Fetal Growth and Development

1. Fetal Growth and Development Fetal Growth and Development, AnS 536

2. To Grow • Grow: • To become larger. To increase in size or amount • Growth: • The progressive act of growing ‘At the moment we are born, we are dying’ Fetal Growth and Development, AnS 536 https://www.123rf.com/photo_6810723_man-s-life-stages.html

3. Fetal Growth • Affected by numerous factors • Genetics • Potential- genetic code • Transcription- phenotype • Physical environment • Uterine Capacity- restrictor • Nutrient availability- metabolism • Interaction between the two • Hormones • Growth factors • Transcription factors PROTEIN Fetal Growth and Development, AnS 536

4. Establishing DNA • Success of reproduction begins prior to fertilization • Quality of gametes produced by the parents • At fertilization, comingling of gametes establishes the genetic makeup of the new offspring • Basis for all further protein production from the fetus Fetal Growth and Development, AnS 536

5. Genetic Influence • Once fertilization occurs, and the new DNA is assembled, the cell begins its process of mitotic divisions, building up the cells that will eventually cleave and differentiate into the organ systems of the body. • Mitotic divisions are generally not influenced by maternal or environmental changes. • Cells are in stage of strict proliferation and cleavage into non specific cells. • Cleavage driven by space within the zona pellucida Fetal Growth and Development, AnS 536

6. Genetic Potential Short, fine boned 4.5% butterfat, 3.5% total protein 3.9% butterfat, 3.3% total protein Tall, heavy frame Fetal Growth and Development, AnS 536 http://www.subzeroicecream.com/a-day-in-the-life-of-a-dairy-cow/

7. Transcription of DNA Fetal Growth and Development, AnS 536 http://www.csus.edu/indiv/l/loom/lect8.htm

8. Blastocyst, Cell Differentiation • Continued mitotic divisions and cleavage of cells form the blastocyst. • Blastocyst is the cellular mass that will hatch from the zona pellucida and implant in the endometrium • Implantation into the endometrium facilitated by trophoblast cells • Trophoblasts differentiate into villous cells of the placenta, attach to the uterus to establish blood flow between fetal and maternal tissues. • Trophoblasts also modify maternal arteries through reduction of resistance, and increasing blood flow. Fetal Growth and Development, AnS 536

9. Trophoblasts • Different types of trophoblast cells have specific jobs in association with the maternal tissue • Cytotrophoblast cells: sites of hormone influence from hCG, placental lactogen, placental GH, estrogen, and progesterone • Syncytiotrophoblast cells: line the placental trophoblast villi, in direct contact with the uterus. • The purpose appears to primarily be the movement of amino acids and other nutrients across the uterus and into the placenta Fetal Growth and Development, AnS 536

10. Comparative Fetal Growth Rates Fetal Growth and Development, AnS 536 http://php.med.unsw.edu.au/embryology/index.php?title=Bovine_Development

11. Fetal Growth- Placenta • As previously discussed in this class, importance of placental establishment during pregnancy cannot be underestimated • Once the trophoblasts have established vascularization in the uterus and created path for nutrient and signal transport, placental growth can begin • Placental growth is influenced by uterine environment • Estrogen influence on placental size also has indirect influences on fetal growth. • Increases in volumes of allantoic and amniotic fluids occur with gestational fluctuations in estrogen levels. • In swine, two peaks of placental growth have been characterized during gestation, (Knight et al., 1977) • Electrolytes appeared to create a “short circuit”. Increase in ion gradient favors the flow of electrolyte ions from the maternal to fetal side of the chorion (Knight et al., 1977) Fetal Growth and Development, AnS 536

12. Fetal Growth-Tissue Development • Fetal growth and development is parallel to placental growth • Proper development of the fetus during gestation is assessed through comparison of fetal size at gestational age time points. • These assessments are made based on comparisons of individual growth potential and population averages • This subjective scale of measurement is utilized as a predictor for preterm pregnancies, and a diagnostic consideration for determining growth abnormalities. • In essence, the proper establishment of the placenta has great influence over the growth of the fetal tissues, and their size at the appropriate gestational ages Fetal Growth and Development, AnS 536

