Register      Login
Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Sex-specific embryonic origin of postnatal phenotypic variability

R. Laguna-Barraza A , P. Bermejo-Álvarez B C , P. Ramos-Ibeas A , C. de Frutos A , A. P. López-Cardona A , A. Calle A , R. Fernandez-Gonzalez A , E. Pericuesta A , M. A. Ramírez A and A. Gutierrez-Adan A D
+ Author Affiliations
- Author Affiliations

A Departamento de Reproducción Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Avda Puerta de Hierro no. 12, Local 10, Madrid 28040, Spain.

B Department of Animal and Avian Sciences, 1413 Animal Sciences Center, University of Maryland, College Park, MD 20742-2311, USA.

C Animal Bioscience and Biotechnology Laboratory, Bldg 230, Beltsville Area Research Center East, 10300 Baltimore Avenue, Beltsville, MD 20705-2350, USA.

D Corresponding author. Email: agutierr@inia.es

Reproduction, Fertility and Development 25(1) 38-47 https://doi.org/10.1071/RD12262
Published: 4 December 2012

Abstract

Preimplantation developmental plasticity has evolved in order to offer the best chances of survival under changing environments. Conversely, environmental conditions experienced in early life can dramatically influence neonatal and adult biology, which may result in detrimental long-term effects. Several studies have shown that small size at birth, which is associated with a greater risk of metabolic syndrome, is largely determined before the formation of the blastocysts because 70%–80% of variation in bodyweight at birth has neither a genetic nor environmental component. In addition, it has been reported that adult bodyweight is programmed by energy-dependent process during the pronuclear stage in the mouse. Although the early embryo has a high developmental plasticity and adapts and survives to adverse environmental conditions, this adaptation may have adverse consequences and there is strong evidence that in vitro culture can be a risk factor for abnormal fetal outcomes in animals systems, with growing data suggesting that a similar link may be apparent for humans. In this context, male and female preimplantation embryos display sex-specific transcriptional and epigenetic regulation, which, in the case of bovine blastocysts, expands to one-third of the transcripts detected through microarray analysis. This sex-specific bias may convert the otherwise buffered stochastic variability in developmental networks in a sex-determined response to the environmental hazard. It has been widely reported that environment can affect preimplantation development in a sex-specific manner, resulting in either a short-term sex ratio adjustment or in long-term sex-specific effects on adult health. The present article reviews current knowledge about the natural phenotypic variation caused by epigenetic mechanisms and the mechanisms modulating sex-specific changes in phenotype during early embryo development resulting in sex ratio adjustments or detrimental sex-specific consequences for adult health. Understanding the natural embryo sexual dimorphism for programming trajectories will help understand the early mechanisms of response to environmental insults.

Additional keywords: developmental origin, epigenetics, long term.


References

Arnold, A. P. (2012). The end of gonad-centric sex determination in mammals. Trends Genet. 28, 55–61.
The end of gonad-centric sex determination in mammals.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhsFSitbk%3D&md5=cb40a2a3fbc471ffe5ee329f1a54f01dCAS |

Banrezes, B., Sainte-Beuve, T., Canon, E., Schultz, R. M., Cancela, J., and Ozil, J. P. (2011). Adult body weight is programmed by a redox-regulated and energy-dependent process during the pronuclear stage in mouse. PLoS One 6, e29388.
Adult body weight is programmed by a redox-regulated and energy-dependent process during the pronuclear stage in mouse.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xms1GgsA%3D%3D&md5=542d87fd6eb4eb0217cdb50ba939d25bCAS |

Barker, D. J. (2004). The developmental origins of well-being. Philos. Trans. R. Soc. Lond. B Biol. Sci. 359, 1359–1366.
The developmental origins of well-being.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD2cvkt1eqtA%3D%3D&md5=038e7f4de6740dc97380f018bd7ff143CAS |

Barker, D. J., and Osmond, C. (1986). Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 327, 1077–1081.
Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales.Crossref | GoogleScholarGoogle Scholar |

Barroso, G., Valdespin, C., Vega, E., Kershenovich, R., Avila, R., Avendano, C., and Oehninger, S. (2009). Developmental sperm contributions: fertilization and beyond. Fertil. Steril. 92, 835–848.
Developmental sperm contributions: fertilization and beyond.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhsFaqtLbE&md5=6e975d0de32e001efbde2429d7285f9dCAS |

Bermejo-Alvarez, P., Rizos, D., Rath, D., Lonergan, P., and Gutierrez-Adan, A. (2008a). Can bovine in vitro-matured oocytes selectively process X- or Y-sorted sperm differentially? Biol. Reprod. 79, 594–597.
Can bovine in vitro-matured oocytes selectively process X- or Y-sorted sperm differentially?Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtFCqtbnE&md5=55e521821e440927b231129499a37f52CAS |

