2 Maternal-Fetal Transfer of Vitamin A …
35
(Kochhar 1976) observed that placental levels peaked 6 h post-injection in the teratogenic group, versus 2 h in the non-teratogenic group. Yolk sac and embryonic levels
were found to peak later than placental levels, but again peaked later in the teratogenic group (12 h) than in the non-teratogenic group (6 h). These studies revealed
the transfer kinetics of various retinoids from mother to fetus, although they did not
yet provide insights into potential molecular mechanisms.
In the late 1960s, RBP was purified and characterized (Kanai et al. 1968). RBP
efficiently mobilizes retinol from the hepatic retinoid stores and distributes it to
the peripheral tissues to maintain their retinoid-dependent functions (Blaner et al.
2016). In the bloodstream, the retinol-RBP complex circulates in association with
a homo-tetramer of transthyretin (TTR), which reduces glomerular filtration of the
relatively small RBP (21 kDa). The serum concentration of retinol-RBP in the blood
is maintained within narrow limits, except during severe VA deficiency and in some
disease states (Blaner et al. 2016). The discovery and characterization of the retinolRBP complex allowed a new set of questions to be asked about the maternal-fetal
transfer of retinol.
Does the transfer involve RBP? Takahashi et al. (1977) suggested that maternal
RBP crossed the placenta, based on the observation that placental and fetal retinol and
RBP levels increased over time after retinol-deficient dams were injected with retinol.
An in vitro study with
125 I-RBP suggested that human placentas could both take
up and release maternal RBP, although the authors acknowledged that the placental
accumulation of
125 I-RBP was much less than the accumulation of
3 H-retinol (Torma
and Vahlquist 1986). On the other hand, Sklan and colleagues (1985) proposed that
RBP in human amniotic fluid and even in the fetal circulation could originate from
the placenta, based on the co-elution of placental cytosolic RBP fractions with those
from amniotic fluid. Likewise, studies in cows seemed to indicate that the placenta
could secrete RBP into the allantoic fluid (Liu et al. 1990).
As for the involvement of TTR, Sklan and colleagues (1985) reported that serum
retinol was exclusively complexed with RBP: TTR in non-pregnant women, while in
pregnant women and their newborns (umbilical arteries), a proportion of the retinol:
RBP was not complexed with TTR. The authors speculated that retinol: RBP could be
transported across the placenta after the dissociation of TTR, or that free retinol could
be transported, and subsequently complexed with fetal RBP and/or TTR. Accordingly, using human brush-border placental membrane vesicles, Sivaprasadarao and
Findlay (Sivaprasadarao and Findlay 1988) suggested that retinol: RBP is not endocytosed, but that RBP delivers retinol to the placental membrane, since TTR reduced
the rate of
3 H-retinol uptake from RBP. These authors, too, proposed that “fetal” RBP
may originate in the placenta, rather than in maternal serum. Sklan and colleagues
(1985) also suggested that retinol could be transferred from the fetus to the mother
in humans, due to the absence of TTR from a portion of both the fetal (umbilical
arterial) and maternal serum retinol: RBP complexes.
Rodent studies on RBP differed somewhat from human studies in that the yolk
sac was also considered as a transfer organ. Based on maternal, embryonic and
extraembryonic RBP and TTR levels in rats throughout gestation and the incorporation of labeled amino acids into these proteins, Sklan and Ross (Sklan and Ross
35
(Kochhar 1976) observed that placental levels peaked 6 h post-injection in the teratogenic group, versus 2 h in the non-teratogenic group. Yolk sac and embryonic levels
were found to peak later than placental levels, but again peaked later in the teratogenic group (12 h) than in the non-teratogenic group (6 h). These studies revealed
the transfer kinetics of various retinoids from mother to fetus, although they did not
yet provide insights into potential molecular mechanisms.
In the late 1960s, RBP was purified and characterized (Kanai et al. 1968). RBP
efficiently mobilizes retinol from the hepatic retinoid stores and distributes it to
the peripheral tissues to maintain their retinoid-dependent functions (Blaner et al.
2016). In the bloodstream, the retinol-RBP complex circulates in association with
a homo-tetramer of transthyretin (TTR), which reduces glomerular filtration of the
relatively small RBP (21 kDa). The serum concentration of retinol-RBP in the blood
is maintained within narrow limits, except during severe VA deficiency and in some
disease states (Blaner et al. 2016). The discovery and characterization of the retinolRBP complex allowed a new set of questions to be asked about the maternal-fetal
transfer of retinol.
Does the transfer involve RBP? Takahashi et al. (1977) suggested that maternal
RBP crossed the placenta, based on the observation that placental and fetal retinol and
RBP levels increased over time after retinol-deficient dams were injected with retinol.
An in vitro study with
125 I-RBP suggested that human placentas could both take
up and release maternal RBP, although the authors acknowledged that the placental
accumulation of
125 I-RBP was much less than the accumulation of
3 H-retinol (Torma
and Vahlquist 1986). On the other hand, Sklan and colleagues (1985) proposed that
RBP in human amniotic fluid and even in the fetal circulation could originate from
the placenta, based on the co-elution of placental cytosolic RBP fractions with those
from amniotic fluid. Likewise, studies in cows seemed to indicate that the placenta
could secrete RBP into the allantoic fluid (Liu et al. 1990).
As for the involvement of TTR, Sklan and colleagues (1985) reported that serum
retinol was exclusively complexed with RBP: TTR in non-pregnant women, while in
pregnant women and their newborns (umbilical arteries), a proportion of the retinol:
RBP was not complexed with TTR. The authors speculated that retinol: RBP could be
transported across the placenta after the dissociation of TTR, or that free retinol could
be transported, and subsequently complexed with fetal RBP and/or TTR. Accordingly, using human brush-border placental membrane vesicles, Sivaprasadarao and
Findlay (Sivaprasadarao and Findlay 1988) suggested that retinol: RBP is not endocytosed, but that RBP delivers retinol to the placental membrane, since TTR reduced
the rate of
3 H-retinol uptake from RBP. These authors, too, proposed that “fetal” RBP
may originate in the placenta, rather than in maternal serum. Sklan and colleagues
(1985) also suggested that retinol could be transferred from the fetus to the mother
in humans, due to the absence of TTR from a portion of both the fetal (umbilical
arterial) and maternal serum retinol: RBP complexes.
Rodent studies on RBP differed somewhat from human studies in that the yolk
sac was also considered as a transfer organ. Based on maternal, embryonic and
extraembryonic RBP and TTR levels in rats throughout gestation and the incorporation of labeled amino acids into these proteins, Sklan and Ross (Sklan and Ross