13. Tissue Development- Humans Fetal Growth and Development, AnS 536 http://www.cerebral-palsy.net/update2001/graphics/cp1.jpg

14. Tissue Development- Cattle Fetal Growth and Development, AnS 536 http://php.med.unsw.edu.au/embryology/index.php?title=Bovine_Development

15. Fetal Growth- Uterine Capacity • Influenced by • Physical maternal size • Maturity of mother, or parity • Placental size and density • Litter bearing or twinning vs. singleton Fetal Growth and Development, AnS 536

16. Uterine Capacity- Growth RestrictionExample • Average US birth weight between 1985-1990: 6.8-7.1 lbs. • Genetic Potential: Paternal side • Siblings size at birth: 7-8.5lbs, 19”-21” • Sibling current W/H: 145-210 lbs, 5’-6”- 6’0” (Ave.-Lrg. body frame) • Uterine Capacity (Restriction of growth) • Baby (at birth): 7lbs 2oz, 19.5” • Mom: 5’3”, 95lbs (Sml. body frame) • Gained only 25lbs during 9mo. Pregnancy • ~25lbs total gain – (~7lbs fetus+~7lbs placenta)= 11 lbs. extra. • No more room for fetus to grow! Fetal Growth and Development, AnS 536

17. Fetal Growth- Uterine Capacity • Uterine capacity increases with parity due to stretching of the uterine muscle and birth canal • Possible other physical changes occur • Increase in abdominal size, age • Sows vs. gilts • After day 35 of gestation, IUGR can be noticed in piglet growth and development, due to restriction of uterine capacity and limited vascular flow • Cows vs. heifers • Sheep- twinning Fetal Growth and Development, AnS 536

18. Fetal Growth- Nutrient Availability • Nutritional regulation of growth is both a reaction to environmental conditions and acting on genetic potential • Environmental situations of nutrient availability are due to maternal intake of the appropriate nutrients • Amino acids, glucose, triglycerides • Vitamins, minerals, water Fetal Growth and Development, AnS 536

19. Fetal Growth- Nutrient Availability • Maternal blood glucose • Increases in maternal blood glucose (instance of hyperglycemia) are often linked to reductions in insulin secretion • Increased availability of the glucose from the maternal blood gets taken up by the placenta and the uterus • Results in a larger fetus • Decreases in blood glucose (maternal hypoglycemia) • result in a smaller fetus, with a higher uptake and demand for glucose Fetal Growth and Development, AnS 536

20. Fetal Growth-Nutrient Availability • Changes to placental uptake of glucose can also influence fetal growth • Placental uptake of glucose normally between 40-60% of all glucose taken up by the conceptus • Increases in uptake create in increase in glucose gradient from the maternal to fetal tissues. • Compensatory for fetal needs of glucose to make up for increased placental uptake. Fetal Growth and Development, AnS 536

21. Fetal Growth • The process of fetal growth and development is dynamic and fluid throughout gestation • Growth of the fetus is encouraged and regulated by a number of redundant and conflicting factors • Most easily controlled influences of fetal growth continue to be genetics and environment • Next time: Expressing the phenotype • Interaction with genetics and environment • Hormones • Growth factors • Transcription factors Fetal Growth and Development, AnS 536

22. Fetal Growth and Development Part 2 Fetal Growth and Development, AnS 536

23. Fetal Growth • Affected by numerous factors • Genetics • Potential- genetic code • Transcription- phenotype • Physical environment • Uterine Capacity- restrictor • Nutrient availability- metabolism • Interaction between the two • Hormones • Growth factors • Transcription factors PROTEIN Fetal Growth and Development, AnS 536

24. Fetal Growth and Development, AnS 536 http://php.med.unsw.edu.au/embryology/index.php?title=File:Inner_cell_mass_cartoon.jpg

