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An Analysis and Review of the Relative
Morphology of Extraembryonic
Membranes in Mammals:
Their Roles in Histiotrophic Nut...
Examples of Uterine Structure
Ramsey, 1982
Gross Anatomy of the Human Female
Reproductive Tract
Netter, 1998
Events in the Female Reproductive
Tract from Fertilization to Implantation
Moore, Persaud & Siota, 1997
Changes in Uterine Wall During
Menstrual Cycle
Nutrition During Early Development
• Follows Ficke’s Law of Diffusion
• Proportional to surface areas and/or
efficiency of...
Placenta
Any apposition of embryonal to parental
tissues for the purpose of physiological
exchange
Implantation of Human Embryo
Carlson, 1999
Establishment of the
Uteroplacental Circulation
Carlson, 1999
Uteroplacental Vasculature Begins
• Early on gestational day 8 in the mouse
• Late gestational day 8/early day 9 in the ra...
Classifications of Placentae
• Gross shape
• Mode of implantation
• Fetal membranes
• Extent of invasiveness
Types of Placentae: Shape
Diffuse
(Placenta
Diffusa)
Multiplex
(Placenta
Cotyledonaria)
Banded
(Placenta
Zonaria)
Discoid
...
Types of Placentae: Mode of Implantation
Central
(Superficial)
Eccentric
Interstitial
Lumen of Uterus
Chorion
Lumen of Ute...
Placentae Are Formed from Different
Fetal Membranes
TRUE CHORIONIC CHORIOVITELLINE
CHORIOALLANTOIC CHORIOVITELLINE/
CHORIO...
Placentae Differ With Respect to
Invasiveness
Classification of Placentae
Placental Characteristics Affecting
Transfer of Substances
• Placental morphology
– Grosser classification
– Number of lay...
Placental Transfer of Chemical
Substances
Assume that EVERY chemical is transferred
across the placenta
The ensuing questi...
Development of Human Embryo is Rapid
3 weeks
5 weeks
6.5 weeks
11 weeks
Developmentally Susceptible Periods
Differentiation
Organogenesis
Tissue Development
Functional Maturation
Implantation
Fe...
Gestational Milestones for Mammals
Primitive Early Organogenesis Usual
Species Implantation Streak Differentiation Ends Pa...
Rodent Inverted Yolk Sac Placenta
Ramsey, 1982
Placentation in Rats:
Development of the Inverted
Yolk Sac Placenta
Gestational Day 7 Gestational Day 8 Gestational Day 10...
Placentation in Rats:
Establishment of the
Chorioallantoic Placenta
Gestational Day 11.5
Modified from Jollie, 1990
Visceral Yolk Sac and Early
Chorioallantoic Placenta
Ida Smoak, UNC
Gestational Day 10 Rat Conceptus
Gestational Day 12 Rat Conceptus
Oviparous
Yolk Sac
Viviparous
Allantois Chorion
Maternal Uterine Tissue
Cytotrophoblast
Syncytiotrophblast
Chorioallantoic...
Inverted Yolk Sac
Maternal Uterine Tissue
Uterine Milk
Parietal YS
and Reichert’s
Membrane
Definitions
• Histiotroph: Total nutrients supplied to the
embryo in viviparous animals from sources
other than the matern...
Countercurrent Blood Flow
CAP
CAP
Temporal Comparison of Early Development:
Rat and Human
Rat
Human
Conception
Day 0
Day 0
5.5 - 7
6-13
Implantation...
Tissue Development
Functional Maturation
Fertilization
Parturition
Time in Gestation
Relative
Susceptibility
22
Organogene...
Developmentally Susceptible Periods:
Rat
Tissue Development
Functional Maturation
Fertilization
Parturition
Time in Gestat...
Types of Placentae Found in Animals
Used in Research
Primate Rodent
Dog Sheep Ramsey, 1987
Colorado State Website
Term Canine Conceptus Dissected
Extraembryonic Membranes and
Placentation in the Dog
Modified from Noden and de Lahunta (1985)
Chorioallantoic
Placenta
Ch...
Chorionic, Amniotic, and Yolk Sac
Cavities Develop Early
Drawings at the same scale of human embryos from stage 2 to stage...
