Prenatal Development Kari Kveim Lie Nasjonalt folkehelseinstitutt, Divisjon for epidemiologi Changing Ideas Over Time • Old idea: The human body is already created in the sperm. The female genital tract is needed as an incubator for the fetus to develop Leonardo Da Vinci ca 1510 Prenatal development 2008 • • • • Genes Regulatory genes important Gene-gene interaction Gene-environmental interaction (naturenurture) Phylogenetic Continuity • The idea that because of our common evolutionary history, humans share physiologic characteristics with other animals. Humans and apes share 98% of the genes Prenatal development Conseption Cell division Cell migration is the movement of cells from their point of origin to somewhere else in the embryo Cell differentiation (from stem cells) Selective death of certain cells, or apoptosis, important in organ development Conseption • Conseption results from the union of two gametes, the egg and the sperm. Gametes are produced through a specialized cell division, meiosis, which results in each gamete’s having only half the genetic material of all other normal cells in the body. The fertilized egg, zygote, has a full set of genetic material Conception Twins • Identical twins originate from the splitting in half of the inner cell mass, resulting in the development of genetically identical individuals • Fraternal twins result when two eggs are released into the fallopian tube at the same time and are fertilized by different sperm By the 4th day after conception, the zygote arranges itself into a hollow sphere of cells with a bulge of cells, the inner cell mass, on one side The Embryo – Placenta: Permits the exchange of materials between the bloodstream of the fetus and that of the mother – Umbilical cord: The tube that contains the blood vessels that travel from the placenta to the developing organism and back again Embryo at 4 Weeks Face Development from 5½ to 8 Weeks Fetus at 9 Weeks Fetus at 11 Weeks Fetus at 16 Weeks Fetus at 18 Weeks Fetus at 20 Weeks Fetus at 28 Weeks Fetal development Formation of genital organs 4-7 weeks: • So called gonadal ridges are formed similar in both sexes – later to develop into ovaries or testicles • Both sexes have two sets of internal ducts – later to develop into ducts connecting the gonads with external genitalia • External genitalia appear female Gonadal differentiation • In males gonadal ridges develop into testicles as result of so called SRY (after Sex Determining Region of the Y chromosome) • In females, due to absence of SRY, expression of other genes trigger the gonadal ridges to develop into ovaries Gonadal differentiation • XY fetus: SRYproduction: Development of testicles • XX fetus: no Y chromosome, no SRY: Development of ovaries Gonadal differentiation - males • The developing testicles produce male hormones that promote growth of the male tubes. These are developing into the structures connecting the testicles with penis. • The testicles also produce a hormone causing the female tubes to disappear • Both sexes are exposed to maternal female hormones Gonadal differentiation - females • Anti-female-tube hormone is not produced: Female tubes develop into fallopian tubes, uterus and upper part of vagina. • Male tube growth factor not produced: • Male tubes disappears • Fetal ovaries produce female hormones, promoting local development in the ovary, but of little importance in development of genital organ structure • Both sexes are exposed to maternal female hormones Development of internal genitalia External genitalia • In males, fetal male hormones masculinize external genitalia. • In females, no or lower level of male hormones, hence, the external genitals remain female. External genitalia Secondary sex characteristics • Sex hormone levels are similar in prepubertal girls and boys • Further maturation of the gonads during puberty, and the resultant hormone production results in the secondary sex characteristics. Differentiation of genital organs – in brief • Female development – default path • Male development – defeminization and masculinization Fetal development– sex differences in brain development • In most animals different exposure of fetal and infant brain to sex hormones produce irreversible differences that correlates with reproductive behaviour • Humans fetuses: Both androgen and oestrogen receptors are found in the brain • Sex-specific genes are expressed differently in male and female brains Sex differences in adult human brain • Structural sex differences are detectible in like size and shape of corpus callosum and certain hypothalamic nuclei. • Differences in brain weight • Different hormonal feedback response in the hypothalamic-pituitary system Psychological sex differentiation – nature and nurture • Gender versus sex ? • John Money and John-Joan • Diamond M. Sigmundson HK. Sex reassignment at birth. Long-term review and clinical implications. Archives of Pediatrics & Adolescent Medicine. 