Animal Reproduction (AR)
Animal Reproduction (AR)
Conference Paper

Understanding the uterine environment in early pregnancy in cattle: How have the omics enhanced our knowledge?

Constantine A. Simintiras, Niamh Forde

Downloads: 0
Views: 1152


Early pregnancy loss in cattle can be attributed to a myriad of sources. One key factor that can influence early pregnancy success or loss is the influence and interactions between the maternal environment and the developing embryo/conceptus. Recent advances in high-throughput ‘omics' technologies coupled with improved bioinformatics capabilities represent a promising avenue for enhancing our understanding of fundamental developmental events – which would have direct agricultural, veterinary, and economic benefits. Thusly this review revolves around recent applications of advanced transcriptomic, proteomic, and metabolomic analyses within a bovine uterine secretomic and interactomic context, with an overriding aim to highlight the advantages of these emerging fields whilst identifying areas for improvement, consideration, and further research and development.


phenomics, interactomics, proteomics, hormonomics, metabolomics, transcriptomics, epigenomics, genomics, uterine biology, reproductive physiology, maternal-embryo communication.


Abd-Elhafeez HH, Soliman SA. 2017. New description of telocyte sheaths in the bovine uterine tube: an immunohistochemical and scanning microscopic study. Cells Tissues Organs, 203:295-315.

Alexopoulos NI, Vajta G, Maddox-Hyttel P, French AJ, Trounson AO. 2005. Stereomicroscopic and histological examination of bovine embryos following extended in vitro culture. Reprod Fertil Dev, 17:799- 808.

Bartol FF, Roberts RM, Bazer FW, Lewis GS, Godkin JD, Thatcher WW. 1985. Characterization of proteins produced in vitro by periattachment bovine conceptuses. Biol Reprod, 32:681-693.

Bauersachs S, Ulbrich SE, Gross K, Schmidt SE, Meyer HH, Einspanier R, Wenigerkind H, Vermehren M, Blum H, Sinowatz F, Wolf E. 2005.

Gene expression profiling of bovine endometrium during the oestrous cycle: detection of molecular pathways involved in functional changes. J Mol Endocrinol, 34:889-908.

Bauersachs S, Ulbirch SE, Gross K, Schmidt SEM, Meyer HH, Wenigerkind H, Vermehren M, Blum H, Wolf E. 2006. Embryo-induced transcriptome changes in bovine endometrium reveal species-specific and common molecular markers of uterine receptivity.

Reproduction, 132:319-331. Bauersachs S, Ulbrich SE, Zakhartchenko V, Minten M, Reichenbach M, Reichenbach HD, Blum H, Spencer TE, Wolf E. 2009. The endometrium responds differently to cloned versus fertilized embryos. Proc Natl Acad Sci, 106:5681-5686.

Bauersachs S, Ulbrich SE, Reichenbach HD, Reichenbach M, Buttner M, Meyer HH, Spencer TE, Minten M, Sax G, Winter G, Wolf E. 2012. Comparison of the effects of early pregnancy with human interferon, alpha 2 (IFNA2), on gene expression in bovine endometrium. Biol Reprod, 86:46. Bazer FW, Spencer TE, Johnson GA, Burghardt RC. 2011. Uterine receptivity to implantation of blastocysts in mammals. Front Biosci (Schol Ed), 3:745-767.

Berjemo-Alvarez P, Rizos D, Rath D, Lonergan P, Gutierrez-Adan A. 2010. Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts. Proc Natl Acad Sci, 107(8):3394-3399.

Betteridge KJ, Eaglesome MD, Randall GCB, Mitchell D. 1980. Collection, description and transfer of embryos from cattle 10-16 days after oestrus. J Reprod. Fertil, 59:205-216.

Binelli M, Scolari SC, Pugliesi G, Van Hoeck V, Gonella-Diaza AM, Andrade SCS, Gasparin GR, Coutinho LL. 2015. The transcriptome signature of the receptive bovine uterus determined at early gestation. PLoS One, 10:e0122874. doi:10.1371/journal. pone.0122874.