Bermejo-Alvarez, P., Rizos, D., Rath, D., Lonergan, P., and Gutierrez-Adan, A. (2008b). Epigenetic differences between male and female bovine blastocysts produced in vitro. Physiol. Genomics 32, 264–272.
Epigenetic differences between male and female bovine blastocysts produced in vitro.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXmt1Wjurw%3D&md5=37a4ae794d754af8f09c9a83af64db8cCAS |

Bermejo-Alvarez, P., Rizos, D., Rath, D., Lonergan, P., and Gutierrez-Adan, A. (2010). Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts. Proc. Natl Acad. Sci. USA 107, 3394–3399.
Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXjtFymtbo%3D&md5=a7d2dcf8073e19aa53fd3b1fb161b442CAS |

Bermejo-Alvarez, P., Pericuesta, E., Miranda, A., de Frutos, C., Perez-Cerezales, S., Lucio, A., Rizos, D., and Gutierrez-Adan, A. (2011a). New challenges in the analysis of gene transcription in bovine blastocysts. Reprod. Domest. Anim. 46, 2–10.

Bermejo-Alvarez, P., Rizos, D., Lonergan, P., and Gutierrez-Adan, A. (2011b). Transcriptional sexual dimorphism during preimplantation embryo development and its consequences for developmental competence and adult health and disease. Reproduction 141, 563–570.
Transcriptional sexual dimorphism during preimplantation embryo development and its consequences for developmental competence and adult health and disease.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXmvFCju7Y%3D&md5=8e2995b577d669041b889ec4f3eada77CAS |

Bermejo-Alvarez, P., Rizos, D., Lonergan, P., and Gutierrez-Adan, A. (2011c). Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes. Reproduction 141, 801–808.
Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXovVCktLg%3D&md5=515b69824d6e5b7c2f15f9f27f83118eCAS |

Bermejo-Alvarez, P., Ramos-Ibeas, P., and Gutierrez-Adan, A. (2012). Solving the ‘X’ in embryos and stem cells. Stem Cells Dev. 21, 1215–1224.
Solving the ‘X’ in embryos and stem cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XmvFems78%3D&md5=b3ef71f59e7c4de4f38033663ad12c67CAS |

Calle, A., Fernandez-Gonzalez, R., Ramos-Ibeas, P., Laguna-Barraza, R., Perez-Cerezales, S., Bermejo-Alvarez, P., Ramirez, M. A., and Gutierrez-Adan, A. (2012a). Long-term and transgenerational effects of in vitro culture on mouse embryos. Theriogenology 77, 785–793.
Long-term and transgenerational effects of in vitro culture on mouse embryos.Crossref | GoogleScholarGoogle Scholar |

Calle, A., Miranda, A., Fernandez-Gonzalez, R., Pericuesta, E., Laguna, R., and Gutierrez-Adan, A. (2012b). Male mice produced by in vitro culture have reduced fertility and transmit organomegaly and glucose intolerance to their male offspring. Biol. Reprod. 87, 34.
Male mice produced by in vitro culture have reduced fertility and transmit organomegaly and glucose intolerance to their male offspring.Crossref | GoogleScholarGoogle Scholar |

Cameron, E. Z. (2004). Facultative adjustment of mammalian sex ratios in support of the Trivers–Willard hypothesis: evidence for a mechanism. Proc. Biol. Sci. 271, 1723–1728.
Facultative adjustment of mammalian sex ratios in support of the Trivers–Willard hypothesis: evidence for a mechanism.Crossref | GoogleScholarGoogle Scholar |

Cameron, E. Z., Lemons, P. R., Bateman, P. W., and Bennett, N. C. (2008). Experimental alteration of litter sex ratios in a mammal. Proc. Biol. Sci. 275, 323–327.
Experimental alteration of litter sex ratios in a mammal.Crossref | GoogleScholarGoogle Scholar |

Ceelen, M., van Weissenbruch, M. M., Vermeiden, J. P., van Leeuwen, F. E., and Delemarre-van de Waal, H. A. (2008). Cardiometabolic differences in children born after in vitro fertilization: follow-up study. J. Clin. Endocrinol. Metab. 93, 1682–1688.
Cardiometabolic differences in children born after in vitro fertilization: follow-up study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXlvFWgs78%3D&md5=1b8570d7cc4329afc5c3eb539e91b3f5CAS |

Díez, C., Bermejo-Alvarez, P., Trigal, B., Caamaño, J. N., Muñoz, M., Molina, I., Gutiérrez-Adán, A., Carrocera, S., Martín, D., and Gómez, E. (2009). Changes in testosterone or temperature during the in vitro oocyte culture do not alter the sex ratio of bovine embryos. J. Exp. Zool. A Ecol. Genet. Physiol. 311, 448–452.
Changes in testosterone or temperature during the in vitro oocyte culture do not alter the sex ratio of bovine embryos.Crossref | GoogleScholarGoogle Scholar |

Dumoulin, J. C., Land, J. A., Van Montfoort, A. P., Nelissen, E. C., Coonen, E., Derhaag, J. G., Schreurs, I. L., Dunselman, G. A., Kester, A. D., Geraedts, J. P., and Evers, J. L. (2010). Effect of in vitro culture of human embryos on birthweight of newborns. Hum. Reprod. 25, 605–612.
Effect of in vitro culture of human embryos on birthweight of newborns.Crossref | GoogleScholarGoogle Scholar |