Chorionic Cavity Expands Rapidly
During Early Gestation
The relative size of the embryo and the chorion at weekly interval...
Points to Remember for Modeling
Purposes
The size of extraembryonic fluid
compartments is large compared to the size
of th...
Points to Remember for Modeling
Purposes
As gestation proceeds:
– Surface area for exchange expands dramatically
– Distanc...
Exocoelomic Sampling Technique
Jauniaux, et al., 1993
Vascularized Yolk Sac and
Chorioallantoic Placenta of Human
Mark Hill, UNSW
Recent Reports Regarding Human
Uteroplacental Circulation (Jauniaux et al.)
• Based on in vivo Doppler ultrasound and dyna...
Comparative Developmental Milestones
Species Fertilization Blastocyst
Implantation
Begins
InvYSP CAP
Neural
Tube
Closure
M...
Hypothetical Impact of Two Concepts of
Early Embryonal Nutrition on Interpretation
of Data for Potential Human Risk
• Clas...
END
• The following are extra slides
1. amnion
2. chorion laeve
3. chorionic villi
4. embryonic
surface
5. umbilical
vessels
Gestational Day 26
England, 1996
Gestational Day 12 Rat Conceptus
Term Canine Zonary Placenta
Rob Foster 2002
Diagram of Integrin
Intra- and Extracellular Relationships
Gilbert, 1997
Possible Mechanism for Control of
Adhesion
• Ovarian steroids (progesterone) elicit
– Expression of β-integrins on surface...
Rat Implantation Chamber
A. Blastocyst
a. Embryoblast
b. Trophoblast
B. Epithelial
depression
C. Subepithelial
fibroblasts...
Species Differences in Developmental
Toxicity Studies
• Plasma protein binding
• Metabolic and biotransformational
capabil...
Chronology of Early Events During
Gestation of Mouse Embryos
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Fertilization
Blastocyst
Impl...
Vascular Flow in Mammals
Vascular Flow in Pregnant Mammals
Conceptual Roadmap of
Embryonic Development
Embryonic
Cellular Potency
Cellular
Differentiation
Interspecies Differences among Embryos
Increase with Age
Gilbert, 1997
Comparative Definitive Placentation
Amniotic Cavity
Extra-Embryonic
Coelom
Decidua
Yolk Sac
Uterine Artery
Decidua
Re-Esta...
Comparative Early Placentation
Amniotic Cavity
Extra-Embryonic
Coelom
Decidua
Yolk Sac
Uterine Lumen
Uterine Artery
Decidu...
Mechanisms of Placental Transfer
• Diffusion (e.g., nearly all drugs and foreign
substances)
– No metabolic energy
– With ...
Mechanisms of Placental Transfer
• Active transport (e.g., essential amino acids, iron)
– Against concentration gradient
–...
1. abdomen
2. amnion
3. amnion on
umbilical cord
4. back
5. chorionic
villi
6. embryo
7. fetus
8. head
9. leg
10. leg bud
...
Diameter of Chorion Greatly Exceeds
Length of Embryo During First 8 Weeks
The length of the embryo
from stage 8 to stage 2...
Conceptual Roadmap of
Embryonic Development
Embryonic
Cellular Potency
Cellular
Differentiation
DeSesso, 1997
Conceptual Roadmap of
Embryonic Development
Embryonic
Cellular Potency
Cellular
Differentiation
Gestational Stage and
Developmental Susceptibility
Usually Not
Affected
Highly
Susceptible:
Malformations
Readily Induced
...
Does the Embryo Occupy a Privileged
Site in an Impregnable Uterus?
After Wilson
Is There a “Placental Barrier”?
• Virtually all substances can and do cross the
placenta
• Closest correlations to a “barr...
Considerations about the Placental
Interface and Toxicity
• Regardless of anatomical differences, all
placentae serve to t...
Considerations about the Placental
Interface and Toxicity
• Placentae are established early and continue to
develop throug...
Generalized Implications from our
Studies and Analysis
 There should be no doubt that the InvYSP can be a target for
toxi...
Relative Morphology of Extraembryonic Membranes in Mammals: Their Roles in Histiotrophic Nutrition and Possible Sites of D...