Black SG, Arnaud F, Burghardt RC, Satterfield MC, Fleming JA, Long CR, Hanna C, Murphy L, Biek R, Palmarini M, Spencer TE. 2010. Viral particles of endogenous betaretroviruses are released in the sheep uterus and infect the conceptus trophectoderm in a transspecies embryo transfer model. J Virol, 84:9078- 9085.

Brandão DO, Maddox-Hyttel P, Lovendahl P, Rumpf R, Stringfellow D, Callesen D. 2004. Post hatching development: a novel system for extended in vitro culture of bovine embryos. Biol Reprod, 71:2048- 2055.

Brooks K, Burns G, Spencer TE. 2014. Conceptus elongation in ruminants: roles of progesterone, prostaglandin, interferon tau and cortisol. J Anim Sci Biotechnol, 5:53. 53.

Burns G, Brooks K, Wildung M, Navakanitworakul R, Christenson LK, Spencer TE. 2014. Extracellular vesicles in luminal fluid of the ovine uterus. PLoS One, 9:e90913.

Burns GW, Brooks KE, Spencer TE. 2016. Extracellular vesicles originate from the conceptus and uterus during early pregnancy in sheep. Biol Reprod, 94:1-11.

Campoy I, Lanau L, Altadill T, Sequeiros T, Cabrera S, Cubo-Abert M, Pérez-Benavente A, Garcia 4, Borrós S, Santamaria A, Ponce J, MatiasGuiu X, Reventós J, Gil-Moreno A, Rigau M, Colas E. 2016. Exosome-like vesicles in uterine aspirates: a comparison of ultracentrifugation-based isolation protocols. J Transl Med, 14:180.

Carter F, Forde N, Duffy P, Wade M, Fair T, Crowe MA, Evans AC, Kenny DA, Roche JF, Lonergan P. 2008. Effect of increasing progesterone concentration from day 3 of pregnancy on subsequent embryo survival and development in beef heifers. Reprod Fertil Dev, 20:368-375

Cerri RL, Thompson IM, Kim IH, Ealy AD, Hansen PJ, Staples CR, Li JL, Santos JE, Thatcher WW. 2012. Effects of lactation and pregnancy on gene expression of endometrium of Holstein cows at day 17 of the estrous cycle or pregnancy. J Dairy Sci, 95:5657- 5675.

Chen S, Palma-Vera SE, Langhammer M, Galuska SP, Braun BC, Krause E, Lucas-Hahn A, Schoen J. 2017. An air-liquid interphase approach for modeling the early embryo-maternal contact zone. Sci Rep, 7:42298.

Cheong Y, Boomsma C, Heijnen C, Macklon N. 2013. Uterine secretomics: a window on the maternalembryo interface. Fertil Steril, 99:1093-1099.

Ciontea SM, Radu E, Regalia T, Ceafalan L, Cretoiu D, Gherghiceanu M, Braga RI, Malincenco M, Zagrean L, Hinescu ME, Popescu LM. 2005. C-kit immunopositive interstitial cells (Cajal-type) in human myometrium. J Cell Mol Med, 9:407420. Cretoiu SM, Cretoiu D, Marin A, Radu BM, Popescu LM. 2013. Telocytes: ultrastructural, immunohistochemical and electrophysiological characteristics in human myometrium. Reproduction, 145:357-370.

Einer-Jensen N, Hunter RHF. 2005. Counter-current transfer in reproductive biology. Reproduction, 129:9- 18.

Forde N, Spencer TE, Bazer FW, Song G, Roche JF, Lonergan P. 2009. Effect of pregnancy and progesterone concentration on expression of genes encoding for transporters or secreted proteins in the bovine endometrium. Phys Genomics, 41:53-62.

Forde N, Beltman ME, Duffy GB, Duffy P, Mehta JP, O’Gaora P, Roche JF, Lonergan P, Crowe MA. 2011a. Changes in the endometrial transcriptome during the bovine estrous cycle: effect of low circulating progesterone and consequences for conceptus elongation. Biol Reprod, 84:266-278.

Forde N, Carter F, Spencer TE, Bazer FW, Sandra O, Mansouri-Attia N, Mehta JP, McBride JP, O’Gaora P, Roche JF, Lonergan P. 2011b.

Conceptus-induced changes in the endometrial transcriptome: how soon does the cow know she is pregnant? Biol Reprod, 85:144-156.

