180
W. R. Jackman and Y. Gibert
Removal of VA from the diet produced a disruption of the odontoblast cell layer
and a production of excess and disorganized dentin, while after a more prolonged time
on the diet, atrophic ameloblasts were also observed, as was an eventual cessation
of enamel formation (Wolbach and Howe 1925). Numerous studies of avitaminosis
A were carried out in subsequent years (Shibata 1931; Simola 1932; Wolbach and
Howe 1933; Burn et al. 1941; Mellanby 1941; Schour et al. 1941; Irving 1949), and
while some variability in outcomes was reported, there was also some consensus:
removing VA from the diet generally had the most rapid and profound negative
effect on the odontoblasts and dentin of rat incisors, but ameloblasts and enamel
were also adversely affected (Fig. 7.2). The extra sensitivity of odontoblasts and
dentin to VA deficiency is perhaps the most important information gleaned from
these early studies and will be interesting to later reconsider in the context of more
recent, targeted studies of RA control of tooth formation.
VA Excess and Tooth Development (rat Incisors)
After an initial 25 years of examining tooth effects of avitaminosis A, researchers
began to investigate the opposite side of the equation: what effects on tooth development might occur with excess VA in the diet, sometimes designated hypervitaminosis
A. Excess dietary VA had been known for some time to have toxic effects on rats, especially on bone homeostasis (Moore and Wang 1945), but nothing had been reported
regarding tooth formation, and general teratogenic effects from excess VA were not
reported until 1953 (Cohlan 1953). Examining excess VA in the diet was an important
transition in the field, as gain-of-function experiments with RA had the potential to
help elucidate what RA was capable of initiating during tooth formation and could
logically complement the avitaminosis/loss-of-function experiments that had been
done previously. The initial experiments focused on the continuously developing rat
incisor, and the first phenotypes observed from hypervitaminosis A were consistent
with what was seen when VA was removed from the diet in that odontoblasts seemed
to be more sensitive than ameloblasts (Irving 1949). The resulting dentin did not form
as readily and ended up as a thinner mineralized layer rather than being overgrown
and disorganized as in avitaminosis A (Irving 1949; Gorlin and Chaudhry 1959).
Not long after the discovery of teratogenic effects from excess VA (Cohlan 1953),
focus shifted from studies of continuously developing adult rat incisors to in utero and
embryonic in vitro studies of not only incisor, but molar tooth formation. Molar tooth
formation represents a more ancestral and natural state for a tooth, with development
of the dentin and enamel only taking place relatively early in development, and then
remaining unchanged throughout life, except in the case of tooth replacement.
A striking set of tooth phenotypes was observed when excess VA was given
to pregnant rats, including fused upper incisors, occasional supernumerary upper
incisors, and a wide range of molar defects, including missing, ectopic, and misshapen
teeth (Kalter 1960). The fusion of the upper incisors was examined in great detail and
was found to result from changes that took place in the ameloblast and odontoblast cell
W. R. Jackman and Y. Gibert
Removal of VA from the diet produced a disruption of the odontoblast cell layer
and a production of excess and disorganized dentin, while after a more prolonged time
on the diet, atrophic ameloblasts were also observed, as was an eventual cessation
of enamel formation (Wolbach and Howe 1925). Numerous studies of avitaminosis
A were carried out in subsequent years (Shibata 1931; Simola 1932; Wolbach and
Howe 1933; Burn et al. 1941; Mellanby 1941; Schour et al. 1941; Irving 1949), and
while some variability in outcomes was reported, there was also some consensus:
removing VA from the diet generally had the most rapid and profound negative
effect on the odontoblasts and dentin of rat incisors, but ameloblasts and enamel
were also adversely affected (Fig. 7.2). The extra sensitivity of odontoblasts and
dentin to VA deficiency is perhaps the most important information gleaned from
these early studies and will be interesting to later reconsider in the context of more
recent, targeted studies of RA control of tooth formation.
VA Excess and Tooth Development (rat Incisors)
After an initial 25 years of examining tooth effects of avitaminosis A, researchers
began to investigate the opposite side of the equation: what effects on tooth development might occur with excess VA in the diet, sometimes designated hypervitaminosis
A. Excess dietary VA had been known for some time to have toxic effects on rats, especially on bone homeostasis (Moore and Wang 1945), but nothing had been reported
regarding tooth formation, and general teratogenic effects from excess VA were not
reported until 1953 (Cohlan 1953). Examining excess VA in the diet was an important
transition in the field, as gain-of-function experiments with RA had the potential to
help elucidate what RA was capable of initiating during tooth formation and could
logically complement the avitaminosis/loss-of-function experiments that had been
done previously. The initial experiments focused on the continuously developing rat
incisor, and the first phenotypes observed from hypervitaminosis A were consistent
with what was seen when VA was removed from the diet in that odontoblasts seemed
to be more sensitive than ameloblasts (Irving 1949). The resulting dentin did not form
as readily and ended up as a thinner mineralized layer rather than being overgrown
and disorganized as in avitaminosis A (Irving 1949; Gorlin and Chaudhry 1959).
Not long after the discovery of teratogenic effects from excess VA (Cohlan 1953),
focus shifted from studies of continuously developing adult rat incisors to in utero and
embryonic in vitro studies of not only incisor, but molar tooth formation. Molar tooth
formation represents a more ancestral and natural state for a tooth, with development
of the dentin and enamel only taking place relatively early in development, and then
remaining unchanged throughout life, except in the case of tooth replacement.
A striking set of tooth phenotypes was observed when excess VA was given
to pregnant rats, including fused upper incisors, occasional supernumerary upper
incisors, and a wide range of molar defects, including missing, ectopic, and misshapen
teeth (Kalter 1960). The fusion of the upper incisors was examined in great detail and
was found to result from changes that took place in the ameloblast and odontoblast cell