Effects of fetal sex and genetics on the bovine placenta: from baseline data to fetal programming and heterosis

Abstract

The placenta is a major determinant of fetal growth and central to fetal programming effects that impact postnatal performance and health. Most reports in human and animals on prenatal growth and programming are based on studies of term placentae and/or birth weight, but information at critical time points of development on (i) fundamental gross morphological and histomorphological characteristics and developmental changes of the placenta that could impact embryo/fetal growth, (ii) influence of sex-specific placental and umbilical cord phenotype on sex differences in fetal growth, (iii) contribution of placenta and umbilical cord in mediating effects of genetics and epigenetics on heterotic fetal growth, and (iv) differences in placental expression of insulin-like growth factor (IGF) system components between sexes and fetal genetic groups, are generally lacking. This information is highly relevant for both animal production and human health, and the present study used cattle, a major livestock species and valuable biomedical animal model, to address research questions and close gaps in knowledge. Purebred and reciprocal cross Bos taurus taurus (Angus, A) and Bos taurus indicus (Brahman, B) concepti recovered at the late embryo (Day 48, n=60) and early accelerated fetal growth (Day 153, n=73) stages (term, 277-291) were used to examine effects of fetal sex and genetics on a broad range of conceptus traits. Data analyzed using general linear models included gross- and histomorphological parameters of the placenta, umbilical cord traits and fetal fluid volume as well as clinical-chemical parameters, circulating IGFs in cord blood, and tissue-specific transcript abundances of IGF system components. The main findings include (i) the significant contribution of convex but not flat placentomes to embryo-fetal growth as revealed by the exclusive positive relationships between number of convex placentomes and embryo-fetal weights and the higher number and average weight of convex placentomes in placentae of Bpaternal×Amaternal and A×A concepti, which ultimately show the highest birth weights; (ii) fetal sex effects on placental and umbilical cord phenotype which mediate sex-specific fetal growth, where normal female fetuses display hallmarks of intrauterine growth restriction that provide a mechanism for sexdifferences in susceptibility to non-communicable diseases; (iii) heterosis of B×A hybrids in utero that is characterized by polar overdominance of paternal B genome on umbilical cord phenotype and complements the superior maternal A genome effects on placenta, a clear indication of heterosis due to high capacity for nutrient extraction and high capacity for nutrient supply; and (iv) differences in circulating IGF2 and transcript abundance of IGF2 in fetal brain and heart between sexes, as well as differences in expression of IGF2, IGF2R, H19, AIRN in placenta between fetal genetic groups demonstrate the important role of IGF2 for fetal growth at mid-gestation. In conclusion, the results of the present study support the hypothesis that differences in placental and umbilical cord phenotypes between males and females and between purebreds and reciprocal cross hybrids determine variation in intrauterine growth at midgestation and contribute to programming of postnatal performance and health. Future studies to be explored include analyses of growth factors associated with development of the placental vasculature and umbilical cord, and involvement of additional imprinted gene clusters in prenatal growth and development.