Forde N, Duffy GB, McGettigan PA, Browne JA, Mehta JP, Kelly AK, Mansouri-Attia N, Sandra O, Loftus BJ, Crowe MA, Fair T, Roche JF, Lonergan P, Evans ACO. 2012a. Evidence for an early endometrial response to pregnancy in cattle: both dependent upon and independent of interferon tau. Physiol Genomics, 44:799-810.

Forde N, Lonergan P. 2012. Transcriptomic analysis of the bovine endometrium: What is required to establish uterine receptivity to implantation in cattle? J Reprod Dev, 58:189-195.

Forde N, Mehta, JP, Minten M, Crowe MA, Roche JF, Spencer TE, Lonergan P. 2012b. Effects of low progesterone on the endometrial transcriptome in cattle. Biol Reprod, 87:1–11.

Forde N, McGettigan PA, Mehta JP, O’Hara L, Mamo S, Bazer FW, Spencer TE, Lonergan P. 2014a. Proteomic analysis of uterine fluid during the pre-implantation period of pregnancy in cattle. Reproduction, 147:575-587.

Forde N, Simintiras CA, Sturmey RG, Mamo S, Spencer TE, Bazer FW, Lonergan P. 2014b. Amino acids in the uterine luminal fluid reflect the temporal changes in transporter expression in the endometrium and conceptus during early pregnancy in cattle. Plos One,9(6):e100010. doi: 10.1371/journal.pone.0100010.

Forde N, Bazer FW, Spencer TE, Lonergan P. 2015. Conceptualizing the endometrium: identification of conceptus-derived proteins during early pregnancy in cattle. Biol Reprod, 92:1-13.

Forde N, Maillo V, O’Agora P, Simintiras CA, Sturmey RG, Ealy AD, Spencer TE, Gutierrez-Adan A, Rizos D, Lonergan P. 2016. Sexually dimorphic gene expression in male and female bovine conceptuses at the initiation of implantation. Biol Reprod, 95:92. doi: biolreprod.116.139857.

Gandomi A, Haider M. 2015. Beyond the hype: big data concepts, methods, and analytics. Int J Info Manag, 35:137-144.

Gao H, Wu G, Spencer TE, Johnson GA, Li X, Bazer FW. 2009. Select nutrients in the ovine uterine lumen. I. Amino acids, glucose, and ions in uterine lumenal flushings of cyclic and pregnant ewes. Biol Reprod, 93:86-93.

Garrett JE, Geisert RD, Zavy MT, Morgan GL. 1988. Evidence for maternal regulation of early conceptus growth and development in beef cattle. J Reprod Fertil, 84:437-446.

Gray CA, Bartol FF, Tarleton BJ, Wiley AA, Johnson GA, Bazer FW, Spencer TE. 2001. Developmental biology of uterine glands. Biol Reprod, 63:1311-1323.

Groebner AE, Rubio-Aliaga I, Schulke K, Reichenbach HD, Daniel H, Wolf E, Meyer HHD, Ulbrich SE. 2011. Increase of essential amino acids in the bovine uterine lumen during preimplantation development. Reproduction, 141:685-695.

Hatta K, Huang M, Weisel RD. 2012. Culture of rat endometrial telocytes. J Cell Mol Med, 16:1392-1396.

Healy LL, Cronin JG, Sheldon IM. 2014. Endometrial cells sense and react to tissue damage during infection of the bovine endometrium via interleukin 1. Sci Rep, 4:7060.

Helmer SD, Hansen PJ, Thatcher WW, Johnson JW. Bazer FW. 1989. Intrauterine infusion of highly enriched bovine trophoblast protein- complex exerts an antiluteolytic effect to extend corpus luteum lifespan in cyclic cattle. J Reprod Fertil, 87:89-101.

Horgen RP, Kenny LC. 2011. Omic technologies: genomics, transcriptomics, proteomics and metabolomics. Obstetr Gynaecol, 13:189-195.

Hugentobler SA, Morris DG, Kane MT, Sreenan JM. 2004. In situ oviduct and uterine pH in cattle. Theriogenology.2004 61:1419-1427.