25. Tissue Accretion • Cell growth= tissue gain • Formation of organ systems occurs through the building of tissue TISSUE Cell Cell Cell Cell Cell Cell Fetal Growth and Development, AnS 536

26. Tissue development- Mouse Fetal Growth and Development, AnS 536 http://php.med.unsw.edu.au/embryology/index.php?title=Mouse_Development

27. Hormone Secretion Progesterone &Estrodiol Placental growth Cell Proliferation Fertilization Implantation Fetal Growth and Development, AnS 536 http://php.med.unsw.edu.au/embryology/index.php?title=Pig_Development

28. Fetal Growth and Development, AnS 536 https://www.ebmedicine.net/topics.php?paction=showTopicSeg&topic_id=130&seg_id=2553

29. Fetal Growth and Development, AnS 536 http://ansci.illinois.edu/static/ansc438/Motherneonate/hormonechanges.html

30. Growth Factors and Hormones • Cells are influenced by growth factors differently depending on their state of development • Progesterone : Estrogen ratio • Insulin, drive nutrients into tissues • Placental growth • Adipose • Muscle • Growth Hormone and IGF axis • Glucocorticoids • Amino acids: protein receptors and signaling compounds Fetal Growth and Development, AnS 536

31. IGF • Insulin-like Growth factor: influence somatic cell growth and proliferation • IGF-I: cell proliferation directly, fetal growth (paternal) • IGF-II: both placental and fetal growth (maternal) • Interaction of IGF and Growth Hormone (GH), termed the IGF/GH axis • Secretion of IGF is driven by syncytiotrophoblast cells • Triggered by growth hormone (GH) and placental lactogen • Greatest during early pregnancy (time of high level of cell proliferation) • Associated with increasing growth in all tissues during development • Fibroblasts and myoblasts in the establishment of skeletal muscle • Increasing hyperplasia Fetal Growth and Development, AnS 536

32. IGFBP • IGF binding proteins (IGFBP): regulate IGFs • Growth restrictor • Serum concentrations determined by maternal genetics and environment • All fetal and placental tissues have exhibited receptors for IGF signals, and most also have sources of IGFBPs within the tissues • Secretion of IGFBP is greatest as the fetus approaches term • Decrease hyperplasia, increase hypertrophy Fetal Growth and Development, AnS 536

33. Glucocorticoids • Glucocorticoids are associated with cell maturation • Improve surfactant when given to premature neonates • Increasing the ratio of lecithin to shyingomyelin in amniotic fluid, subsequent surfactant • Influence of glucocorticoids prior to birth have been linked to reduced fetal growth and premature increases in maturity of fetal development • Thought to suppress the influence of IGF axis (Bloomfield, et al., 2001) • Glucocorticoids are involved in a variety of life processes • Appear more beneficial to cells that have been differentiated, as opposed to cells that are still within a proliferative state Fetal Growth and Development, AnS 536

34. Glucocorticoids • Glucocorticoids are regulated during fetal development • 11β-HSD, a regulatory protein known as the placental glucocorticoid barrier • This protein is secreted heavily during early gestation • Measured changes in maternal glucocorticoid levels have apparently little to no effect on the fetus that in adequate secretion of the 11β-HSD protein Fetal Growth and Development, AnS 536

35. Amino Acids • Necessary in the creation of these transporters for moving other molecules into conceptus • Lack of functional transporters can lead to deficiency, despite availability • Taurine, essential for fetal development • Without a functioning transporter, a fetus can be taurine deficient • Functional amino acids (FAA): primarily transport proteins Fetal Growth and Development, AnS 536

36. Amino Acids • Expression of transport amino acids increases throughout gestation, as the demand for increased nutrient transport increases • Reduced concentrations of polyamines have been associated with IUGR in fetuses • Reduction in amino acids important and biosynthesis can have the greatest overall effect on fetal growth Fetal Growth and Development, AnS 536

37. Fetal Growth and Development, AnS 536 Wu, G., Bazer, F. W., Cudd, T. A., Meininger, C. J., & Spencer, T. E. (2004). Maternal Nutrition and Fetal Development, (13), 2169–2172.