Fauque, P., Ripoche, M. A., Tost, J., Journot, L., Gabory, A., Busato, F., Le Digarcher, A., Mondon, F., Gut, I., Jouannet, P., Vaiman, D., Dandolo, L., and Jammes, H. (2010). Modulation of imprinted gene network in placenta results in normal development of in vitro manipulated mouse embryos. Hum. Mol. Genet. 19, 1779–1790.
Modulation of imprinted gene network in placenta results in normal development of in vitro manipulated mouse embryos.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXksFKns70%3D&md5=cf47959f78912c19037213ac364f4a68CAS |

Fernandez-Gonzalez, R., Moreira, P., Bilbao, A., Jimenez, A., Perez-Crespo, M., Ramirez, M. A., Rodriguez De Fonseca, F., Pintado, B., and Gutierrez-Adan, A. (2004). Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior. Proc. Natl Acad. Sci. USA 101, 5880–5885.
Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXjsFKnsrc%3D&md5=de0f5306b827dc070b57644199100062CAS |

Fernandez-Gonzalez, R., Ramirez, M. A., Bilbao, A., De Fonseca, F. R., and Gutierrez-Adan, A. (2007). Suboptimal in vitro culture conditions: an epigenetic origin of long-term health effects. Mol. Reprod. Dev. 74, 1149–1156.
Suboptimal in vitro culture conditions: an epigenetic origin of long-term health effects.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXpt1alsbY%3D&md5=86f09cf71036e58c52d93a8e401ee554CAS |

Fernandez-Gonzalez, R., Moreira, P. N., Perez-Crespo, M., Sanchez-Martin, M., Ramirez, M. A., Pericuesta, E., Bilbao, A., Bermejo-Alvarez, P., de Dios Hourcade, J., de Fonseca, F. R., and Gutierrez-Adan, A. (2008). Long-term effects of mouse intracytoplasmic sperm injection with DNA-fragmented sperm on health and behavior of adult offspring. Biol. Reprod. 78, 761–772.
Long-term effects of mouse intracytoplasmic sperm injection with DNA-fragmented sperm on health and behavior of adult offspring.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXjvVaiu7w%3D&md5=6a4192a933970b5d084d5b56e85371d6CAS |

Fernandez-Gonzalez, R., Ramirez, M. A., Pericuesta, E., Calle, A., and Gutierrez-Adan, A. (2010). Histone modifications at the blastocyst Axin1(Fu) locus mark the heritability of in vitro culture-induced epigenetic alterations in mice. Biol. Reprod. 83, 720–727.
Histone modifications at the blastocyst Axin1(Fu) locus mark the heritability of in vitro culture-induced epigenetic alterations in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtlGls77M&md5=f1e347571f302932ef0eeb9924ebde5cCAS |

Gabory, A., Attig, L., and Junien, C. (2009). Sexual dimorphism in environmental epigenetic programming. Mol. Cell. Endocrinol. 304, 8–18.
Sexual dimorphism in environmental epigenetic programming.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXls1ylsLY%3D&md5=b0e387d9c633c4400f7e79844c897865CAS |

García-Herreros, M., Bermejo-Álvarez, P., Rizos, D., Gutiérrez-Adan, A., Fahey, A. G., and Lonergan, P. (2010). Intrafollicular testosterone concentration and sex ratio in individually cultured bovine embryos. Reprod. Fertil. Dev. 22, 533–538.
Intrafollicular testosterone concentration and sex ratio in individually cultured bovine embryos.Crossref | GoogleScholarGoogle Scholar |

Gartner, K. (1990). A third component causing random variability beside environment and genotype. A reason for the limited success of a 30 year long effort to standardize laboratory animals? Lab. Anim. 24, 71–77.
A third component causing random variability beside environment and genotype. A reason for the limited success of a 30 year long effort to standardize laboratory animals?Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK3c7lslemtQ%3D%3D&md5=5eccacc20e36ded250c9023900202ff4CAS |

Gartner, K. (2012a). Commentary: random variability of quantitative characteristics, an intangible epigenomic product, supporting adaptation. Int. J. Epidemiol. 41, 342–346.
Commentary: random variability of quantitative characteristics, an intangible epigenomic product, supporting adaptation.Crossref | GoogleScholarGoogle Scholar |

Gartner, K. (2012b). A third component causing random variability beside environment and genotype. A reason for the limited success of a 30 year long effort to standardize laboratory animals? Int. J. Epidemiol. 41, 335–341.
A third component causing random variability beside environment and genotype. A reason for the limited success of a 30 year long effort to standardize laboratory animals?Crossref | GoogleScholarGoogle Scholar |

