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Mechanisms of Teratogenesis

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Tissue susceptibility changes over time, however usually rapidly dividing ... teratogens may have a molecular component that alters tissue susceptibility ... – PowerPoint PPT presentation

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Title: Mechanisms of Teratogenesis


1
Mechanisms of Teratogenesis
Lynda B. Fawcett, Ph.D. Assistant Professor of
Pediatrics Thomas Jefferson University Alfred I
duPont Hospital For Children Wilmington, DE
2
Structural Anomalies/Dysmorphology
  • Malformation the normal developmental process is
    altered such that a given structure cannot form
    or forms improperly, the error is intrinsic to
    the morphogenetic process itself.
  • Deformation alterations to already existing
    structures. Alterations in body shape, form, or
    position. Often due to uterine constraint
    (twinning, oligohydramnios etc). ex dislocation
    of the hip, clubfoot, and some facial anomalies
  • Disruption alterations to already existing
    structures, often involving extensive destruction
    of tissue, and/or prevention of later tissue or
    organ formation. Can arise from mechanical or
    physiological factors. ex amniotic band
    syndrome, fetal vascular occlusion, placental
    emboli, localized or general hypoxia, vascular
    insults.

3
Disruption Syndactyly/adactyly
Hypoxia, hemorrhage, necrosis ROS Usually
asymmetrical
EX Cocaine CVS
4
Mechanism of action
Mode of Action
Outcomes
cell death altered cell-cell interactions cell
signaling reduced biosynthesis impaired cell
migration reduced/impaired proliferation alter
ed differentiation
ROS/Lipid peroxidation DNA damage Altered gene
expression Metabolic disturbance Enzyme
inhibition Growth factor imbalance Receptor
agonist/antagonist
Malformation Deformation Death Functional
deficit Growth retardation
Pathogenesis
5
Cytotoxic Teratogens
  • Irradiation
  • 2Deoxyadenosine
  • 4-CP (metabolites)
  • Hyperthermia
  • Ethanol

Whether a toxicant induces cell death depends on
dose and timing of exposure as well as the nature
of the toxicant
6
Apoptosis
Necrosis
The blebs fuse and become larger, no organelles
in blebs
The nucleus begins to break apart, DNA breaks
into small pieces organelles in to blebs
Blebs
The cell membrane ruptures and releases the
cells contents, the organelles are not
functional
The cell breaks into several apoptotoc
bodies the organelles are still functional
7
Apoptosis
SIGMA-ALDRICH
Receptor mediated - Extrinsic (TNF Signaling)
Mitochondrial Intrinsic CytC, caspase 9
8
Characteristics of Cell Death Mediated
Teratogenesis Replication associated cytotoxicity
  • Tissue susceptibility changes over time, however
    usually rapidly dividing undifferentiated tissues
    are most affected with agents that induce direct
    cytotoxicity
  • Tissue sensitivity greatest during organogenesis
    in the neuroepithelium, limb buds and least in
    heart and yolk sac
  • Characteristic malformations include NTDs,
    anopthalmia, limb defects but, generally, not
    heart defects (time dependent).
  • Occurs because
  • DNA more accessible in S phase
  • Defects manifest sooner, critical mass, windows
    of oportunity
  • Molecular mechanisms

9
Tissue sensitivity Irradiation/mouse
studies/organogenesis
  • Molecular basis for tissue sensitivity may be due
    to differential expression of P53 in tissues
  • Temporal/spacial expression of P53 mirrors that
    of tissues most effected by cytotoxic teratogens
  • Irradiation caused activation of P53 in rapidly
    proliferating, undifferentiated tissues (used a
    lac Z reporter model). Neuroepithelium, limb
    buds, arches (Gottli et al, 1997)

