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. 2013 Aug;27(8):3249-56.
doi: 10.1096/fj.13-231852. Epub 2013 May 7.

Maternal-fetal transfer of selenium in the mouse

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Maternal-fetal transfer of selenium in the mouse

Raymond F Burk et al. FASEB J. 2013 Aug.

Abstract

Selenoprotein P (Sepp1) is taken up by receptor-mediated endocytosis for its selenium. The other extracellular selenoprotein, glutathione peroxidase-3 (Gpx3), has not been shown to transport selenium. Mice with genetic alterations of Sepp1, the Sepp1 receptors apolipoprotein E receptor-2 (apoER2) and megalin, and Gpx3 were used to investigate maternal-fetal selenium transfer. Immunocytochemistry (ICC) showed receptor-independent uptake of Sepp1 and Gpx3 in the same vesicles of d-13 visceral yolk sac cells, suggesting uptake by pinocytosis. ICC also showed apoER2-mediated uptake of maternal Sepp1 in the d-18 placenta. Thus, two selenoprotein-dependent maternal-fetal selenium transfer mechanisms were identified. Selenium was quantified in d-18 fetuses with the mechanisms disrupted. Maternal Sepp1 deletion, which lowers maternal whole-body selenium, decreased fetal selenium under selenium-adequate conditions but deletion of fetal apoER2 did not. Fetal apoER2 deletion did decrease fetal selenium, by 51%, under selenium-deficient conditions, verifying function of the placental Sepp1-apoER2 mechanism. Maternal Gpx3 deletion decreased fetal selenium, by 13%, but only under selenium-deficient conditions. These findings indicate that the selenoprotein uptake mechanisms ensure selenium transfer to the fetus under selenium-deficient conditions. The failure of their disruptions (apoER2 deletion, Gpx3 deletion) to affect fetal selenium under selenium-adequate conditions indicates the existence of an additional maternal-fetal selenium transfer mechanism.

Keywords: apolipoprotein E receptor-2; glutathione peroxidase-3; placenta; selenoprotein P; visceral yolk sac.

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Figures

Figure 1.
Figure 1.
Uptake of maternal Sepp1 (green) and Gpx3 (red) by d-13 visceral yolk sac. Nuclei are stained blue. A, B) Sepp1 (A) and Gpx3 (B) staining of the same tissue section from a wild-type mouse. C) Merged image of panels A and B. D) Gpx3 staining of the visceral yolk sac from a Gpx3+/− fetus in a Gpx3−/− dam. E) Sepp1 staining of the visceral yolk sac from a Sepp1+/− fetus in a Sepp1−/− dam.
Figure 2.
Figure 2.
Uptake of Sepp1 and Gpx3 by d-13 visceral yolk sac independent of apoER2 and megalin. Nuclei are stained blue. A) Presence of megalin (green) on the apical aspect of visceral yolk sac epithelial cells. B) Absence of apoER2 staining (red). C) Merged image of Sepp1 (green) and Gpx3 (red) staining of the visceral yolk sac of a megalin−/− fetus in a megalin+/− dam. D) Merged image of Sepp1 (green) and Gpx3 (red) staining of the visceral yolk sac of an apoER2−/− fetus in an apoER2+/− dam.
Figure 3.
Figure 3.
ApoER2-mediated uptake of maternal long-isoform Sepp1 by d-18 placenta. Panels show Sepp1 or apoER2 immunolocalization in red and nuclei in blue. A) Placenta of a Sepp1+/+ d-18 fetus from a Sepp1+/+ dam stained with antibody to Sepp1. B) Placenta of a Sepp1+/+ d-18 fetus from a Sepp1+/+ dam stained with antibody to apoER2. C) Placenta of a d-18 Sepp1+/− fetus from a Sepp1−/− dam stained for Sepp1. D) Placenta of a d-18 Sepp1Δ240–361/+ fetus whose Sepp1Δ240–361/Δ240–361 mother expresses only the N-terminal domain of Sepp1 stained for Sepp1. E) Placenta of a d-18 apoER2−/− fetus from an apoER2+/− dam stained with antibody to Sepp1.
Figure 4.
Figure 4.
Maternal Sepp1 is not transferred to the d-18 fetal kidney. Sections are from d-18 fetus kidney cortex stained red for Sepp1, blue for nuclei, and green (phalloidin) for actin. A) Sepp1+/− fetus from a Sepp1−/− dam. B) Sepp1−/− fetus from a Sepp1+/− dam.
Figure 5.
Figure 5.
Maternal plasma selenoproteins during pregnancy. Plasma from pregnant C57BL/6 dams fed rodent chow was assayed for Sepp1 concentration and Gpx activity. Values are expressed as means with 1 sd shown by a bracket; n = 3. *P < 0.05 vs. preceding value; 1-way ANOVA with Tukey's multiple-comparison test.
Figure 6.
Figure 6.
Effect of Sepp1 and Gpx3 maternal genotypes on selenium concentrations of their d-18 fetuses. In the Sepp1 experiment, the mice had not been backcrossed. Sepp1−/− dams were mated with Sepp1+/+ sires, resulting in Sepp1+/− fetuses (n=48). Sepp1+/+ dams were mated with Sepp1+/− sires, and the resulting fetuses (n=63) were genotyped. Fetal Sepp1 genotype had no statistically significant effect on fetal selenium, so values of all fetuses were combined. In the Gpx3 experiment with the dams receiving 0.25 mg Se/kg diet, fetuses resulted from Gpx3−/− by Gpx3−/− or Gpx3+/+ by Gpx3+/+ matings, and thus were Gpx3−/− (n=36) or Gpx3+/+ (n=22). In the Gpx3 experiment with the dams receiving selenium-deficient diet, Gpx3+/− fetuses (n=10 fetuses for each maternal genotype) resulted from mating Gpx3−/− dams with Gpx3+/+ sires and Gpx3+/+ dams with Gpx3−/− sires. Values are expressed as means with a bracket indicating 1 sd. Paired values that were different by Student's t test are indicated by the percentages.
Figure 7.
Figure 7.
Effects of apoER2 (A) and megalin (B) genotypes of d-18 fetuses on their selenium concentrations under conditions of selenium adequacy and selenium deficiency. Fetuses resulted from heterozygous matings, and the dams had been fed the respective diets for ≥4 wk before mating. Values are expressed as means with a bracket indicating 1 sd; n = 4–13. The value marked 49% in panel A was significantly different from the corresponding wild-type value by Student's t test. Other values were not different from the wild-type values within dietary groups.
Figure 8.
Figure 8.
Effects of dietary selenium on whole-body selenium concentrations of nonpregnant female Sepp1−/− mice (A) and pregnant Sepp1−/− dams and their d-18 fetuses (B). The mice were fed the respective diets for ≥8 wk beginning at weaning. Values are means with a bracket indicating 1 sd; n = 4–7 adult female mice and 13–34 fetuses. Pairs were all significantly different (P<0.05) by Student's t test, and differences are indicated by the percentage values.

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