Gebert, C., Wrenzycki, C., Herrmann, D., Groger, D., Thiel, J., Reinhardt, R., Lehrach, H., Hajkova, P., Lucas-Hahn, A., Carnwath, J. W., and Niemann, H. (2009). DNA methylation in the IGF2 intragenic DMR is re-established in a sex-specific manner in bovine blastocysts after somatic cloning. Genomics 94, 63–69.
DNA methylation in the IGF2 intragenic DMR is re-established in a sex-specific manner in bovine blastocysts after somatic cloning.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXmvVOqs7Y%3D&md5=961be3f5c5f3538a550bd5f797af1b91CAS |

Gluckman, P. D., and Hanson, M. A. (2004). The developmental origins of the metabolic syndrome. Trends Endocrinol. Metab. 15, 183–187.
The developmental origins of the metabolic syndrome.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXjsVegurk%3D&md5=25c38fa97adf095b59abd49b5ede1c41CAS |

Grant, V. J., and Chamley, L. W. (2007). Sex-sorted sperm and fertility: an alternative view. Biol. Reprod. 76, 184–188.
Sex-sorted sperm and fertility: an alternative view.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXhtFWqsLs%3D&md5=fe512c2df93bae8effa6538f171d5996CAS |

Griesinger, G., Kolibianakis, E. M., Diedrich, K., and Ludwig, M. (2008). Ovarian stimulation for IVF has no quantitative association with birthweight: a registry study. Hum. Reprod. 23, 2549–2554.
Ovarian stimulation for IVF has no quantitative association with birthweight: a registry study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXht1Ois73K&md5=5285e63169371e02b07e64149678edf2CAS |

Gutiérrez-Adán, A., Behboodi, E., Andersen, G. B., Medrano, J. F., and Murray, J. D. (1996). Relationship between stage of development and sex of bovine IVM-IVF embryos cultured in vitro versus in the sheep oviduct. Theriogenology 46, 515–525.
Relationship between stage of development and sex of bovine IVM-IVF embryos cultured in vitro versus in the sheep oviduct.Crossref | GoogleScholarGoogle Scholar |

Gutiérrez-Adán, A., Perez, G., Granados, J., Garde, J. J., Pérez-Guzman, M., Pintado, B., and De La Fuente, J. (1999). Relationship between sex ratio and time of insemination according to both time of ovulation and maturational state of oocyte. Zygote 7, 37–43.
Relationship between sex ratio and time of insemination according to both time of ovulation and maturational state of oocyte.Crossref | GoogleScholarGoogle Scholar |

Gutiérrez-Adán, A., Oter, M., Martínez-Madrid, B., Pintado, B., and De La Fuente, J. (2000). Differential expression of two genes located on the X chromosome between male and female in vitro-produced bovine embryos at the blastocyst stage. Mol. Reprod. Dev. 55, 146–151.
Differential expression of two genes located on the X chromosome between male and female in vitro-produced bovine embryos at the blastocyst stage.Crossref | GoogleScholarGoogle Scholar |

Gutiérrez-Adán, A., Perez-Crespo, M., Fernandez-Gonzalez, R., Ramirez, M. A., Moreira, P., Pintado, B., Lonergan, P., and Rizos, D. (2006). Developmental consequences of sexual dimorphism during pre-implantation embryonic development. Reprod. Domest. Anim. 41, 54–62.
Developmental consequences of sexual dimorphism during pre-implantation embryonic development.Crossref | GoogleScholarGoogle Scholar |

Hansen, M., Bower, C., Milne, E., de Klerk, N., and Kurinczuk, J. J. (2005). Assisted reproductive technologies and the risk of birth defects: a systematic review. Hum. Reprod. 20, 328–338.
Assisted reproductive technologies and the risk of birth defects: a systematic review.Crossref | GoogleScholarGoogle Scholar |

Hassold, T., and Sandison, A. (1983). The effect of chromosome constitution on growth in culture of human spontaneous abortions. Hum. Genet. 63, 166–170.
The effect of chromosome constitution on growth in culture of human spontaneous abortions.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaL3s7osVehtQ%3D%3D&md5=7e68d7ff6af1de114eeccfeb0444ce9fCAS |

Hochberg, Z., Feil, R., Constancia, M., Fraga, M., Junien, C., Carel, J. C., Boileau, P., Le Bouc, Y., Deal, C. L., Lillycrop, K., Scharfmann, R., Sheppard, A., Skinner, M., Szyf, M., Waterland, R. A., Waxman, D. J., Whitelaw, E., Ong, K., and Albertsson-Wikland, K. (2011). Child health, developmental plasticity, and epigenetic programming. Endocr. Rev. 32, 159–224.
Child health, developmental plasticity, and epigenetic programming.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXmsFWmsbo%3D&md5=45734174d58ab9ed0775e29c66643444CAS |

Jackson, R. A., Gibson, K. A., Wu, Y. W., and Croughan, M. S. (2004). Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet. Gynecol. 103, 551–563.
Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis.Crossref | GoogleScholarGoogle Scholar |