Relative Morphology of Extraembryonic Membranes in Mammals: Their Roles in Histiotrophic Nutrition and Possible Sites of D...
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Relative Morphology of Extraembryonic Membranes in Mammals: Their Roles in Histiotrophic Nutrition and Possible Sites of Developmental Insult

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Presented by John DeSesso and Joseph F. Holson in Symposium I ("A Detective Story: Is the Prenatal Toxicity of a Therapeutic in Rats Relevant to Human Risk?", J.F. Holson and L. B. Pearce, co-chairpersons) at the Forty-Third Annual Meeting of the Teratology Society, Philadelphia, PA, June 26, 2003.

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Relative Morphology of Extraembryonic Membranes in Mammals: Their Roles in Histiotrophic Nutrition and Possible Sites of Developmental Insult

  1. 1. An Analysis and Review of the Relative Morphology of Extraembryonic Membranes in Mammals: Their Roles in Histiotrophic Nutrition and Possible Sites of Developmental Insult John M. DeSesso, PhD, Fellow ATS Mitretek Systems Joseph F. Holson, PhD, DABFE WIL Research Laboratories
  2. 2. Examples of Uterine Structure Ramsey, 1982
  3. 3. Gross Anatomy of the Human Female Reproductive Tract Netter, 1998
  4. 4. Events in the Female Reproductive Tract from Fertilization to Implantation Moore, Persaud & Siota, 1997
  5. 5. Changes in Uterine Wall During Menstrual Cycle
  6. 6. Nutrition During Early Development • Follows Ficke’s Law of Diffusion • Proportional to surface areas and/or efficiency of exchange • Becomes increasingly inefficient when the diameter of the conceptus exceeds 0.2 mm
  7. 7. Placenta Any apposition of embryonal to parental tissues for the purpose of physiological exchange
  8. 8. Implantation of Human Embryo Carlson, 1999
  9. 9. Establishment of the Uteroplacental Circulation Carlson, 1999
  10. 10. Uteroplacental Vasculature Begins • Early on gestational day 8 in the mouse • Late gestational day 8/early day 9 in the rat • Gestational day 13 in humans Onset of Embryonic Heartbeat • Gestational day 8½ - ¾ in the mouse • Gestational day 9½ in the rat • ~ Gestational day 23 in humans
  11. 11. Classifications of Placentae • Gross shape • Mode of implantation • Fetal membranes • Extent of invasiveness
  12. 12. Types of Placentae: Shape Diffuse (Placenta Diffusa) Multiplex (Placenta Cotyledonaria) Banded (Placenta Zonaria) Discoid (Placenta Discoidalis) Pig Horse Rhinoceros Ruminants e.g. Cow Sheep Goat Deer Carnivores e.g. Dog Cat Seal Insectivores Rodents Higher Primates
  13. 13. Types of Placentae: Mode of Implantation Central (Superficial) Eccentric Interstitial Lumen of Uterus Chorion Lumen of Uterus Chorion DeSesso, 1997
  14. 14. Placentae Are Formed from Different Fetal Membranes TRUE CHORIONIC CHORIOVITELLINE CHORIOALLANTOIC CHORIOVITELLINE/ CHORIOALLANTOIC DEVELOPING COMPLETE NON- VASCULAR VASCULAR Ramsey, 1982
  15. 15. Placentae Differ With Respect to Invasiveness
  16. 16. Classification of Placentae
  17. 17. Placental Characteristics Affecting Transfer of Substances • Placental morphology – Grosser classification – Number of layers between maternal and embryonic circulation • Placental metabolism • Placental age – Thickness – Surface area
  18. 18. Placental Transfer of Chemical Substances Assume that EVERY chemical is transferred across the placenta The ensuing questions are • HOW MUCH reaches the fetus? • HOW RAPIDLY does it cross to the fetal circulation? • HOW LONG does it remain in the fetus?
