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Developmental Stages

Preimplantation Period Totipotent cells Damage is all-or-nothing Possible exception: mutagens Organogenesis Pattern formation Organ formation Physical defects Fetal Period Maturation and growth Functional deficits. Birth to maturity Cognitive development

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Developmental Stages

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  1. Preimplantation Period Totipotent cells Damage is all-or-nothing Possible exception: mutagens Organogenesis Pattern formation Organ formation Physical defects Fetal Period Maturation and growth Functional deficits Birth to maturity Cognitive development Brain continues to add neurons until ~ age 12 Connections continue to be made until early 20s Growth Adequate nutrition Gene expression Sexual development Adequate nutrition Hormonal balance Senescence Long-term effects of early nutrition? Environmental effects of childhood exposures? PCBs? Developmental Stages

  2. Early cleavage in mammals • Early cleavage to blastula • Preimplantation • Totipotent cells • All-or-nothing effects of toxicants • Some catch-up growth may be needed • Determination of fate begins with gastrulation • Around time of implantation • Cells limited to more & more restricted fates • Positional information helps determine fates

  3. Implantation • Occurs approximately at gastrulation • GD 5-6 in rat, mouse • GD 6-7 in human • Decreased autonomy of embryo • Maternal organism manages • nutrition • oxygen • waste removal • Placental role develops with placenta • Selective permeability • Hormonal changes signal pregnancy • Organogenesis proceeds rapidly after implantation

  4. The Placenta • Placental transport: • Passive diffusion • oxygen, CO2, fatty acids, steroids, nucleosides, electrolytes, fat-soluble vitamins • Facilitated diffusion • sugars • Active transport • Amino acids, some cations (Ca, Fe, I, PO4), water-soluble vitamins • Solvent drag • electrolytes

  5. Human embryos at 33, 50, and 56 days after ovulation (from the beginning of weeks 5 until the end of week 8 of gestation, with another 32 weeks to go before term birth. Note changes in form during this 3 week period: internalization of the heart, development of the eyelids, limb formation, ribs. Note: 2 ways of timing human gestation

  6. Developmental Stages of the Mouse

  7. Organogenesis involves Fate determination • Rapid cell division • Cell migration • Genetic regulation • Rapid turning on and off of genes • Very precise sequences of gene expression Consider: Brain development Limb development Palate development

  8. Cretekos CJ, Weatherbee SD, Chen C-H, Badwaik NK, Niswander L, Behringer RR, Rasweiler JJ (2005) Embryonic staging system for the short-tailed fruit bat, Carollia perspicillata, a model organism for the mammalian order Chiroptera, based upon timed pregnancies in captive-bred animals. Developmental Dynamics 233(3):721-738.

  9. Mouse embryo, day 9: • Neural tube closure beginning • Organogenesis proceeds through day 13 (approximately) when the palate closes; • Birth occurs between day 18 and 21, depending on the strain of mouse. • Each stage of organogenesis depends on successful accomplishment of earlier stages, because cell division, movement and differentiation are ‘cued’ by neighboring cells and previous events. • Example: neural tube induces development of brain, face.

  10. Exencephaly in mice; Anencephaly in humans.

  11. Palate Development

  12. Frontal view of palatal shelves Looking up at roof of mouth

  13. Principles • Access to the fetus • Dose response • Threshold phenomenon • 4 Endpoints • Genetics & Environment • Sensitivity varies with time • Mechanisms

  14. 1. Access to the Embryo • Agents that do not reach the embryo cannot cause developmental toxicity • Physical agents must penetrate maternal tissues to ‘reach’ embryo • X-rays: High doses cause microcephaly • Hyperthermia • Raising core body temperature > 37 oC increases risk of neural tube defects • Fevers, saunas, animal experiments • Chemicals must cross placenta • Chemical structure: smaller molecules cross quite easily • Time of gestation: placental permeability varies -- Rubella • Exception: trypan blue • stays in placenta; probably blocks nutrients from reaching embryos • Deficiency states are also “agents” • Must override maternal homeostasis and/or fetal requisitioning of maternal resources

  15. Access to the Embryo • Physical Agents • Must penetrate maternal organism • X-rays • Heat • Animal experiments • Saunas, fever • Pathogens • Rubella • Toxoplasmosis

  16. Access to the Embryo • Chemicals must cross the placenta • Smaller molecules cross easily • Pemeability of placenta varies over time • Rubella • Exception: trypan blue • Animal teratogen • Sits in placenta • Blocks nutrietns from reaching embryo

  17. Access to the Embryo • Deficiency states • Hypovitaminosis A • Hypothyroidism • Maternal homeostasis must be overcome • But pregnancy must be maintained

  18. 2. There are 4 Manifestations of Perturbed Development • Death • Malformation • Growth Retardation • Functional Deficit • Each of these may be independent of the other, or it may be part of a continuum of response • For example: death may or may not be a more severe form of malformation

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