Kano, H., Godoy, I., Courtney, C., Vetter, M. R., Gerton, G. L., Ostertag, E. M., and Kazazian, H. H. (2009). L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes Dev. 23, 1303–1312.
L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXntlegsbk%3D&md5=457798b3197c5b1be6cea2a090c50c6eCAS |

Khosla, S., Dean, W., Brown, D., Reik, W., and Feil, R. (2001a). Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biol. Reprod. 64, 918–926.
Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXhsVKjtrc%3D&md5=638bb2ef34af9e3f7df509964d265569CAS |

Khosla, S., Dean, W., Reik, W., and Feil, R. (2001b). Culture of preimplantation embryos and its long-term effects on gene expression and phenotype. Hum. Reprod. Update 7, 419–427.
Culture of preimplantation embryos and its long-term effects on gene expression and phenotype.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXlvVKjtLo%3D&md5=f7c84080946d9bed5085f2518f285109CAS |

Klemetti, R., Gissler, M., Sevon, T., Koivurova, S., Ritvanen, A., and Hemminki, E. (2005). Children born after assisted fertilization have an increased rate of major congenital anomalies. Fertil. Steril. 84, 1300–1307.
Children born after assisted fertilization have an increased rate of major congenital anomalies.Crossref | GoogleScholarGoogle Scholar |

Kobayashi, S., Isotani, A., Mise, N., Yamamoto, M., Fujihara, Y., Kaseda, K., Nakanishi, T., Ikawa, M., Hamada, H., Abe, K., and Okabe, M. (2006). Comparison of gene expression in male and female mouse blastocysts revealed imprinting of the X-linked gene, Rhox5/Pem, at preimplantation stages. Curr. Biol. 16, 166–172.
Comparison of gene expression in male and female mouse blastocysts revealed imprinting of the X-linked gene, Rhox5/Pem, at preimplantation stages.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xosl2mtw%3D%3D&md5=04ebab9c4f773b0a2536a8dd11599015CAS |

Kraemer, R., Aebi, C., Casaulta Aebischer, C., and Gallati, S. (2000). Early detection of lung disease and its association with the nutritional status, genetic background and life events in patients with cystic fibrosis. Respiration 67, 477–490.
Early detection of lung disease and its association with the nutritional status, genetic background and life events in patients with cystic fibrosis.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3Mzitlyjtw%3D%3D&md5=d0dcef6c666f4de340ccd877479ad67cCAS |

Lane, M., and Gardner, D. K. (2003). Ammonium induces aberrant blastocyst differentiation, metabolism, pH regulation, gene expression and subsequently alters fetal development in the mouse. Biol. Reprod. 69, 1109–1117.
Ammonium induces aberrant blastocyst differentiation, metabolism, pH regulation, gene expression and subsequently alters fetal development in the mouse.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXnsV2nsr8%3D&md5=752647a0cb5eecb57d1f4d8172084a91CAS |

Lemos, B., Branco, A. T., and Hartl, D. L. (2010). Epigenetic effects of polymorphic Y chromosomes modulate chromatin components, immune response, and sexual conflict. Proc. Natl Acad. Sci. USA 107, 15 826–15 831.
Epigenetic effects of polymorphic Y chromosomes modulate chromatin components, immune response, and sexual conflict.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtFOru7vI&md5=0ebbc3759305bc622e315c614a14b190CAS |

Lopes, A. M., Burgoyne, P. S., Ojarikre, A., Bauer, J., Sargent, C. A., Amorim, A., and Affara, N. A. (2010). Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome. BMC Genomics 11, 82.
Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome.Crossref | GoogleScholarGoogle Scholar |

Mann, M. R., Lee, S. S., Doherty, A. S., Verona, R. I., Nolen, L. D., Schultz, R. M., and Bartolomei, M. S. (2004). Selective loss of imprinting in the placenta following preimplantation development in culture. Development 131, 3727–3735.
Selective loss of imprinting in the placenta following preimplantation development in culture.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXnt1elt7c%3D&md5=751676b9c655297890fd3ba2223fbbe6CAS |

Mayer, W., Niveleau, A., Walter, J., Fundele, R., and Haaf, T. (2000). Demethylation of the zygotic paternal genome. Nature 403, 501–502.
Demethylation of the zygotic paternal genome.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXht1ShsbY%3D&md5=500fb89430f60fa10d4c9f262ee86acbCAS |

McDonald, S. D., Han, Z., Mulla, S., Murphy, K. E., Beyene, J., and Ohlsson, A. (2009). Preterm birth and low birth weight among in vitro fertilization singletons: a systematic review and meta-analyses. Eur. J. Obstet. Gynecol. Reprod. Biol. 146, 138–148.
Preterm birth and low birth weight among in vitro fertilization singletons: a systematic review and meta-analyses.Crossref | GoogleScholarGoogle Scholar |

McIntire, D. D., and Leveno, K. J. (2008). Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet. Gynecol. 111, 35–41.
Neonatal mortality and morbidity rates in late preterm births compared with births at term.Crossref | GoogleScholarGoogle Scholar |

