High Preformed Vitamin A Intake during Pregnancy Prevents Embryonic Accumulation of Intact β-Carotene from the Maternal Circulation in Mice

Abstract

Background: The vitamin A precursor β-carotene (BC) promotes mammalian embryonic development by serving as a source of retinoids (vitamin A derivatives) to the developing tissues. In the Western world, increased consumption of dietary supplements, including vitamin A and BC, is common; however, the consequences of maternal high preformed vitamin A intake on embryonic uptake and metabolism of BC are poorly understood.

Objective: This study investigated vitamin A and BC metabolism in developing mouse tissues after a single BC administration to pregnant wild-type (WT) mice fed purified diets with different vitamin A concentrations.

Methods: WT dams fed a sufficient vitamin A (VA-S; 4.2 μg of retinol/g of diet), high vitamin A (VA-H; 33 μg of retinol/g of diet), or excess vitamin A (VA-E; 66 μg of retinol/g of diet) diet throughout gestation were intraperitoneally injected with BC or vehicle at 13.5 d postcoitum (dpc). At 14.5 dpc, retinoid and BC concentrations in maternal serum and liver, placenta, and embryo were quantified by HPLC; expressions of genes controlling retinoid and BC homeostasis were analyzed by quantitative polymerase chain reaction. Maternal lipoprotein BC concentrations were analyzed by density gradient ultracentrifugation followed by HPLC.

Results: Intact BC was undetectable only in embryos from VA-E + BC dams. Relative to the VA-S + vehicle group, placentas from VA-S + BC dams showed 39% downregulation of LDL-receptor-related protein 1 (Lrp1 ); 35% downregulation of VLDL receptor (Vldlr); 56% reduced mRNA expression of β-carotene 15,15'-oxygenase (Bco1); and 80% upregulation of β-carotene 9',10'-oxygenase (Bco2). Placental cytochrome P450, family 26, subfamily A, polypeptide 1 (Cyp26A1) was upregulated 2-fold in the VA-E group compared with the VA-S group, regardless of maternal treatment.

Conclusions: In mice, transfer of intact BC to the embryo is attenuated by high tissue vitamin A concentrations. Maternal vitamin A intake and BC availability activate a placental transcriptional response to protect the embryo from retinoid and carotenoid excess.

Keywords: embryo; maternal-fetal β-carotene metabolism; placenta; retinoids; vitamin A.

FIGURE 1

Vitamin A concentrations in serum (A), liver (B), placenta (C), and embryo (D) 24 h after vehicle or BC administration to WT mouse dams fed diets with different vitamin A contents. Data are means ± SDs; n = 4, VA-S + BC; n = 4, VA-H + BC; n = 3, VA-E + BC. Statistical analysis by 1-factor ANOVA. BC, β-carotene; ND, not detected (serum, 0.0186 nmol/L; tissues, 0.186 nmol/g); VA-E, excess vitamin A; VA-H, high vitamin A; VA-S, sufficient vitamin A; WT, wild type.

FIGURE 2

qPCR analysis of genes involved in retinoid and carotenoid metabolism 24 h after Veh or BC administration to WT mouse dams fed VA-S or VA-E diets. Embryo (A, B) or placenta (C) from VA-S + Veh–treated dams set as a calibrator at 1. Data are means ± SDs fold change of the calibrator; n = 3–4 group. Statistical analysis by a 2-factor ANOVA, with D × T as factors. Labeled means (within each gene) without a common letter differ, P < 0.05. Figure represents data from 1 of 2 repeat analyses, which yielded similar results. BC, β-carotene; Bco1, β-carotene 15,15′-oxygenase; Bco2, β-carotene 9,10′-oxygenase; Cd36, cluster of differentiation 36; Cyp26A1, cytochrome P450, family 26, subfamily A, polypeptide 1; D, diet; Dhrs3, dehydrogenase/reductase member 3; Ldlr, LDL receptor; Lpl, lipoprotein lipase; Lrat, lecithin:retinol acyltransferase; Lrp1, LDL-receptor–related protein 1; Raldh2, retinaldehyde dehydrogenase 2; Rdh10, retinol dehydrogenase 10; Srb1, scavenger receptor B type 1; T, treatment; VA-E, excess vitamin A; VA-S, sufficient vitamin A; Veh, vehicle; Vldlr, VLDL receptor; WT, wild type.