6 Retinoic Acid Signaling and Development of the Respiratory System
159
History
Mammalian Respiratory System Malformations Induced
by Maternal Vitamin a Deficiency (VAD)
The importance of VA, or “fat-soluble A,” in regulating growth through cell proliferation and differentiation was recognized early in the twentieth century (McCollum
and Davis1913; Wolbach 1925). Most of the earlier studies on VAD and mammalian
lung development were performed in rats using a dietary VA deprivation method.
In the 1940 and 1950s, Anderson was the first to describe the effect of VAD on
the developing respiratory system (Anderson 1941, 1949). She conducted studies
on a strain of rats in which CDH occurred as a hereditary defect in 2.7% of the
animals. The frequency of CDH increased to 19% if the rats were fed a VAD diet.
The incidence of CDH varied, depending on the amount, duration, and timing of
supplemental VA given during pregnancy.
At the same time, Warkany and colleagues published their landmark studies
describing the syndrome of defects in rat embryos from VAD mothers (Warkany
et al. 1948; Warkany and Schraffenberger 1946; Wilson and Barch 1949; Wilson
et al. 1953; Wilson and Warkany 1948). In these studies, the dams were maintained
on VAD diets before and during pregnancy, which ensured that the embryos were
also VAD, since the only source of VA for embryonic tissues is maternal retinol, the
circulating form of VA. Of the VAD offspring, 4% had lung agenesis or hypoplasia
and 31% had CDH. When the VAD dams were given a single dose of 16,000 I.U.
of VA on E10 (at the onset of lung morphogenesis) the incidence of lung malformation and CDH in offspring was reduced to zero. Supplementation with VA at E12
or later failed to rescue lung and diaphragm malformations (Wilson et al. 1953).
These results indicated VA was required for normal rat lung development during a
relatively narrow window of time (E10-E12). The same results have been described
in VAD embryos of other animals, including pigs, sheep, cattle, rabbits, and mice
(Kalter and Warkany 1959).
While the dietary VAD model revealed a need for VA at distinct stages of development, the approach was limited. This is because a complete state of embryonic VAD
was not compatible with pregnancy. Furthermore, VAD mammalian embryos often
suffer major heart defects that cause embryonic lethality prior to the completion of
lung development, which defeats its use in studying effects of VAD on later stages
of lung development.
Effects of Retinoids on Avian Respiratory System Development
The avian embryo can be made VAD by giving the hen a VAD diet which results in
egg yolks that are deficient in VA. Similar to mammalian embryos, avian embryos
developing without a source of VA die of cardiovascular defects (at E3.0) prior to
159
History
Mammalian Respiratory System Malformations Induced
by Maternal Vitamin a Deficiency (VAD)
The importance of VA, or “fat-soluble A,” in regulating growth through cell proliferation and differentiation was recognized early in the twentieth century (McCollum
and Davis1913; Wolbach 1925). Most of the earlier studies on VAD and mammalian
lung development were performed in rats using a dietary VA deprivation method.
In the 1940 and 1950s, Anderson was the first to describe the effect of VAD on
the developing respiratory system (Anderson 1941, 1949). She conducted studies
on a strain of rats in which CDH occurred as a hereditary defect in 2.7% of the
animals. The frequency of CDH increased to 19% if the rats were fed a VAD diet.
The incidence of CDH varied, depending on the amount, duration, and timing of
supplemental VA given during pregnancy.
At the same time, Warkany and colleagues published their landmark studies
describing the syndrome of defects in rat embryos from VAD mothers (Warkany
et al. 1948; Warkany and Schraffenberger 1946; Wilson and Barch 1949; Wilson
et al. 1953; Wilson and Warkany 1948). In these studies, the dams were maintained
on VAD diets before and during pregnancy, which ensured that the embryos were
also VAD, since the only source of VA for embryonic tissues is maternal retinol, the
circulating form of VA. Of the VAD offspring, 4% had lung agenesis or hypoplasia
and 31% had CDH. When the VAD dams were given a single dose of 16,000 I.U.
of VA on E10 (at the onset of lung morphogenesis) the incidence of lung malformation and CDH in offspring was reduced to zero. Supplementation with VA at E12
or later failed to rescue lung and diaphragm malformations (Wilson et al. 1953).
These results indicated VA was required for normal rat lung development during a
relatively narrow window of time (E10-E12). The same results have been described
in VAD embryos of other animals, including pigs, sheep, cattle, rabbits, and mice
(Kalter and Warkany 1959).
While the dietary VAD model revealed a need for VA at distinct stages of development, the approach was limited. This is because a complete state of embryonic VAD
was not compatible with pregnancy. Furthermore, VAD mammalian embryos often
suffer major heart defects that cause embryonic lethality prior to the completion of
lung development, which defeats its use in studying effects of VAD on later stages
of lung development.
Effects of Retinoids on Avian Respiratory System Development
The avian embryo can be made VAD by giving the hen a VAD diet which results in
egg yolks that are deficient in VA. Similar to mammalian embryos, avian embryos
developing without a source of VA die of cardiovascular defects (at E3.0) prior to