Maternal-Fetal Transfer of Vitamin A and Its Impact on Mammalian Embryonic Development.

The placenta, a hallmark of mammalian embryogenesis, allows nutrients to be exchanged between the mother and the fetus. Vitamin A (VA), an essential nutrient, cannot be synthesized by the embryo, and must be acquired from the maternal circulation through the placenta. Our understanding of how this transfer is accomplished is still in its infancy. In this chapter, we recapitulate the early studies about the relationship between maternal dietary/supplemental VA intake and fetal VA levels. We then describe how the discovery of retinol-binding protein (RBP or RBP4), the development of labeling and detection techniques, and the advent of knockout mice shifted this field from a macroscopic to a molecular level. The most recent data indicate that VA and its derivatives (retinoids) and the pro-VA carotenoid, ß-carotene, are transferred across the placenta by distinct proteins, some of which overlap with proteins involved in lipoprotein uptake. The VA status and dietary intake of the mother influence the expression of these proteins, creating feedback signals that control the uptake of retinoids and that may also regulate the uptake of lipids, raising the intriguing possibility of crosstalk between micronutrient and macronutrient metabolism. Many questions remain about the temporal and spatial patterns by which these proteins are expressed and transferred throughout gestation. The answers to these questions are highly relevant to human health, considering that those with either limited or excessive intake of retinoids/carotenoids during pregnancy may be at risk of obtaining improper amounts of VA that ultimately impact the development and health of their offspring.

ß-apo-10'-carotenoids support normal embryonic development during vitamin A deficiency.

Vitamin A deficiency is still a public health concern affecting millions of pregnant women and children. Retinoic acid, the active form of vitamin A, is critical for proper mammalian embryonic development. Embryos can generate retinoic acid from maternal circulating ß-carotene upon oxidation of retinaldehyde produced via the symmetric cleavage enzyme ß-carotene 15,15'-oxygenase (BCO1). Another cleavage enzyme, ß-carotene 9',10'-oxygenase (BCO2), asymmetrically cleaves ß-carotene in adult tissues to prevent its mitochondrial toxicity, generating ß-apo-10'-carotenal, which can be converted to retinoids (vitamin A and its metabolites) by BCO1. However, the role of BCO2 during mammalian embryogenesis is unknown. We found that mice lacking BCO2 on a vitamin A deficiency-susceptible genetic background (Rbp4-/-) generated severely malformed vitamin A-deficient embryos. Maternal ß-carotene supplementation impaired fertility and did not restore normal embryonic development in the Bco2-/-Rbp4-/- mice, despite the expression of BCO1. These data demonstrate that BCO2 prevents ß-carotene toxicity during embryogenesis under severe vitamin A deficiency. In contrast, ß-apo-10'-carotenal dose-dependently restored normal embryonic development in Bco2-/-Rbp4-/- but not Bco1-/-Bco2-/-Rbp4-/- mice, suggesting that ß-apo-10'-carotenal facilitates embryogenesis as a substrate for BCO1-catalyzed retinoid formation. These findings provide a proof of principle for the important role of BCO2 in embryonic development and invite consideration of ß-apo-10'-carotenal as a nutritional supplement to sustain normal embryonic development in vitamin A-deprived pregnant women.

ß-Carotene supplementation decreases placental transcription of LDL receptor-related protein 1 in wild-type mice and stimulates placental ß-carotene uptake in marginally vitamin A-deficient mice.

The human diet contains ß-carotene as the most abundant precursor of vitamin A, an essential nutrient for embryogenesis. Our laboratory previously showed the importance of ß-carotene metabolism via ß-carotene-15,15'-oxygenase (CMOI) to support mouse embryonic development. However, the mechanisms regulating embryonic acquisition and utilization of ß-carotene from the maternal circulation via placenta remain unknown. We used wild-type (WT) and Lrat(-/-)Rbp(-/-) (L(-/-)R(-/-)) mice, the latter being a model of marginal vitamin A deficiency. Pregnant dams, fed a nonpurified diet sufficient in vitamin A throughout life, were i.p. supplemented with ß-carotene or vehicle at 13.5 d postcoitum (dpc). Effects of this acute maternal supplementation on retinoid and ß-carotene metabolism in maternal (serum, liver) and developing tissues (placenta, yolk sac, embryo) were investigated at 14.5 dpc. We showed that, upon supplementation, placental ß-carotene concentrations were greater in L(-/-)R(-/-) than in WT mice. However, the retinoid (retinol and retinyl ester) concentrations remained unchanged in placenta (and in all other tissues analyzed) of both genotypes upon ß-carotene administration. We also showed that upon a single i.p. ß-carotene supplementation, placental LDL receptor-related protein (Lrp1) mRNA expression was lower in WT mice, and embryonic CmoI mRNA expression was greater in L(-/-)R(-/-) mice. Together, these data suggest a potential role of LRP1 in mediating the uptake of ß-carotene across the placenta and that even a marginally impaired maternal vitamin A status may influence uptake and utilization of ß-carotene by the placenta and the embryo.

Maternal-fetal transfer and metabolism of vitamin A and its precursor ß-carotene in the developing tissues.

The requirement of the developing mammalian embryo for retinoic acid is well established. Retinoic acid, the active form of vitamin A, can be generated from retinol and retinyl ester obtained from food of animal origin, and from carotenoids, mainly ß-carotene, from vegetables and fruits. The mammalian embryo relies on retinol, retinyl ester and ß-carotene circulating in the maternal bloodstream for its supply of vitamin A. The maternal-fetal transfer of retinoids and carotenoids, as well as the metabolism of these compounds in the developing tissues are still poorly understood. The existing knowledge in this field has been summarized in this review in reference to our basic understanding of the transport and metabolism of retinoids and carotenoids in adult tissues. The need for future research on the metabolism of these essential lipophilic nutrients during development is highlighted. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.