38. Fatty Acids • Fatty acid metabolism is driven by protein carrier transport. • Important mostly in the development of brain and nerve tissues. • Lipoprotein lipase (LPL) • Active role in metabolism of triglycerides taken up by the conceptus from the maternal blood • Hydrolyzes lipoproteins • Promotes the cellular uptake of chylomicrons, cholesterol-rich lipoproteins, and free fatty acids • Lack of enzyme is associated with reduced growth and preterm births • Formation of sterols: Steroid hormones • Cell membrane development: phosolipid membrane Fetal Growth and Development, AnS 536

39. Glucose • Fetus has minimal capacity for gluconeogenesis • Glucose uptake is regulated by GLUT (glutamine) transporters and glucose gradient • Cellular energy: glycolysis and ATP production • ATP: the elixir of life Fetal Growth and Development, AnS 536

40. Immune response & Growth • Nitric oxide (NO): biosynthetic compound, primary functions in association with muscle contraction and by product of immune response in adults • Synthesized from L-arginine • Macrophages • Fetal development: Capable of inhibiting the development of adipocytes • Stimulating oxidation of fatty acids and glucose within muscle • NO may have a greater influence in the differentiation of somatic stem cells into secondary muscle fibers (Wu et al., 1998). • FAA’s such as arginine, regulate the partitioning of nutrients, favoring muscle growth over that of adipocyte accretion Fetal Growth and Development, AnS 536

41. Immune response & Growth • The influence of NO on the differentiation of muscle cells and the formation of secondary muscle cells can have lasting effects postnatally. • The development of muscle tissue is well characterized and provides a clear picture of the effect of nutrients, endocrine signaling, and genetic potential on the development of the fetus. • Fetal muscle development, and subsequent postnatal growth, is • influenced by the number of myofibers, which are produced during proliferation of designated somatic cells • Extreme genetic example: ‘double’ muscling, Belgian Blue • NO: increased muscle differentiation, decreased muscle fiber numbers, increased muscle fiber size, decreased accretion of adipose Fetal Growth and Development, AnS 536

42. Abnormal Development • “Cloned cattle fetuses with the same nuclear genetics are more variable than contemporary half-siblings resulting from artificial insemination and exhibit fetal and placental growth deregulation even in the first trimester.” • Lee et al., 2004 • Nuclear Transfer calves, clones, as compared to in vitro fertilization (IVF) and artificial insemination (AI) • NT fetuses have a notoriously reduced survival rate • Fetal and placental growth measured at d 50, 100, and 150 post implantation Fetal Growth and Development, AnS 536

43. Basic Cloning Process, Nuclear DNA Transfer Fetal Growth and Development, AnS 536

44. Fetal Growth- Abnormal Development • Increased fetal size and slightly advanced development was noted within the NT fetuses. • Tendency for the placental tissues to have a greater weight and density • No growth factors were measured • Suggested by the investigators that the lack of opposing IGF signals may be to blame. Fetal Growth and Development, AnS 536

45. Fetal Growth- Abnormal Development • Moore and Haig (1991) suggest that different IGF signals are controlled by different parental genomic mechanisms. • IGF-I promotes fetal growth, Paternal alleles • IGF-II regulates growth of the placenta, Maternal alleles • In the case of the NT calf or cloned calf, are IGF signals not regulatory of each other? • Due to the replication of a complete genome sequence, instead of the formation of a parental mix? Fetal Growth and Development, AnS 536