  19. 19. Development of Human Embryo is Rapid 3 weeks 5 weeks 6.5 weeks 11 weeks
  20. 20. Developmentally Susceptible Periods Differentiation Organogenesis Tissue Development Functional Maturation Implantation Fertilization Parturition Time in Gestation Embryonic Period Fetal Period Post Natal Period Relative Susceptibility 0 CA D EB DeSesso, 1997
  21. 21. Gestational Milestones for Mammals Primitive Early Organogenesis Usual Species Implantation Streak Differentiation Ends Parturition Rat 5-6 8.5 10 15 21-22 Mouse 5 6.5 9 15 19-20 Rabbit 7.5 7.25 9 18 30-32 Hamster 4.5-5 7 8 13 16 Guinea Pig 6 12 14.5 ~29 67-68 Monkey 9 17 21 ~44-45 166 Human 6-7 13 21 ~50-56 266 A2 1 In gestational days; day of confirmed mating = gestational day 0 2 Letters refer to positions on Conceptual Roadmap of Embryonic Development B C D E Gestational Milestone1 DeSesso, 1997
  22. 22. Rodent Inverted Yolk Sac Placenta Ramsey, 1982
  23. 23. Placentation in Rats: Development of the Inverted Yolk Sac Placenta Gestational Day 7 Gestational Day 8 Gestational Day 10 Jollie, 1990
  24. 24. Placentation in Rats: Establishment of the Chorioallantoic Placenta Gestational Day 11.5 Modified from Jollie, 1990
  25. 25. Visceral Yolk Sac and Early Chorioallantoic Placenta Ida Smoak, UNC
  26. 26. Gestational Day 10 Rat Conceptus
  27. 27. Gestational Day 12 Rat Conceptus
  28. 28. Oviparous Yolk Sac Viviparous Allantois Chorion Maternal Uterine Tissue Cytotrophoblast Syncytiotrophblast Chorioallantoic Yolk Sac Chorion Cytotrophoblast Syncytiotrophblast Maternal Uterine Tissue Choriovitelline Routes of Embryonic Nutrient Uptake
  29. 29. Inverted Yolk Sac Maternal Uterine Tissue Uterine Milk Parietal YS and Reichert’s Membrane
  30. 30. Definitions • Histiotroph: Total nutrients supplied to the embryo in viviparous animals from sources other than the maternal blood • Hemotroph: Total nutrients supplied to the embryo from the maternal blood
  31. 31. Countercurrent Blood Flow
  32. 32. CAP CAP Temporal Comparison of Early Development: Rat and Human Rat Human Conception Day 0 Day 0 5.5 - 7 6-13 Implantation Primitive Streak Appears 13.5 8.5 9 18 Neural Folds To reach equivalent lengths – 3 mm – Human: 25 days vs. Rat: 9 days (From: O’Rahilly & Muller, 1987) 27 11.511 26 InvYSP InvYSP First Somite Formed First Heartbeat 9.5 19 23 Chorioallantoic Placenta Circulation Begins 10 Forelimb Bud
  33. 33. Tissue Development Functional Maturation Fertilization Parturition Time in Gestation Relative Susceptibility 22 Organogenesis Developmentally Susceptible Periods: Rat Differentiation Implantation Embryonic Period Fetal Period Post Natal Period 0 105 158.5
  34. 34. Developmentally Susceptible Periods: Rat Tissue Development Functional Maturation Fertilization Parturition Time in Gestation Fetal Period Post Natal Period Relative Susceptibility 15 22 Implantation 0 105 8.5 CAPYSP Organogenesis Differentiation
  35. 35. Types of Placentae Found in Animals Used in Research Primate Rodent Dog Sheep Ramsey, 1987
  36. 36. Colorado State Website Term Canine Conceptus Dissected
  37. 37. Extraembryonic Membranes and Placentation in the Dog Modified from Noden and de Lahunta (1985) Chorioallantoic Placenta Choriovitelline Placenta Amniotic Cavity Allantoic Cavity Allantois Chorion Yolk Sac
  38. 38. Chorionic, Amniotic, and Yolk Sac Cavities Develop Early Drawings at the same scale of human embryos from stage 2 to stage 5c illustrating implantation. Asterisk, primary yolk sac cavity. O’Rahilly and Muller, 1987
  39. 39. Chorionic Cavity Expands Rapidly During Early Gestation The relative size of the embryo and the chorion at weekly intervals. The stages shown are 6, 10, 13, 16, 17, 20, and 23. O’Rahilly and Muller, 1987
  40. 40. Points to Remember for Modeling Purposes The size of extraembryonic fluid compartments is large compared to the size of the embryo during organogenesis
