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A. Fainsod et al.
the presence of acetaldehyde. The results demonstrated that acetaldehyde functions
as a concentration-dependent inhibitor of retinaldehyde oxidation.
Reduced RA Levels Induce Developmental Malformations
and Neurobehavioral Anomalies that Phenocopy FASD
What is the evidence supporting the suggestion that reduced RA levels in humans
give rise to FASD? Several human syndromes are directly connected to reduced RA
and exhibit multiple developmental malformations resembling FASD. These syndromes include vitamin A Deficiency Syndrome (VAD), Matthew-Wood Syndrome,
Smith-Magenis Syndrome, DiGeorge/VeloCardioFacial Syndrome, CHARGE Syndrome, PAGOD Syndrome, and Zika virus associated microcephaly (Golzio et al.
2007; Chassaing et al. 2009; Girirajan et al. 2009; Clagett-Dame and Knutson 2011;
Elsea and Williams 2011; Wiseman et al. 2017; Brainstorm Consortium et al. 2018;
Macayran et al. 2002; Vermot et al. 2003; Roberts et al. 2006; Gavrilova et al. 2009;
Micucci et al. 2014; Kumar et al. 2016; Jun et al. 2017; Yao et al. 2018). All of these
syndromes have been directly linked to reduced RA signaling and the neurodevelopmental anomalies and developmental malformations they exhibit partially resemble
each other and the malformations and anomalies in FASD.
The human condition, VAD, exemplifies the outcome of human embryogenesis
with reduced RA signaling (Sarma 1959; Underwood 1994; Lanska 2010; ClagettDame and Knutson 2011; Wiseman et al. 2017). Maternal diet, in particular the
balance and content of retinoids and carotenoids, can severely affect the outcome
of pregnancy. Severe VAD can hamper reproduction, while milder forms of VAD
result in numerous developmental malformations (Underwood 1994). Blindness,
anophthalmia, cleft palate, cleft lip, genitourinary tract, kidney (including arrested
ascension of the kidneys), aortic arch and heart defects, and agenesis of a rudimentary
pulmonary system are among the commonly observed abnormalities. VAD can also
induce behavioral anomalies and mental disability (Hou et al. 2015; Wiseman et al.
2017). Many of these developmental malformations and neurodevelopmental phenotypes have been reproduced in multiple experimental models including rats, pigs,
mouse, quail and others (Hale 1935; Warkany and Schrafenberger 1946; Wilson and
Warkany 1948, 1949; Wilson et al. 1953; Grummer and Zachman 1990; Morriss-Kay
and Sokolova 1996; White et al. 1998; Cui et al. 2003; Schuster et al. 2008; See et al.
2008). These VAD-induced developmental and behavioral anomalies resemble the
phenotypes attributed to fetal alcohol exposure along the FASD spectrum.
Besides VAD and the experimental induction of VAD, manipulation of either the
catabolism or synthesis of RA in vivo has been used to experimentally reduce RA
levels. CYP26A1, B1 and C1 deplete RA stores by targeting RA for subsequent
degradation (White et al. 1997; Marikar et al. 1998; Sonneveld et al. 1998; McSorley
and Daly 2000; Chithalen et al. 2002; Niederreither et al. 2002; Dobbs-McAuliffe
et al. 2004). Overexpression of Cyp26A1 in vertebrate embryos has been shown to
A. Fainsod et al.
the presence of acetaldehyde. The results demonstrated that acetaldehyde functions
as a concentration-dependent inhibitor of retinaldehyde oxidation.
Reduced RA Levels Induce Developmental Malformations
and Neurobehavioral Anomalies that Phenocopy FASD
What is the evidence supporting the suggestion that reduced RA levels in humans
give rise to FASD? Several human syndromes are directly connected to reduced RA
and exhibit multiple developmental malformations resembling FASD. These syndromes include vitamin A Deficiency Syndrome (VAD), Matthew-Wood Syndrome,
Smith-Magenis Syndrome, DiGeorge/VeloCardioFacial Syndrome, CHARGE Syndrome, PAGOD Syndrome, and Zika virus associated microcephaly (Golzio et al.
2007; Chassaing et al. 2009; Girirajan et al. 2009; Clagett-Dame and Knutson 2011;
Elsea and Williams 2011; Wiseman et al. 2017; Brainstorm Consortium et al. 2018;
Macayran et al. 2002; Vermot et al. 2003; Roberts et al. 2006; Gavrilova et al. 2009;
Micucci et al. 2014; Kumar et al. 2016; Jun et al. 2017; Yao et al. 2018). All of these
syndromes have been directly linked to reduced RA signaling and the neurodevelopmental anomalies and developmental malformations they exhibit partially resemble
each other and the malformations and anomalies in FASD.
The human condition, VAD, exemplifies the outcome of human embryogenesis
with reduced RA signaling (Sarma 1959; Underwood 1994; Lanska 2010; ClagettDame and Knutson 2011; Wiseman et al. 2017). Maternal diet, in particular the
balance and content of retinoids and carotenoids, can severely affect the outcome
of pregnancy. Severe VAD can hamper reproduction, while milder forms of VAD
result in numerous developmental malformations (Underwood 1994). Blindness,
anophthalmia, cleft palate, cleft lip, genitourinary tract, kidney (including arrested
ascension of the kidneys), aortic arch and heart defects, and agenesis of a rudimentary
pulmonary system are among the commonly observed abnormalities. VAD can also
induce behavioral anomalies and mental disability (Hou et al. 2015; Wiseman et al.
2017). Many of these developmental malformations and neurodevelopmental phenotypes have been reproduced in multiple experimental models including rats, pigs,
mouse, quail and others (Hale 1935; Warkany and Schrafenberger 1946; Wilson and
Warkany 1948, 1949; Wilson et al. 1953; Grummer and Zachman 1990; Morriss-Kay
and Sokolova 1996; White et al. 1998; Cui et al. 2003; Schuster et al. 2008; See et al.
2008). These VAD-induced developmental and behavioral anomalies resemble the
phenotypes attributed to fetal alcohol exposure along the FASD spectrum.
Besides VAD and the experimental induction of VAD, manipulation of either the
catabolism or synthesis of RA in vivo has been used to experimentally reduce RA
levels. CYP26A1, B1 and C1 deplete RA stores by targeting RA for subsequent
degradation (White et al. 1997; Marikar et al. 1998; Sonneveld et al. 1998; McSorley
and Daly 2000; Chithalen et al. 2002; Niederreither et al. 2002; Dobbs-McAuliffe
et al. 2004). Overexpression of Cyp26A1 in vertebrate embryos has been shown to