46. Fetal Growth- Abnormal Development NT Fetus Normal Fetal Growth and Development, AnS 536

47. Sources • Bazer, F. W., Roberts, R. M., & William, W. (2013). ACTIONS OF HORMONES ON THE UTERUS AND EFFECT ON CONCEPTUS DEVELOPMENT. Journal of Animal Science, 35–45. • Bloomfield, F. H., Knight, D. B., Breier, B. H., & Harding, J. E. (2001). Growth restriction in dexamethasone-treated preterm infants may be mediated by reduced IGF-I and IGFBP-3 plasma concentrations.Clinical endocrinology (Vol. 54, pp. 235–242). • Bukowski, R. (2004). Fetal growth potential and pregnancy outcome. Seminars in Perinatology, 28(1), 51–58. doi:10.1053/j.semperi.2003.12.003 • Caspi, E., Schreyer, P., Weinraub, Z., Bukovsky, I., & Tamir, I. (1975). Changes in amniotic fluid lecithin-sphingomyelin ratio following maternal dexamethasone administration. American Journal of Obstetrics and Gynecology, 122(3), 327–331. • Curet, L. B. and D. C. (1971). Effect of estrogen and progesterone on the uptake of amino acids by the uterus of the nonpregnant ewe. Amer. J. Obstet. and Gynecol, 109(548). • Knight, J. W., Bazer, F. W., Thatcher, W. W., Franke, D. E., & Wallace, D. (1977). Conceptus Development in Intact and Unilaterally Hysterectomized-Ovariectomized Gilts : Interrelations among Hormonal Status , Placental Development , Fetal Fluids and Fetal Growth The online version of this article , along with updated information and se, 620–637. • Lee, R. S. F., Peterson, a J., Donnison, M. J., Ravelich, S., Ledgard, A. M., Li, N., … Wells, D. N. (2004). Cloned cattle fetuses with the same nuclear genetics are more variable than contemporary half-siblings resulting from artificial insemination and exhibit fetal and placental growth deregulation even in the first trimester. Biology of Reproduction, 70(1), 1–11. doi:10.1095/biolreprod.103.020982 Fetal Growth and Development, AnS 536

48. Magnusson, A. L., Waterman, I. J., Wennergren, M., Jansson, T., & Powell, T. L. (2004). Triglyceride hydrolase activities and expression of fatty acid binding proteins in the human placenta in pregnancies complicated by intrauterine growth restriction and diabetes. The Journal of Clinical Endocrinology and Metabolism, 89(9), 4607–4614. doi:10.1210/jc.2003-032234 • Moore, T., & Haig, D. (1991). Genomic imprinting in mammalian development: a parental tug-of-war. Trends in Genetics : TIG, 7(2), 45–49. doi:10.1016/0168-9525(91)90230-N • Murphy, V. E., Smith, R., Giles, W. B., & Clifton, V. L. (2006). Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. Endocrine Reviews, 27(2), 141–69. doi:10.1210/er.2005-0011 • Regnault, T. R. H., Friedman, J. E., Wilkening, R. B., Anthony, R. V, & Hay, W. W. (2005). Fetoplacental transport and utilization of amino acids in IUGR--a review. Placenta, 26 Suppl A, S52–62. doi:10.1016/j.placenta.2005.01.003 • Roos, S., Powell, T. L., & Jansson, T. (2004). Human placental taurine transporter in uncomplicated and IUGR pregnancies: cellular localization, protein expression, and regulation. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 287(4), R886–R893. doi:10.1152/ajpregu.00232.2004 • Roskoski, Robert Jr., and D. F. S. (1967). The effect of estrogen on sugar transport in the rat uterus. Biochimica et, 35, 717–726. • Wu, G., Bazer, F. W., Burghardt, R. C., Johnson, G. a, Kim, S. W., Li, X. L., … Spencer, T. E. (2010). Impacts of amino acid nutrition on pregnancy outcome in pigs: mechanisms and implications for swine production. Journal of Animal Science, 88(13 Suppl), E195–204. doi:10.2527/jas.2009-2446 • Wu, G., Pond, W. G., Flynn, S. P., Ott, T. L., & Bazer, F. W. (1998). Maternal dietary protein deficiency decreases nitric oxide synthase and ornithine decarboxylase activities in placenta and endometrium of pigs during early gestation. The Journal of Nutrition, 128(12), 2395–402. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9868187 Fetal Growth and Development, AnS 536