8 Fetal Alcohol Spectrum Disorder: Embryogenesis Under …
213
Relevance
FASD is probably the most common neurodevelopmental birth defect and mental
disability in humans (Joya et al. 2015). It is estimated that about 2.9 per 1,000 children globally exhibit the severe form of alcohol exposure, FAS, while about 22.8
per 1,000 children exhibit FASD (Roozen et al. 2016; Denny et al. 2017; Lange
et al. 2017). Although fully preventable in theory, human nature and habits make
alcohol the most common teratogen. The Centers for Disease Control and Prevention reports that alcohol drinking during pregnancy has risen from 7.6% pregnant
drinkers in 2012 to 10.2% in 2015 (Tan et al. 2015; Denny et al. 2017). In the same
period, binge drinking during pregnancy more than doubled from 1.4 to 3.1%. The
anatomical malformations, neurological deficits and behavioral anomalies induced
by alcohol exposure during pregnancy severely affect the quality of life of the affected
individuals (Gupta et al. 2016; Denny et al. 2017). Therefore, FASD is a severe condition affecting the patient, the family and society, placing heavy burdens on medical,
social, financial and even judicial systems. For this reason, understanding the etiology of this syndrome is important to ameliorate the severity or reduce the prevalence
of FASD and perhaps provide diagnostic tools.
From a scientific perspective, the link between FASD and reduced RA signaling
provides an additional tool to study the function and regulation of RA signaling during
embryogenesis. Extensive efforts have been put forth to better characterize alcohol
treated experimental animal models and determine their overlap with the human
condition (Lipinski et al. 2012; Fainsod and Kot-Leibovich 2018; Fernandes et al.
2018; Flentke and Smith 2018; Parnell et al. 2018; Petrelli et al. 2018). An extensive
body of research has shown that RA gain-of-function induces an expansion of the
hindbrain at the expense of loss of anterior head structures (Durston et al. 1989; Sive
et al. 1989; Koide et al. 2001; Weston et al. 2003; Halilagic et al. 2007; Crandall et al.
2011; Parker and Krumlauf 2017). This head-reducing effect of RA has been linked
to the ectopic activation of homeobox genes, including the Hox genes (Conlon and
Rossant 1992; Alexandre et al. 1996; Whiting 1997). On the other hand, FAS and the
syndromes resembling it, exhibit microcephaly and they are suspected to arise from
reduced RA (Popova et al. 2016; Petrelli et al. 2019). The connection between reduced
RA and microcephaly suggests this signal is required for normal head induction or
formation. This apparent contradiction will require in-depth analysis to understand
the contribution of RA signaling to head formation in vertebrate embryos.
The Future
The efficiency with which both mother and fetus overcome the alcohol exposure is to
a large extent dependent upon their genetic constitutions. This was initially demonstrated in studies of twin pregnancies. The focus on twin pregnancy centered on an
effort to equalize the amount and stage of alcohol exposure, maternal weight, age,
213
Relevance
FASD is probably the most common neurodevelopmental birth defect and mental
disability in humans (Joya et al. 2015). It is estimated that about 2.9 per 1,000 children globally exhibit the severe form of alcohol exposure, FAS, while about 22.8
per 1,000 children exhibit FASD (Roozen et al. 2016; Denny et al. 2017; Lange
et al. 2017). Although fully preventable in theory, human nature and habits make
alcohol the most common teratogen. The Centers for Disease Control and Prevention reports that alcohol drinking during pregnancy has risen from 7.6% pregnant
drinkers in 2012 to 10.2% in 2015 (Tan et al. 2015; Denny et al. 2017). In the same
period, binge drinking during pregnancy more than doubled from 1.4 to 3.1%. The
anatomical malformations, neurological deficits and behavioral anomalies induced
by alcohol exposure during pregnancy severely affect the quality of life of the affected
individuals (Gupta et al. 2016; Denny et al. 2017). Therefore, FASD is a severe condition affecting the patient, the family and society, placing heavy burdens on medical,
social, financial and even judicial systems. For this reason, understanding the etiology of this syndrome is important to ameliorate the severity or reduce the prevalence
of FASD and perhaps provide diagnostic tools.
From a scientific perspective, the link between FASD and reduced RA signaling
provides an additional tool to study the function and regulation of RA signaling during
embryogenesis. Extensive efforts have been put forth to better characterize alcohol
treated experimental animal models and determine their overlap with the human
condition (Lipinski et al. 2012; Fainsod and Kot-Leibovich 2018; Fernandes et al.
2018; Flentke and Smith 2018; Parnell et al. 2018; Petrelli et al. 2018). An extensive
body of research has shown that RA gain-of-function induces an expansion of the
hindbrain at the expense of loss of anterior head structures (Durston et al. 1989; Sive
et al. 1989; Koide et al. 2001; Weston et al. 2003; Halilagic et al. 2007; Crandall et al.
2011; Parker and Krumlauf 2017). This head-reducing effect of RA has been linked
to the ectopic activation of homeobox genes, including the Hox genes (Conlon and
Rossant 1992; Alexandre et al. 1996; Whiting 1997). On the other hand, FAS and the
syndromes resembling it, exhibit microcephaly and they are suspected to arise from
reduced RA (Popova et al. 2016; Petrelli et al. 2019). The connection between reduced
RA and microcephaly suggests this signal is required for normal head induction or
formation. This apparent contradiction will require in-depth analysis to understand
the contribution of RA signaling to head formation in vertebrate embryos.
The Future
The efficiency with which both mother and fetus overcome the alcohol exposure is to
a large extent dependent upon their genetic constitutions. This was initially demonstrated in studies of twin pregnancies. The focus on twin pregnancy centered on an
effort to equalize the amount and stage of alcohol exposure, maternal weight, age,