  41. 41. Points to Remember for Modeling Purposes As gestation proceeds: – Surface area for exchange expands dramatically – Distance between maternal and offspring blood decreases – Maternal plasma volume increases up to 50% – Maternal protein binding decreases
  42. 42. Exocoelomic Sampling Technique Jauniaux, et al., 1993
  43. 43. Vascularized Yolk Sac and Chorioallantoic Placenta of Human Mark Hill, UNSW
  44. 44. Recent Reports Regarding Human Uteroplacental Circulation (Jauniaux et al.) • Based on in vivo Doppler ultrasound and dynamic oxygen tension measurements – Erosion of maternal capillaries (week 3) allows blood into intervillous space (IVS), but sluggish movement – No “connections” between spiral arteries and IVS until week 4 (presence of cytotrophoblast plugs) – Minimal maternal blood flow through IVS until week 6 – Fully established uteroplacental circulation by week 10
  45. 45. Comparative Developmental Milestones Species Fertilization Blastocyst Implantation Begins InvYSP CAP Neural Tube Closure Mouse 0 3-6 5 7.2 9.1 9.1 Rat 0 3.5-5.5 5.5 9.5 11.5 10.75 Rabbit 0 3-6 7.5 9 10 9.75 Dog 0 12-16 16 ---* 22 21 Rhesus 0 5-6 9 --- ~28 31 Human 0 4-6.5 6.5 --- 27 27 DeSesso, 1997 * Yolk sac of the dog abuts chorion ~19.5 day of gestation
  46. 46. Hypothetical Impact of Two Concepts of Early Embryonal Nutrition on Interpretation of Data for Potential Human Risk • Classic Anatomical Model: – Uteroplacental circulation begins on gestational day 13 – Hemotrophic nutrition begins – No impact on embryonic nutrition • Recent Clinical Reports: – Spiral arteries are ‘plugged’ until 8th week, preventing uteroplacental circulation – Product unlikely to reach trophoblast cells – No impact on embryonic nutrition
  47. 47. END • The following are extra slides
  48. 48. 1. amnion 2. chorion laeve 3. chorionic villi 4. embryonic surface 5. umbilical vessels Gestational Day 26 England, 1996
  49. 49. Gestational Day 12 Rat Conceptus
  50. 50. Term Canine Zonary Placenta Rob Foster 2002
  51. 51. Diagram of Integrin Intra- and Extracellular Relationships Gilbert, 1997
  52. 52. Possible Mechanism for Control of Adhesion • Ovarian steroids (progesterone) elicit – Expression of β-integrins on surface of endometrial cells for a window of time – Secretion of signal molecules, including the cytokine leukemia inhibitory factor (LIF), into uterine lumen • Blastocyst responds to LIF – Expresses the glycoprotein L-secretin on trophoblast cells • Expression of both glycoproteins occurs in discrete areas • Carbohydrate moieties of the glycoproteins interact
  53. 53. Rat Implantation Chamber A. Blastocyst a. Embryoblast b. Trophoblast B. Epithelial depression C. Subepithelial fibroblasts showing decidual reaction Hebel and Stromberg, 1986
  54. 54. Species Differences in Developmental Toxicity Studies • Plasma protein binding • Metabolic and biotransformational capabilities • Genotypic susceptibility • Developmental schedules
  55. 55. Chronology of Early Events During Gestation of Mouse Embryos 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Fertilization Blastocyst Implantation Inv Yolk Sac Placenta Chorioallantoic Placenta (20 Somites) Days of Gestation
  56. 56. Vascular Flow in Mammals
  57. 57. Vascular Flow in Pregnant Mammals
  58. 58. Conceptual Roadmap of Embryonic Development Embryonic Cellular Potency Cellular Differentiation
  59. 59. Interspecies Differences among Embryos Increase with Age Gilbert, 1997
  60. 60. Comparative Definitive Placentation Amniotic Cavity Extra-Embryonic Coelom Decidua Yolk Sac Uterine Artery Decidua Re-Established Uterine Lumen Amniotic Cavity Visceral Yolk Sac Vascular Lacuna Human Conceptus at the Time of Chorioallantoic Placental Establishment Day 12 Rat Conceptus Chorioallantoic Placenta Chorioallantoic Placenta Modified from Holson, 1973
  61. 61. Comparative Early Placentation Amniotic Cavity Extra-Embryonic Coelom Decidua Yolk Sac Uterine Lumen Uterine Artery Decidua Ectoplacenta Allantois Visceral Yolk Sac Vascular Lacuna Human Conceptus (Pre-Chorioallantoic Placental Stage) Day 10 Rat Conceptus Modified from Holson, 1973
