2 Maternal-Fetal Transfer of Vitamin A …
47
and will have important translational implications in the development of appropriate
dietary practices during pregnancy.
The Future
Research on the maternal-fetal metabolism of VA and its carotenoid precursor βcarotene is still in its infancy, with many gaps in knowledge yet to be filled. Important
remaining questions include
(1) At which stage of mammalian development does the transfer of retinoids and
carotenoids begin?
(2) Which form of VA is transferred?
(3) Does the transfer of specific forms depend on the developmental stage?
(4) Is there a lag time between the transfer/delivery of VA to the embryo and the
beginning of its activity/function?
In the avian model, it has been demonstrated that the VA requirement for development begins at neurulation, at the 4/5 somitic stage (Zile 2001). However, there is no
maternal-fetal transfer of vitamins, or of other nutrients, in such vertebrates. A seminal work by Ulven and colleagues (2000) began addressing the above-mentioned
questions by assessing the presence of the metabolic machinery to generate RA at
early stages of mouse development, and by directly measuring VA metabolites in
early embryos by HPLC analysis. These authors detected only retinaldehyde at 6.5
dpc (egg-cylinder stage; pre-primitive streak stage), together with the mRNA for all
the Rar and Rxr subtypes, two retinol-oxidizing enzymes and the retinoid-binding
proteins. Importantly, though, the mRNA encoding the enzyme that converts retinaldehyde into RA (Raldh2) was found to be expressed only from 7.5 dpc onwards
(mid-primitive streak stage and late allantoic bud stage), when not only retinaldehyde but also retinol and RA were detected. While these findings may help to frame
the beginning of the retinoid activity during mammalian development, they do not
address the question of transfer.
Takahashi et al. (1977) indicated that maternal-fetal retinol transfer began at about
11 dpc in rats, in the form of retinol bound to RBP. Nevertheless, a critical developmental window of retinoid necessity has been clearly identified between 7.5 and 9.5
dpc (Clagett-Dame and Knutson 2011), implying that perhaps transfer occurs much
earlier during mammalian embryonic development. Do these retinoids originate in
the maternal circulation or in the maternal (uterine) cells at the implantation site?
Hopefully, the long-overdue systematic expression analysis of the key components
of retinoid and carotenoid metabolism throughout gestation in maternal and fetal
tissues, done in a comparative fashion, will elucidate the answers to these questions.
In the same vein, we would expect improvements in analytical techniques such as
LC-MS and novel imaging approaches to assist investigators in reaching this goal.
How do retinoids cross the multi-layered maternal-fetal barrier? A number of
approaches could provide answers to this complex question. (1) Experiments with
47
and will have important translational implications in the development of appropriate
dietary practices during pregnancy.
The Future
Research on the maternal-fetal metabolism of VA and its carotenoid precursor βcarotene is still in its infancy, with many gaps in knowledge yet to be filled. Important
remaining questions include
(1) At which stage of mammalian development does the transfer of retinoids and
carotenoids begin?
(2) Which form of VA is transferred?
(3) Does the transfer of specific forms depend on the developmental stage?
(4) Is there a lag time between the transfer/delivery of VA to the embryo and the
beginning of its activity/function?
In the avian model, it has been demonstrated that the VA requirement for development begins at neurulation, at the 4/5 somitic stage (Zile 2001). However, there is no
maternal-fetal transfer of vitamins, or of other nutrients, in such vertebrates. A seminal work by Ulven and colleagues (2000) began addressing the above-mentioned
questions by assessing the presence of the metabolic machinery to generate RA at
early stages of mouse development, and by directly measuring VA metabolites in
early embryos by HPLC analysis. These authors detected only retinaldehyde at 6.5
dpc (egg-cylinder stage; pre-primitive streak stage), together with the mRNA for all
the Rar and Rxr subtypes, two retinol-oxidizing enzymes and the retinoid-binding
proteins. Importantly, though, the mRNA encoding the enzyme that converts retinaldehyde into RA (Raldh2) was found to be expressed only from 7.5 dpc onwards
(mid-primitive streak stage and late allantoic bud stage), when not only retinaldehyde but also retinol and RA were detected. While these findings may help to frame
the beginning of the retinoid activity during mammalian development, they do not
address the question of transfer.
Takahashi et al. (1977) indicated that maternal-fetal retinol transfer began at about
11 dpc in rats, in the form of retinol bound to RBP. Nevertheless, a critical developmental window of retinoid necessity has been clearly identified between 7.5 and 9.5
dpc (Clagett-Dame and Knutson 2011), implying that perhaps transfer occurs much
earlier during mammalian embryonic development. Do these retinoids originate in
the maternal circulation or in the maternal (uterine) cells at the implantation site?
Hopefully, the long-overdue systematic expression analysis of the key components
of retinoid and carotenoid metabolism throughout gestation in maternal and fetal
tissues, done in a comparative fashion, will elucidate the answers to these questions.
In the same vein, we would expect improvements in analytical techniques such as
LC-MS and novel imaging approaches to assist investigators in reaching this goal.
How do retinoids cross the multi-layered maternal-fetal barrier? A number of
approaches could provide answers to this complex question. (1) Experiments with