32
L. Quadro and E. K. Spiegler
an interesting connection between maternal VA deficiency and fetal death, observing that the placentas of VA-deficient rats exhibited signs of injury (e.g., changes
to the epithelial lining) that could have jeopardized the nutrient supply to the fetus.
Interestingly, in later studies, VA excess was also found to damage the placenta;
for instance, morphological changes such as an increased decidual cell membrane
surface area were observed in the placentas of rats treated with excess VA palmitate
(Morriss 1973), and the administration of excess VA (retinol or retinyl palmitate) to
rats at 9 dpc was shown to cause placental agenesis and a dose-dependent increase
in embryonic resorption (Love and Vickers 1976).
Maternal Dietary VA Intake and Fetal Retinoid Concentrations
Due to the novelty of the field and the limitations of the existing experimental tools,
the maternal-fetal transfer of VA was initially described on a macroscopic level, with
an emphasis on the factors affecting fetal VA levels. Dann (Dann 1934a) determined
that the hepatic VA stores of newborn rats increased only slightly following highly
excessive maternal VA intake (estimated by the authors to be 5000 times greater than
the minimum requirement) for four weeks before and during pregnancy. Baumann
and colleagues (1934) also demonstrated that the VA stores in the newborn rat liver
increased only marginally when the maternal diet was supplemented with halibut
liver oil during the last five days of gestation. Henry et al. (1949) reported that the
hepatic VA stores of newborn rats varied only slightly (from ~5 to 10 IU in their
livers) in comparison to the variation in maternal stores (from ~30 to 20000 IU) following increased dietary VA intake. These authors also demonstrated that preformed
VA (retinol and/or retinyl esters) was used much more efficiently than β-carotene
(dietary VA precursor) by VA-depleted rats, as evidenced by the three-fold greater
maternal liver VA stores and ~28% greater newborn liver stores in VA-deficient rats
given preformed VA than in those given an identical dose of β-carotene. Later, Moore
(Moore 1971) found that the transfer of retinol to fetal mice and rats was only slightly
lower when the maternal retinol intake was “restricted” than when it was “liberal”
(i.e., VA-deficient diet vs. 2.4 μg of retinol/g of diet). Thus, Moore concluded that
physiological mechanisms stimulate the fetal transfer of retinol when the maternal
intake is low and may limit the transfer when the maternal intake is high, at least up to
a certain limit beyond which toxicity occurs. At this time, the authors hypothesized a
role for retinol-binding protein (RBP or RBP4), the sole specific carrier for retinol in
the circulation (Wendler et al. 2003; Quadro et al. 1999), not only in mobilizing VA
from the hepatic stores, but also in transferring VA from the maternal bloodstream
to the developing fetus. Interestingly, after feeding VA-depleted rats different diets
during pregnancy, Wallingford and Underwood observed that the placental and fetal
VA concentrations of rats fed 10 retinol equivalents/day differed significantly from
those of rats deprived of VA during pregnancy, while the VA concentrations of various maternal tissues (eye, kidney, adrenal gland, ovary and intestine) did not differ
according to the gestational diet. The authors concluded that embryos and placentas
L. Quadro and E. K. Spiegler
an interesting connection between maternal VA deficiency and fetal death, observing that the placentas of VA-deficient rats exhibited signs of injury (e.g., changes
to the epithelial lining) that could have jeopardized the nutrient supply to the fetus.
Interestingly, in later studies, VA excess was also found to damage the placenta;
for instance, morphological changes such as an increased decidual cell membrane
surface area were observed in the placentas of rats treated with excess VA palmitate
(Morriss 1973), and the administration of excess VA (retinol or retinyl palmitate) to
rats at 9 dpc was shown to cause placental agenesis and a dose-dependent increase
in embryonic resorption (Love and Vickers 1976).
Maternal Dietary VA Intake and Fetal Retinoid Concentrations
Due to the novelty of the field and the limitations of the existing experimental tools,
the maternal-fetal transfer of VA was initially described on a macroscopic level, with
an emphasis on the factors affecting fetal VA levels. Dann (Dann 1934a) determined
that the hepatic VA stores of newborn rats increased only slightly following highly
excessive maternal VA intake (estimated by the authors to be 5000 times greater than
the minimum requirement) for four weeks before and during pregnancy. Baumann
and colleagues (1934) also demonstrated that the VA stores in the newborn rat liver
increased only marginally when the maternal diet was supplemented with halibut
liver oil during the last five days of gestation. Henry et al. (1949) reported that the
hepatic VA stores of newborn rats varied only slightly (from ~5 to 10 IU in their
livers) in comparison to the variation in maternal stores (from ~30 to 20000 IU) following increased dietary VA intake. These authors also demonstrated that preformed
VA (retinol and/or retinyl esters) was used much more efficiently than β-carotene
(dietary VA precursor) by VA-depleted rats, as evidenced by the three-fold greater
maternal liver VA stores and ~28% greater newborn liver stores in VA-deficient rats
given preformed VA than in those given an identical dose of β-carotene. Later, Moore
(Moore 1971) found that the transfer of retinol to fetal mice and rats was only slightly
lower when the maternal retinol intake was “restricted” than when it was “liberal”
(i.e., VA-deficient diet vs. 2.4 μg of retinol/g of diet). Thus, Moore concluded that
physiological mechanisms stimulate the fetal transfer of retinol when the maternal
intake is low and may limit the transfer when the maternal intake is high, at least up to
a certain limit beyond which toxicity occurs. At this time, the authors hypothesized a
role for retinol-binding protein (RBP or RBP4), the sole specific carrier for retinol in
the circulation (Wendler et al. 2003; Quadro et al. 1999), not only in mobilizing VA
from the hepatic stores, but also in transferring VA from the maternal bloodstream
to the developing fetus. Interestingly, after feeding VA-depleted rats different diets
during pregnancy, Wallingford and Underwood observed that the placental and fetal
VA concentrations of rats fed 10 retinol equivalents/day differed significantly from
those of rats deprived of VA during pregnancy, while the VA concentrations of various maternal tissues (eye, kidney, adrenal gland, ovary and intestine) did not differ
according to the gestational diet. The authors concluded that embryos and placentas