Hugentobler SA, Diskin MG, Leese HJ, Humpherson, PG, Watson T, Sreenan JM, Morris DG. 2007a. Amino acids in oviduct and uterine fluid and blood plasma during the estrous cycle in the bovine. Mol Reprod Dev, 74:445-454.

Hugentobler SA, Morris DG, Sreenan JM, Diskin MG. 2007b. Ion concentrations in oviduct and uterine fluid and blood serum during the estrous cycle in the bovine. Theriogenology, 68:538-548

Hugentobler SA, Humpherson PG, Leese HJ, Sreenan JM, Morris DG. 2008. Energy substrates in bovine oviduct and uterine fluid and blood plasma during the oestrous cycle. Mol Reprod Dev, 75:496-503.

Hussain AM, Daniel RCW, O’Boyle D. 1989. Nacetyl-β-D-glucosaminidase activity in bovine uterine fluid and blood serum during the postpartum period. Theriogenology, 32:507-514.

Ioannidis J, Donadeu FX. 2017. Changes in circulating microRNA levels can be identified as early as day 8 of pregnancy in cattle. PLoS One, 12:e0174892. pone.0174892.

Klein C, Bauersachs S, Ulbrich SE, Einspanier R, Meyer HH, Schmidt SE, Reichenbach HD, Vermehren M, Sinowatz F, Blum H, Wolf E. 2006.

Monozygotic twin model reveals novel embryo-induced transcriptome changes of bovine endometrium in the preattachment period. Biol Reprod, 74:253-264.

Knickenbocker JJ, Thatcher WW, Bazer FW, Drost M, Barron DH, Fincher KB, Roberts RM. 1986a.

Proteins secreted by day 16 to 18 bovine conceptuses extend corpus luteum function in cows. J Reprod Fertil, 77:381-391.

Knickerbocker JJ, Thatcher WW, Foster DB, Wolfenson D, Bartol FF, Caton D. 1986b. Uterine prostaglandin and blood flow responses to estradiol-17 beta in cyclic cattle. Prostaglandins, 31:757-776.

Krisher RL, Schoolcraft WB, Katz-Jaffe MG. 2015. Omics as a window to view embryo viability. Fertil Steril, 103:333-341.

Leese HJ. Hugentobler SA, Gray SM, Morris DG, Sturmey RG, Whitear SL, Sreenan JM. 2008. Female reproductive tract fluids: composition, mechanism of formation and potential role in the developmental origins of health and disease. Reprod Fertil Dev, 20:1-8.

Leese HJ. 2012. Metabolism of the preimplantation embryo: 40 Years on. Reproduction, 143:417-427.

Lonergan P, Forde N, Spencer TE. 2016. Progesterone and conceptus-derived factors important for conceptus survival and growth. Anim Reprod, 13:143-152.

Machtinger R, Combelles CMH, Missmer SA, Correia KF, Fox JH, Racowsky C. 2012. The association between severe obesity and characteristics of failed fertilized oocytes, Hum Reprod, 27:3198-3207.

Mansouri-Attia N, Aubert J, Reinaud P, GiraudDelville C, Taghouti G, Galio L, Everts RE, Degrelle S, Richard C, Hue I, Yang X, Tian XC, Lewin HA, Renard JP, Sandra O. 2009a. Gene expression profiles of bovine caruncular and intercaruncular endometrium at implantation. Physiol Genomics, 39:14-27.

Mansouri-Attia N, Sandra O, Aubert J, Degrelle S, Everts RE, Giraud-Delville C, Heyman Y, Galio, L, Hue I, Yang X, Tian XC, Lewin HA, Renard JP. 2009b Endometrium as an early sensor of in vitro embryo manipulation technologies. Proc Natl Acad Sci USA, 106:5687-5692.

Meier S, Mitchell MD, Walker CG, Roche JR, Verkerk GA. 2014. Amino acid concentrations in uterine fluid during early pregnancy differ in fertile and subfertile dairy cow strains. J Dairy Sci, 97:1364-1376.

Mesquita FS, Ramos RS, Pugliesi G, Andrade SCS, Van Hoeck V, Langbeen A, Oliveira ML, GonellaDiaza AM, Gasparin G, Fukumasu H, Pulz LH, Membrive CM, Coutinho LL, Binelli M. 2015. The receptive endometrial transcriptomic signature indicates an earlier shift from proliferation to metabolism at early diestrus in the cow. Biol Reprod, 93:52. doi: 10.1095/biolreprod.115.129031.

