Chapter 8
Fetal Alcohol Spectrum Disorder:
Embryogenesis Under Reduced Retinoic
Acid Signaling Conditions
Abraham Fainsod, Liat Bendelac-Kapon, and Yehuda Shabtai
Abstract Fetal Alcohol Spectrum Disorder (FASD) is a complex set of developmental malformations, neurobehavioral anomalies and mental disabilities induced by
exposing human embryos to alcohol during fetal development. Several experimental
models and a series of developmental and biochemical approaches have established
a strong link between FASD and reduced retinoic acid (RA) signaling. RA signaling
is involved in the regulation of numerous developmental decisions from patterning
of the anterior–posterior axis, starting at gastrulation, to the differentiation of specific cell types within developing organs, to adult tissue homeostasis. Being such an
important regulatory signal during embryonic development, mutations or environmental perturbations that affect the level, timing or location of the RA signal can
induce multiple and severe developmental malformations. The evidence connecting
human syndromes to reduced RA signaling is presented here and the resulting phenotypes are compared to FASD. Available data suggest that competition between
ethanol clearance and RA biosynthesis is a major etiological component in FASD.
Keywords Retinoic acid · Signaling · Vitamin A deficiency · Ethanol · Retinol ·
Development · Embryogenesis · Malformations · Birth Defects · Teratology ·
Fetal alcohol spectrum disorder · FASD · Human · Xenopus · Fetal alcohol
syndrome · FAS · Acetaldehyde · Metabolism · Biosynthesis · Alcohol clearance
A. Fainsod (B) · L. Bendelac-Kapon · Y. Shabtai
Department of Developmental Biology and Cancer Research, Institute for Medical Research
Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, POB
12271, 9112102 Jerusalem, Israel
e-mail: abraham.fainsod@mail.huji.ac.il
L. Bendelac-Kapon
e-mail: liat.bendelac@mail.huji.ac.il
Y. Shabtai
e-mail: yehuda.shabtai@mail.huji.ac.il
© Springer Nature Switzerland AG 2020
M. A. Asson-Batres and C. Rochette-Egly (eds.), The Biochemistry of Retinoid
Signaling III, Subcellular Biochemistry 95,
https://doi.org/10.1007/978-3-030-42282-0_8
197
Fetal Alcohol Spectrum Disorder:
Embryogenesis Under Reduced Retinoic
Acid Signaling Conditions
Abraham Fainsod, Liat Bendelac-Kapon, and Yehuda Shabtai
Abstract Fetal Alcohol Spectrum Disorder (FASD) is a complex set of developmental malformations, neurobehavioral anomalies and mental disabilities induced by
exposing human embryos to alcohol during fetal development. Several experimental
models and a series of developmental and biochemical approaches have established
a strong link between FASD and reduced retinoic acid (RA) signaling. RA signaling
is involved in the regulation of numerous developmental decisions from patterning
of the anterior–posterior axis, starting at gastrulation, to the differentiation of specific cell types within developing organs, to adult tissue homeostasis. Being such an
important regulatory signal during embryonic development, mutations or environmental perturbations that affect the level, timing or location of the RA signal can
induce multiple and severe developmental malformations. The evidence connecting
human syndromes to reduced RA signaling is presented here and the resulting phenotypes are compared to FASD. Available data suggest that competition between
ethanol clearance and RA biosynthesis is a major etiological component in FASD.
Keywords Retinoic acid · Signaling · Vitamin A deficiency · Ethanol · Retinol ·
Development · Embryogenesis · Malformations · Birth Defects · Teratology ·
Fetal alcohol spectrum disorder · FASD · Human · Xenopus · Fetal alcohol
syndrome · FAS · Acetaldehyde · Metabolism · Biosynthesis · Alcohol clearance
A. Fainsod (B) · L. Bendelac-Kapon · Y. Shabtai
Department of Developmental Biology and Cancer Research, Institute for Medical Research
Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, POB
12271, 9112102 Jerusalem, Israel
e-mail: abraham.fainsod@mail.huji.ac.il
L. Bendelac-Kapon
e-mail: liat.bendelac@mail.huji.ac.il
Y. Shabtai
e-mail: yehuda.shabtai@mail.huji.ac.il
© Springer Nature Switzerland AG 2020
M. A. Asson-Batres and C. Rochette-Egly (eds.), The Biochemistry of Retinoid
Signaling III, Subcellular Biochemistry 95,
https://doi.org/10.1007/978-3-030-42282-0_8
197