ucd ssra presentation
TRANSCRIPT
GENE & TONIC: EXPLORING THE MOLECULAR MECHANISMS
UNDERLYING FETAL ALCOHOL SYNDROMELeia Judge1, Deirdre Brennan1
1 UCD Anatomy, School of Medicine, University College Dublin, Belfield, Dublin 4.
Fetal Alcohol Spectrum Disorders
• Fetal Alcohol Effects
• Alcohol Related Neurodevelopmental Disorder (ARND)
• Alcohol Related Birth Defects (ARBD)
• Fetal Alcohol Syndrome (FAS)
40-70 : 1000
20 : 1000
8 : 1000
15 : 1000
15 : 1000
FAS is a Global Problem
In Europe estimated to occur in 1 : 1000 live births
(Abel EL. Curr Pharm Des. 2006;12:1521-9)
What is Fetal Alcohol Syndrome (FAS)?
1. Growth Retardation
2. Craniofacial Dysmorphology
3. Neurodevelopmental Delay
FAS Ocular Phenotype
Busby A et al. Arch Dis Child Fetal Neonatal Ed. 1998;79(3):F168-73. Gregory-Evans CY et al. J Med Genet. 2004;41:881-91 Strömland K, Pinazo-Durán MD. Alcohol Alcohol. 2002;37(1):2-8.
Microphthalmia Coloboma
Strabismus Optic nerve hypoplasia
Eye Development
Paired Box Gene 2 (Pax2)• Tissue Fusion, Neural Retina (NR) & Optic Nerve
Bone Morphogenic Protein 4 (Bmp4)• Retinal Pigmented Epithelium (RPE)
0% Ethanol
1% Ethanol
5% Ethanol
10% Ethanol
20% Ethanol
Hypothesis: Expression of Bmp4 & Pax2 are altered in the eye in FAS.
• Physiologically mimic chronic human fetal ethanol exposure in a novel chick embryo model.
• Produce phenotypes closely resembling human FAS.
• Examine resulting expression patterns using immunohistochemistry.
0.73% Saline
Treatment regimen(n=60)
My Study
E1 + 40 Hours (n=25)
Methodology – Chick Embryo Model
E1 + 5 Days (n=35)
Saline 1% 5% 10% 20%0%
10%20%30%40%50%60%70%80%90%
100%
Growth Retarded Vascular None
% o
f tre
atm
ent g
roup
Morphological Defects (E1 + 40 Hours)
Control
Control 1% 5% 10% 20%
Saline 1% 5% 10% 20%0%
10%20%30%40%50%60%70%80%90%
100%
Vascular Growth Retarded Eye Defect None
% o
f tre
atm
ent g
roup
Morphological Defects (E1 + 5 Days)
Control
Control
1% 5% 10% 20%
Immunohistochemistry – Bmp4
Saline Control
1% 5%
• Aberrant Bmp4 expression throughout ocular region.• Hyperplasia of RPE observed from 5-20%.• Complete tissue disruption in 20% groups.
BMP4
Immunohistochemistry – Pax2
Saline Control
• Pax2 expression decreased in a dose-dependent manner.• Punctate expression pattern at the transitional border
between RPE & NR.• Complete tissue disruption in 20% groups.
Sonic Hedgehog – Supporting Research
Antagonistic Relationship Stimulatory Relationship
Shh
Bmp4
Shh
Pax2
Novel Findings
• Molecular deficits of Bmp4 & Pax2 could play a pivotal role in the pathogenesis of FAS.
• Judge L., Giles S., Brennan D. (2016) Reprod Toxicol 64:45.
Conclusion
1. Novel chick embryo model of FAS developed.
2. Aberrant Bmp4 expression Retinal Disruption.
3. Decreased Pax2 expression Optic Nerve Hypoplasia, Colobomas.
GENE & TONIC: EXPLORING THE MOLECULAR MECHANISMS
UNDERLYING FETAL ALCOHOL SYNDROMELeia Judge1, Deirdre Brennan1
1 UCD Anatomy, School of Medicine, University College Dublin, Belfield, Dublin 4.