  62. 62. Mechanisms of Placental Transfer • Diffusion (e.g., nearly all drugs and foreign substances) – No metabolic energy – With concentration gradient – Affected by molecular size and charge • Facilitated diffusion (e.g., glucose) – Involves carrier substance – Rate greater than that expected by diffusion – No metabolic energy – With concentration gradient
  63. 63. Mechanisms of Placental Transfer • Active transport (e.g., essential amino acids, iron) – Against concentration gradient – Saturable – Inhibited by metabolic poisons – Competition exists • Pinocytosis / receptor-mediated endocytosis (e.g., immunoproteins) – Vacuolizations • Leakage (e.g., erythroblastosis fetalis) – Discontinuities
  64. 64. 1. abdomen 2. amnion 3. amnion on umbilical cord 4. back 5. chorionic villi 6. embryo 7. fetus 8. head 9. leg 10. leg bud 11. umbilical cord 12. umbilical vessels Week 8 England, 1996
  65. 65. Diameter of Chorion Greatly Exceeds Length of Embryo During First 8 Weeks The length of the embryo from stage 8 to stage 23, approximately 2-1/2 to 8 postovulatory weeks, based on the measurements of more than 100 specimens that had been graded as excellent in quality. The maximum diameter of the shaded band includes approximately 80 percent of the specimens. At 4 weeks the embryo is about 5mm in length and the chorion about 25mm in diameter. At 8 weeks the embryo is about 30 mm in length and the chorion is about 65mm in diameter. Weeks Millimeters O’Rahilly and Muller, 1987
  66. 66. Conceptual Roadmap of Embryonic Development Embryonic Cellular Potency Cellular Differentiation DeSesso, 1997
  67. 67. Conceptual Roadmap of Embryonic Development Embryonic Cellular Potency Cellular Differentiation
  68. 68. Gestational Stage and Developmental Susceptibility Usually Not Affected Highly Susceptible: Malformations Readily Induced Increasingly Resistant; Functional Deficits Possible DeSesso, 1997 after Wilson
  69. 69. Does the Embryo Occupy a Privileged Site in an Impregnable Uterus? After Wilson
  70. 70. Is There a “Placental Barrier”? • Virtually all substances can and do cross the placenta • Closest correlations to a “barrier” – Expression of the mdr gene in trophoblast cells – Presence of p-glycoprotein on placental trophoblast
  71. 71. Considerations about the Placental Interface and Toxicity • Regardless of anatomical differences, all placentae serve to transport nutrients, metabolites, and gases between parent and offspring
  72. 72. Considerations about the Placental Interface and Toxicity • Placentae are established early and continue to develop throughout gestation • Placentae exhibit wide interspecies differences in morphology • In contrast to humans, many experimental animals (e.g., rat, mouse, rabbit) possess an inverted visceral yolk sac placenta that is established earlier than the chorioallantoic placenta, transports materials by a different mechanism, and remains functional until (nearly?) term
  73. 73. Generalized Implications from our Studies and Analysis  There should be no doubt that the InvYSP can be a target for toxicity leading to serious developmental disruption. To the contrary, it has not been demonstrated that the noninverted yolk sac is a similar target.  Caution should be exercised In generalizing too broadly the findings of studies of this product, which by design, was given at high doses (mass) of hemoglobin protein, 6 g/kg.  Large and/or proteinaceous agents 1) with no pharmacologic action on the biochemical modalities of the InvYSP or 2) which do not contain a moiety with toxic properties would not be expected to exert similar effects.  The former types of agents would appear to represent a small number of the universe of xenobiotics and no broad sense lessens the value of current models.

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