Mittwoch, U. (2004). The elusive action of sex-determining genes: mitochondria to the rescue? J. Theor. Biol. 228, 359–365.
The elusive action of sex-determining genes: mitochondria to the rescue?Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXjsl2ntr8%3D&md5=5e59ee03a629624f68c309d15b6c25f5CAS |

Morton, K. M., Herrmann, D., Sieg, B., Struckmann, C., Maxwell, W. M., Rath, D., Evans, G., Lucas-Hahn, A., Niemann, H., and Wrenzycki, C. (2007). Altered mRNA expression patterns in bovine blastocysts after fertilisation in vitro using flow-cytometrically sex-sorted sperm. Mol. Reprod. Dev. 74, 931–940.
Altered mRNA expression patterns in bovine blastocysts after fertilisation in vitro using flow-cytometrically sex-sorted sperm.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXntVOhtbc%3D&md5=f4fe6e2d1da9c9cdaaf872907542a728CAS |

Nakanishi, T., Kuroiwa, A., Yamada, S., Isotani, A., Yamashita, A., Tairaka, A., Hayashi, T., Takagi, T., Ikawa, M., Matsuda, Y., and Okabe, M. (2002). FISH analysis of 142 EGFP transgene integration sites into the mouse genome. Genomics 80, 564–574.
FISH analysis of 142 EGFP transgene integration sites into the mouse genome.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38Xps1Onsrk%3D&md5=3545b1afc86a4d05b0bcb7618b2e2160CAS |

Navara, K. J. (2010). Programming of offspring sex ratios by maternal stress in humans: assessment of physiological mechanisms using a comparative approach. J. Comp. Physiol. B 180, 785–796.
Programming of offspring sex ratios by maternal stress in humans: assessment of physiological mechanisms using a comparative approach.Crossref | GoogleScholarGoogle Scholar |

Nelissen, E. C., Van Montfoort, A. P., Coonen, E., Derhaag, J. G., Geraedts, J. P., Smits, L. J., Land, J. A., Evers, J. L., and Dumoulin, J. C. (2012). Further evidence that culture media affect perinatal outcome: findings after transfer of fresh and cryopreserved embryos. Hum. Reprod. 27, 1966–1976.
Further evidence that culture media affect perinatal outcome: findings after transfer of fresh and cryopreserved embryos.Crossref | GoogleScholarGoogle Scholar |

Ombelet, W., Martens, G., De Sutter, P., Gerris, J., Bosmans, E., Ruyssinck, G., Defoort, P., Molenberghs, G., and Gyselaers, W. (2006). Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: a cohort study. Hum. Reprod. 21, 1025–1032.
Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: a cohort study.Crossref | GoogleScholarGoogle Scholar |

Peaston, A. E., Evsikov, A. V., Graber, J. H., de Vries, W. N., Holbrook, A. E., Solter, D., and Knowles, B. B. (2004). Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos. Dev. Cell 7, 597–606.
Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXptlGjur4%3D&md5=be38dc4cb242d51e2f17277ed8d3b6b1CAS |

Pelinck, M. J., Hoek, A., Simons, A. H., Heineman, M. J., van Echten-Arends, J., and Arts, E. G. (2010). Embryo quality and impact of specific embryo characteristics on ongoing implantation in unselected embryos derived from modified natural cycle in vitro fertilization. Fertil. Steril. 94, 527–534.
Embryo quality and impact of specific embryo characteristics on ongoing implantation in unselected embryos derived from modified natural cycle in vitro fertilization.Crossref | GoogleScholarGoogle Scholar |

Penfold, L. M., Holt, C., Holt, W. V., Welch, G. R., Cran, D. G., and Johnson, L. A. (1998). Comparative motility of X and Y chromosome-bearing bovine sperm separated on the basis of DNA content by flow sorting. Mol. Reprod. Dev. 50, 323–327.
Comparative motility of X and Y chromosome-bearing bovine sperm separated on the basis of DNA content by flow sorting.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXjsFSns7s%3D&md5=25e0386c5336e43ae07da319ea480419CAS |

Pérez-Crespo, M., Ramírez, M. A., Fernández-González, R., Rizos, D., Lonergan, P., Pintado, B., and Gutiérrez-Adán, A. (2005). Differential sensitivity of male and female mouse embryos to oxidative induced heat-stress is mediated by glucose-6-phosphate dehydrogenase gene expression. Mol. Reprod. Dev. 72, 502–510.
Differential sensitivity of male and female mouse embryos to oxidative induced heat-stress is mediated by glucose-6-phosphate dehydrogenase gene expression.Crossref | GoogleScholarGoogle Scholar |

Pergament, E., Fiddler, M., Cho, N., Johnson, D., and Holmgren, W. J. (1994). Sexual differentiation and preimplantation cell growth. Hum. Reprod. 9, 1730–1732.
| 1:STN:280:DyaK2M7jvVaksw%3D%3D&md5=b85979dd14abccae3946affd72ee96d3CAS |