151(3):298-304, 1997 Mar. Psychological sex differentiation – nature and nurture • Reiner WG, Kropp BP. A 7-year experience of genetic males with severe phallic inadequacy assigned female. The Journal of Urology Volume 172, Issue 6, Part 1, December 2004, Pages 2395-2398 • All patients demonstrated marked male typical behaviours and interest.10 live as males, and 6 as females • Those reared male and those reared female and converted to male: functional psychosocial development • Those not converting to male: less succsessful psychosocial development Sex differentiation – what could og wrong? • Genes – environment • Structure - function Sex differentiation what could og wrong • Defect ormation of gonadal ridges, genital tubes and early outer genitalia • Hormon receptor defect – lack of hormon effect • Hormon metabolism or production irregularity – to much hormone Fetal development The Embryo • The neural tube is a U-shaped groove formed from the top layer of differentiated cells in the embryo – It eventually becomes the brain and the spinal cord Brain development • Migration of cells • Formation of nerval tracts in the brain • Formation of synapses – continues after birth Brain development • Cell division • Cell migration • Development of synapses, receptors and transmittor activity • Involution of nerve tissue and nerve connections The Fetus: An active contributor to its own development • By 12 weeks after gestation, most of the movements that will be present at birth have appeared – Swallowing amniotic fluid promotes the normal development of the palate and aids in the maturation of the digestive system – Movement of the chest wall and pulling in and expelling small amounts of amniotic fluid help the respiratory Fetal Rest-Activity Cycles • Become stable during the second half of pregnancy • Circadian rhythms are also apparent • Near the end of pregnancy, the fetus’s sleep and wake states are similar to those of the newborn Sensation • The sensory structures are present relatively early in prenatal development and play a vital role in fetal development and learning – The fetus experiences tactile stimulation as a result of its own activity, and tastes and smells the amniotic fluid – It responds to sounds from at least the 6th month of gestation – Prenatal visual experience, however, is negligible The Fetus is protected, but-• The placental membrane is a barrier against some, but not all toxins and infectious agents • The amniotic sac, a membrane filled with fluid in which the fetus floats, provides a protective buffer for the fetus What can go wrong? Miscarriage • By far the most common misfortune in prenatal development is spontaneous abortion (miscarriage) • Around 45% or more of conceptions result in very early miscarriages • The majority of embryos that miscarry very early have severe defects What can go wrong in the central nervous system? • Genetic defect • Environmental damage What can go wrong? • Malformation • Other structural and or functional abnormality • Metabolic process Spina bifida Closing of the neural tube occurs day 24-26 after conception I Norway around 60 children are born every year with spina bifida Neural tube defects Norway 19672002 Neurodevelopmental disorders Genetic factors • Chromosomal disorder • Single gene disorder • Gene-gene interaction • Gene-environment interaction Neurodevelopmental disorders Environmental factors • Reduced blood circulation/placenta function • Infections • Toxic substances • Nutritional deficiencies Compromised blood sirculation gas exchange and metabolism • Placenta disorders • Cerebral ”stroke” in the fetus • Birth related disorders in the mother Neurodevelopmental disorders • Preterm birth is a risk factor for several neurodevlopmental disorders. • The mechanisms involved is largely unknown Neurodevelopmental disorders Infection • • • • • Syphilis, Toxoplasmosis Rubella (german measles – røde hunder) CMV-infection Others Infections during pregnancy mechanisms for fetal injury • Fetal infection • Mother’s infection leads to secretion of inflammatory mediators, which are harming the fetus • Autoimmune mechanism Toxic factors • Mercury - high concentrations (Minamata disease) • Polutants • Metabolic products – PKU (Følling disease) Toxic substances – Talidomid – Antiepileptics – Alcohol – Heroin – Nicotin Alcohol • Maternal alcoholism can lead to fetal alcohol syndrome (FAS), which is associated with mental retardation, facial deformity, and other problems Cigarette smoking • Cigarette smoking during pregnancy is linked to retarded growth and low birth weight – Cigarette smoking has also been linked to SIDS although the ultimate causes of SIDS are still unknown – Child behaviour disorders (?) Some mechanisms for disordered development of the brain • Interference with cell division and migration • Interference with development of synapses, receptors and transmittor activity • Interference with normal involution of nerve tissue and nerve connections • Altered expression of regulatory genes: Retinoic acid, Valproate (antiepileptic drug) Deficiencies • • • • Lack of iodine Lack of folate Lack of certain fatty acids (?) Thyroid disorders in the mother (and hence in the child) Why is it difficult to find out? • The same environmental factor might result in different symptoms according to stage in fetal development – Rubella, other intrauterine infections – Cytostatics, other medicins – In animal experiments: The same toxin may result in hyperactivity or hypoactivity, depending on fetal age at exposure Why is it difficult to find out? • Various environmental exposure may result in the same symptoms • Autistic symptoms may develop after intrauterin rubella and after major intrauterine alcohol exposure Why is it difficult to find out? • Environmental factor is harmful only for the genetic vulnerable fetus • Folic acid supplement is important primarily for a small group of pregnancies predisposed to neural tube defects Neurologic developmental disorders • Cerebral palsy, autism, ADHD and other developmental disorders where the diagnose at present is based on presenting symptoms, may be reclassified completely when causal pathways are better understood.