  Basic fibroblast growth factor expression in isolated small human ovarian follicles. , 2004, Molecular human reproduction.

[32]  M. Skinner,et al.  Kit ligand and basic fibroblast growth factor interactions in the induction of ovarian primordial to primary follicle transition , 2004, Molecular and Cellular Endocrinology.

[33]  H. Yao,et al.  AMH induces mesonephric cell migration in XX gonads , 2003, Molecular and Cellular Endocrinology.

[34]  K. Song,et al.  Follicular Expression of c-Kit/SCF and Inhibin-α in Mouse Ovary During Development , 2003 .

[35]  M. Skinner,et al.  Bone Morphogenetic Protein-4 Acts as an Ovarian Follicle Survival Factor and Promotes Primordial Follicle Development1 , 2003, Biology of reproduction.

[36]  K. Song,et al.  Follicular expression of c-Kit/SCF and inhibin-alpha in mouse ovary during development. , 2003, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[37]  M. De Felici,et al.  KL/KIT co-expression in mouse fetal oocytes. , 2002, The International journal of developmental biology.

[38]  M. Skinner,et al.  Insulin but not insulin-like growth factor-1 promotes the primordial to primary follicle transition , 2002, Molecular and Cellular Endocrinology.

[39]  M. Skinner,et al.  Leukemia inhibitory factor (LIF) promotes the primordial to primary follicle transition in rat ovaries , 2002, Molecular and Cellular Endocrinology.

[40]  R. Kaul,et al.  Insulin like growth factor 1 and regulation of ovarian function in mammals. , 2002, Indian journal of experimental biology.

[41]  M. Skinner,et al.  Basic fibroblast growth factor induces primordial follicle development and initiates folliculogenesis , 2001, Molecular and Cellular Endocrinology.

[42]  R. van den Hurk,et al.  Insulin‐like growth factor‐I (IGF‐I) stimulates the development of cultured rat pre‐antral follicles , 2001, Molecular reproduction and development.

[43]  R. Cortvrindt,et al.  Roles of KIT and KIT LIGAND in ovarian function. , 2000, Reviews of reproduction.

[44]  R. Cortvrindt,et al.  Effects of kit ligand and anti‐kit antibody on growth of cultured mouse preantral follicles , 2000, Molecular reproduction and development.

[45]  R. D. Roberts,et al.  Mitogenic effects of fibroblast growth factors on chicken granulosa and theca cells in vitro. , 1999, Biology of reproduction.

[46]  J. Tilly,et al.  Oocyte apoptosis: like sand through an hourglass. , 1999, Developmental biology.

[47]  M. Skinner,et al.  Kit-Ligand/Stem Cell Factor Induces Primordial Follicle Development and Initiates Folliculogenesis1. , 1999, Endocrinology.

[48]  P. Donahoe,et al.  Requirement for phosphatidylinositol-3'-kinase in cytokine-mediated germ cell survival during fetal oogenesis in the mouse. , 1999, Endocrinology.

[49]  P. Donovan,et al.  Role of fibroblast growth factors and their receptors in mouse primordial germ cell growth. , 1998, Biology of reproduction.

[50]  S. Tsang,et al.  Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[51]  I. Konishi,et al.  Immunohistochemical localization of basic fibroblast growth factor (bFGF) during folliculogenesis in the human ovary. , 1997, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[52]  J. Baker,et al.  Effects of an Igf1 gene null mutation on mouse reproduction. , 1996, Molecular endocrinology.

[53]  W. Tilley,et al.  Immunohistochemical localization of basic fibroblast growth factor in bovine ovarian follicles , 1995, Molecular and Cellular Endocrinology.

[54]  R. Rodgers,et al.  Anchorage-independent culture of bovine granulosa cells: the effects of basic fibroblast growth factor and dibutyryl cAMP on cell division and differentiation. , 1994, Experimental cell research.

[55]  D. Monniaux,et al.  Control of proliferation and differentiation of ovine granulosa cells by insulin-like growth factor-I and follicle-stimulating hormone in vitro. , 1992, Biology of reproduction.

[56]  D. Gospodarowicz,et al.  Fibroblast and epidermal growth factors are mitogenic agents for cultured granulosa cells of rodent, porcine, and human origin. , 1979, Endocrinology.

[57]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[58]  T. Pedersen,et al.  Proposal for a classification of oocytes and follicles in the mouse ovary. , 1968, Journal of reproduction and fertility.

[59]  Board on Agriculture,et al.  Nutrient requirements of swine , 1964 .