Pergament, E., Todydemir, P. B., and Fiddler, M. (2002). Sex ratio: a biological perspective of ‘Sex and the City’. Reprod. Biomed. Online 5, 43–46.
Sex ratio: a biological perspective of ‘Sex and the City’.Crossref | GoogleScholarGoogle Scholar |

Rimm, A. A., Katayama, A. C., Diaz, M., and Katayama, K. P. (2004). A meta-analysis of controlled studies comparing major malformation rates in IVF and ICSI infants with naturally conceived children. J. Assist. Reprod. Genet. 21, 437–443.
A meta-analysis of controlled studies comparing major malformation rates in IVF and ICSI infants with naturally conceived children.Crossref | GoogleScholarGoogle Scholar |

Rivera, R. M., Stein, P., Weaver, J. R., Mager, J., Schultz, R. M., and Bartolomei, M. S. (2008). Manipulations of mouse embryos prior to implantation result in aberrant expression of imprinted genes on Day 9.5 of development. Hum. Mol. Genet. 17, 1–14.
Manipulations of mouse embryos prior to implantation result in aberrant expression of imprinted genes on Day 9.5 of development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXhsVKiur%2FJ&md5=0aab801e8b45298df71d0807d40ad8adCAS |

Romundstad, L. B., Romundstad, P. R., Sunde, A., von During, V., Skjaerven, R., Gunnell, D., and Vatten, L. J. (2008). Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study. Lancet 372, 737–743.
Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study.Crossref | GoogleScholarGoogle Scholar |

Rooke, J. A., McEvoy, T. G., Ashworth, C. J., Robinson, J. J., Wilmut, I., Young, L. E., and Sinclair, K. D. (2007). Ovine fetal development is more sensitive to perturbation by the presence of serum in embryo culture before rather than after compaction. Theriogenology 67, 639–647.
Ovine fetal development is more sensitive to perturbation by the presence of serum in embryo culture before rather than after compaction.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD2s%2Fht1Cqtg%3D%3D&md5=5149d92878303d3f469942d5a12fe931CAS |

Rougier, N., Bourc’his, D., Gomes, D. M., Niveleau, A., Plachot, M., Paldi, A., and Viegas-Pequignot, E. (1998). Chromosome methylation patterns during mammalian preimplantation development. Genes Dev. 12, 2108–2113.
Chromosome methylation patterns during mammalian preimplantation development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXkvF2rs70%3D&md5=12274fae39e3ac5d64455790d9440306CAS |

Schwarzer, C., Esteves, T. C., Arauzo-Bravo, M. J., Le Gac, S., Nordhoff, V., Schlatt, S., and Boiani, M. (2012). ART culture conditions change the probability of mouse embryo gestation through defined cellular and molecular responses. Hum. Reprod. 27, 2627–2640.
ART culture conditions change the probability of mouse embryo gestation through defined cellular and molecular responses.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xht1WlsbzP&md5=834c6929377ed3ae8b6fa85034873f5aCAS |

Sinclair, K. D., and Singh, R. (2007). Modelling the developmental origins of health and disease in the early embryo. Theriogenology 67, 43–53.
Modelling the developmental origins of health and disease in the early embryo.Crossref | GoogleScholarGoogle Scholar |

Sinclair, K. D., Allegrucci, C., Singh, R., Gardner, D. S., Sebastian, S., Bispham, J., Thurston, A., Huntley, J. F., Rees, W. D., Maloney, C. A., Lea, R. G., Craigon, J., McEvoy, T. G., and Young, L. E. (2007). DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc. Natl Acad. Sci. USA 104, 19 351–19 356.
DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXisVOjug%3D%3D&md5=24729f0cd5c5cffe79662fc6622deab9CAS |

Sjoblom, C., Roberts, C. T., Wikland, M., and Robertson, S. A. (2005). Granulocyte–macrophage colony-stimulating factor alleviates adverse consequences of embryo culture on fetal growth trajectory and placental morphogenesis. Endocrinology 146, 2142–2153.
Granulocyte–macrophage colony-stimulating factor alleviates adverse consequences of embryo culture on fetal growth trajectory and placental morphogenesis.Crossref | GoogleScholarGoogle Scholar |

Sturmey, R. G., Bermejo-Alvarez, P., Gutierrez-Adan, A., Rizos, D., Leese, H. J., and Lonergan, P. (2010). Amino acid metabolism of bovine blastocysts: a biomarker of sex and viability. Mol. Reprod. Dev. 77, 285–296.
| 1:CAS:528:DC%2BC3cXotFSmuw%3D%3D&md5=dc83b4caab1c33db32d9baf1830e5ae7CAS |

Swamy, G. K., Ostbye, T., and Skjaerven, R. (2008). Association of preterm birth with long-term survival, reproduction, and next-generation preterm birth. JAMA 299, 1429–1436.
Association of preterm birth with long-term survival, reproduction, and next-generation preterm birth.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXjslyitb4%3D&md5=4c4910153a3627c7ae60c970dfce5d85CAS |