Mochida K, Shinozaki K. 2017. Advances in omics and bioinformatics tools for systems analyses of plant functions. Plant Cell Physiol, 52:2017-2038.

Morris DG, Humpherson PG, Leese HJ, Sreenan JM. 2002. Amino acid turnover by elongating cattle blastocysts recovered on days 14-16 after insemination. Reproduction, 124:667-673.

Northey DL, French LR. 1980. Effect of embryo removal and intrauterine infusion of embryonic homogenates on the lifespan of the bovine corpus luteum. J Anim Sci, 50:298-302.

Popescu LM, Faussone-Pellegrini MS. 2010. Telocytes: a case of serendipity: the winding way from interstitial cells of cajal (ICC), via interstitial cajal-like cells (ICLC) to telocytes. J Cell Mol Med, 14:729-740.

Raposo G. Stoorvogel W. 2013. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol, 200:373-383.

Roatesi I, Radu BM, Cretiou D, Cretiou SM. 2015. Uterine telocytes: a review of current knowledge. Biol Reprod, 93:10. doi:10.1095/biolreprod.114.125906.

Saadelin IM, Oh HJ, Lee BC. 2015. Embryonicmaternal cross-talk via exosomes: potential implications. Stem Cells and Cloning, 8:103-107.

Sathyapalan T, David R, Gooderham NJ, Atkin SL. 2015. Increased expression of circulating miRNA-93 in women with polycystic ovary syndrome may represent a novel, non-invasive biomarker for diagnosis. Sci Rep, 5:16890.

Sheldon IM, Cronin JG, Healey GD, Gabler C, Heuwieser W, Streyl D, Bromfield JJ, Miyamoto A, Fergani C, Dobson H. 2014. Innate immunity and inflammation of the bovine female reproductive tract in health and disease. Reproduction, 48:41-51.

Simintiras CA, Fröhlich T, Sathyapalan T, Arnold G, Ulbrich S, Leese HJ, Sturmey RG. 2017. Modelling aspects of oviduct fluid formation in vitro. Reproduction, 153:23-33.

Simintiras CA, Sturmey RG. 2017. Genistein crosses the bioartificial oviduct and alters secretion composition. Reprod Toxicol, 71:63-70.

Singh J. Murray RD, Mshelia G, Woldehiwet Z. 2008. The immune status of the bovine uterus during the peripartum period. Vet J, 175:301-309.

Souza DK, Salles LP, Rosa e Silva AAM. 2015. Aspects of energetic substrate metabolism of in vitro and in vivo bovine embryos. Braz J Med Biol Res, 48:191-197.

Spencer TE, Forde N, Lonergan P. 2016. The role of progesterone and conceptus-derived factors in uterine biology during early pregnancy in ruminants. J Dairy Sci,2016 99:5941-5950.

Sturmey RG, Rizos D, Leese HJ. 2010. Amino acid metabolism of bovine blastocysts: a biomarker of sex and viability. Mol Reprod Dev, 77:285-296.

Velazquez MA, Parrilla I, Soom AV, Verberckmoes S. 2010. Sampling techniques for oviductal and uterine luminal fluid in cattle. Theriogenology,; 73:758-767.

Wale PL, Gardner DK. 2010. Time-lapse analysis of mouse embryo development in oxygen gradients. Reprod BioMed Online, 21:402-410.

Walker CG, Meier S, Littlejohn MD, Lehnert K, Roche JR, Mitchell MD. 2010. Modulation of the maternal immune system by the pre-implantation embryo. BMC Genomics, 11:1-13. 10.1186/1471-2164-11-474.

Wirtu G, Pope CE, Damiani P, Miller F, Dresser BL, Short CR, Godke RA, Bavister BD. 2003. Development of in-vitro-derived bovine embryos in protein-free media: effects of amino acids, glucose, pyruvate, lactate, phosphate and osmotic pressure. Reprod Fertil Dev, 15:439-449.

5b71e6de0e8825f5318068a8 animreprod Articles
Links & Downloads

Anim Reprod

Share this page
Page Sections