10
(No Transcript)
11
P53 KO studies
Consistent findings / apoptosis, cell cycle
check G1/S /- apoptosis and necrosis -/-
necrosis, no cell cycle check (M,S)
12
Replication associated cytotoxicity
Open NT, reduced tissues Anopthalmia Growth
retardation
Control 11.5 d
AA deficiency (Met)
13
Demethylating agents. Whole Mount Immunostaining
165 kD NF
Control
-AA (Met)
CL (-SAM)
NTD only ?165 Kd NF Mechanism probably more
specific, not general cytotoxicity
NTD GR, Reduced Size Protein Somite Pairs
limb buds Anopthalmia No heart defects
14
Effects of Homocysteine on Rat Embryos Cultured
in Vitro from 9.5-11.5 p.c Cardiac Defects
Control
Hcy
Hcy
Control
15
Effects of Hcy on Rat Embryos Cultured in Vitro
from 9.5-11.5 p.c Somite/Vertebral/Arch
Abnormalities (450 ?g/ml)
control
16
  • Although defects such as NTDs may result from
    death, other mechanisms can also result in NTD
  • Specific mechanisms of action
  • Receptor mediated - directly or indirectly
  • Display some type of ligand specificity (enzyme)
  • downstream alterations in cell signaling (growth
    factors differentiation)
  • altered expression of key genes involved in
    morphogenesis.
  • Closure defects have discrete window of
    susceptibility, and less chance for recuperation.
    for NTD reduced proliferation in neuroepithelium,
    failure of neural fold elevation, failure of
    neural fold fusion due to specific mechanisms may
    resemble cytotoxicity at term

17
Tissue specificity and TeratogenesisSpecific
Mechanism Usually receptor mediated
  • Only affect tissues bearing appropriate
    receptors
  • ex sex steroids - genitourinary

18
Receptor-Mediated Teratogenesis
19
Retinoic Acid
  • Accutane 13-cis retinoic acid, used for
    dematological and oncology therapies

RAE Spectrum of defects and potential for all
organ systems to be affected Most common defects
are craniofacial, external ear (BA 1-2)
20
Specificity Teratogenesis RA
  • Vitamin A derivatives involved in signaling
    pathways during normal development - Morphogen
    directly alter/control developmental programs.
  • 1) Induces differentiation or apoptosis of
    various cell types breast carcinoma, prostate
    cancer, AL
  • 2) Produces homeotic mutations in experimental
    animals (limb duplications)
  • Proposed Mode of action for defects
  • Promotes excessive cell death in regions
    undergoing programmed cell death (Alles Sulik,
    89, 90 etc)
  • Alters specification of tissues (NC) HOX genes
  • Alters expression of other RARE genes

21
RA receptors
  • RAR ??? (all trans and 9-cis) RXR???(9 cis)
  • Multiple isoforms exist for all RAR
  • RAR/RXR form heterodimers RXR homodimers,
    heterodimers with thyroid hormone R, peroxisome
    proliferators and others
  • RAR, RXR differentially expressed in embryo
    temporal and spatial pattern
  • RA interacts with other receptors (CRABP)

22
CRABP1
RA
RA
RA
RA
RA
RAR/RXR
CRABP-II
(???)
RA
Other involvment
CRABP1, II
Biosynthesis RA ADH - ETOH hypervitamitosis vitami
n deficiency
Transcription RARE
AP-1 transcription factor block
RAR/RXR
Nucleus
23
  • RAR? -/- Vitamin A deficiency, Resistant to RA
    induced limb defects. Agonists
    RAR?gtRAR?gtRAR? for inducing limb defects
    in wild type
  • RAR? -/- Normal, Resistant to BA 1-2 fusion
    by RA
  • / RAR? agonist caused BA fusions
  • RAR? upregulated in limbs following RA
  • RAR? -/- Vitamin A deficiency defects, normal
    craniofacial and posterior axial skeleton
    resistant to RA induced posterior axial
    skeleton truncation but not cranial, partial
    resistance to other except limb
  • RXR? -/- Lethal, cardiac. Resistant to RA induced
    limb defects

Limb
Craniofacial
Posterior
Cardiomorphogenesis
(Matt et al., 2003 Collins and Mao, 1999)
24
Chromatin condensation suppresses RAREs (RARß2)
VPA
Potential for increased RARß2 destabilization of
chromatin Inappropriate expression of other
genes (p21 p53 cell death)
RARE
25
Summary
  • Teratogenic mechanisms can be broadly separated
    into specific (receptor mediated) and
    non-specific (cell death)
  • Teratogens can have both specific and
    non-specific mechanisms (alcohol)
  • Even general cytotoxic/genotoxic teratogens may
    have a molecular component that alters tissue
    susceptibility
  • Initial molecular mechanisms have the potential
    to result in myriad responses cell death,
    differentiation, altered signaling. Pathogenesis
    must be considered when evaluating the action of
    teratogens
  • Understanding the molecular mechanisms of
    teratogens furthers our understanding of
    development, and allows for the development of
    therapeutics with reduced chance of
    teratogenicity
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