Tesarik, J. (2005). Paternal effects on cell division in the human preimplantation embryo. Reprod. Biomed. Online 10, 370–375.
Paternal effects on cell division in the human preimplantation embryo.Crossref | GoogleScholarGoogle Scholar |

Thompson, J. G., Gardner, D. K., Pugh, P. A., McMillan, W. H., and Tervit, H. R. (1995). Lamb birth weight is affected by culture system utilized during in vitro pre-elongation development of ovine embryos. Biol. Reprod. 53, 1385–1391.
Lamb birth weight is affected by culture system utilized during in vitro pre-elongation development of ovine embryos.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXpsVeisrs%3D&md5=5df20bf7e34820ebe5fb7f2535dd52d7CAS |

Thompson, J. G., Kind, K. L., Roberts, C. T., Robertson, S. A., and Robinson, J. S. (2002). Epigenetic risks related to assisted reproductive technologies: short- and long-term consequences for the health of children conceived through assisted reproduction technology: more reason for caution? Hum. Reprod. 17, 2783–2786.
Epigenetic risks related to assisted reproductive technologies: short- and long-term consequences for the health of children conceived through assisted reproduction technology: more reason for caution?Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XptFOrtLg%3D&md5=bea0ad1f0c7d07cb0a3874add753d5e8CAS |

Thomson, F., Shanbhag, S., Templeton, A., and Bhattacharya, S. (2005). Obstetric outcome in women with subfertility. Br. J. Obstet. Gynaecol. 112, 632–637.
Obstetric outcome in women with subfertility.Crossref | GoogleScholarGoogle Scholar |

Trivers, R. L., and Willard, D. E. (1973). Natural selection of parental ability to vary the sex ratio of offspring. Science 179, 90–92.
Natural selection of parental ability to vary the sex ratio of offspring.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaE3s%2Fls1Wqsg%3D%3D&md5=e37339e73540d3e73ecfefe0270c7c6bCAS |

van den Hurk, J. A., Meij, I. C., Seleme, M. C., Kano, H., Nikopoulos, K., Hoefsloot, L. H., Sistermans, E. A., de Wijs, I. J., Mukhopadhyay, A., Plomp, A. S., de Jong, P. T., Kazazian, H. H., and Cremers, F. P. (2007). L1 retrotransposition can occur early in human embryonic development. Hum. Mol. Genet. 16, 1587–1592.
L1 retrotransposition can occur early in human embryonic development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXosFektL4%3D&md5=14e6b317a5cfe99860ff7c0db4206309CAS |

Watkins, A. J., Ursell, E., Panton, R., Papenbrock, T., Hollis, L., Cunningham, C., Wilkins, A., Perry, V. H., Sheth, B., Kwong, W. Y., Eckert, J. J., Wild, A. E., Hanson, M. A., Osmond, C., and Fleming, T. P. (2008). Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease. Biol. Reprod. 78, 299–306.
Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXht1Kru7c%3D&md5=4a420967561ff09b8bd329ce4124c6e5CAS |

Whitelaw, N. C., and Whitelaw, E. (2008). Transgenerational epigenetic inheritance in health and disease. Curr. Opin. Genet. Dev. 18, 273–279.
Transgenerational epigenetic inheritance in health and disease.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtFOltL7L&md5=bc40bcfbe0943b2b3c4fbf9fbe787694CAS |

Wijchers, P. J., and Festenstein, R. J. (2011). Epigenetic regulation of autosomal gene expression by sex chromosomes. Trends Genet. 27, 132–140.
Epigenetic regulation of autosomal gene expression by sex chromosomes.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXjvV2murg%3D&md5=94e30da3f4ffafe1a71f7af16df4d7d3CAS |

Wijchers, P. J., Yandim, C., Panousopoulou, E., Ahmad, M., Harker, N., Saveliev, A., Burgoyne, P. S., and Festenstein, R. (2010). Sexual dimorphism in mammalian autosomal gene regulation is determined not only by Sry but by sex chromosome complement as well. Dev. Cell 19, 477–484.
Sexual dimorphism in mammalian autosomal gene regulation is determined not only by Sry but by sex chromosome complement as well.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtFGht7rP&md5=15ae850e6fdfa4b1cd3101df5c05a925CAS |

Xu, J., Deng, X., and Disteche, C. M. (2008). Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain. PLoS One 3, e2553.
Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain.Crossref | GoogleScholarGoogle Scholar |

Young, L. E. (2001). Imprinting of genes and the Barker hypothesis. Twin Res. 4, 307–317.
| 1:STN:280:DC%2BD387jsFCksw%3D%3D&md5=92c4f035fb398785ca5d2e2e5934ee24CAS |

Zvetkova, I., Apedaile, A., Ramsahoye, B., Mermoud, J. E., Crompton, L. A., John, R., Feil, R., and Brockdorff, N. (2005). Global hypomethylation of the genome in XX embryonic stem cells. Nat. Genet. 37, 1274–1279.
Global hypomethylation of the genome in XX embryonic stem cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXhtFGhsLrP&md5=867276442def6c5669ac91095eb26fadCAS |