Dynamic glucose enhanced MRI of the placenta in a mouse model of intrauterine inflammation

Abstract

Introduction: We investigated the feasibility of dynamic glucose enhanced (DGE) MRI in accessing placental function in a mouse model of intrauterine inflammatory injury (IUI). DGE uses the glucose chemical exchange saturation transfer (glucoCEST) effect to reflect infused d-glucose.

Methods: IUI was induced in pregnant CD1 mice by intrauterine injection of lipopolysaccharide (LPS) on embryonic day 17. In vivo MRI was performed on an 11.7 T scanner at 6 h s after injury, and glucoCEST effect was measured using an on-resonance variable delay multi-pulse (onVDMP) technique. onVDMP acquisition was repeated over a period of 25 min, and d-glucose was infused 5 min after the start. The time-resolved glucoCEST signals were characterized using the normalized signal difference (ΔS_N) between onVDMP-labeled and nonlabeled images.

Results: ΔS_N in the PBS-exposed placentae (n = 6) showed an initial drop between 1 and 3 min after infusion, followed by a positive peak between 5 and 20 min, the time period expected to be associated with the process of glucose uptake and transport. In the LPS-exposed placentae (n = 10), the positive peak was reduced or even absent, and the corresponding area-under-the-curve (AUC) was significantly lower than that in the controls. Particularly, the AUC maps suggested prominent group differences in the fetal side of the placenta. We also found that glucose transporter 1 in the LPS-exposed placentae did not respond to maternal glucose challenge.

Discussion: DGE-MRI is useful for evaluating placental functions related to glucose utilization. The technique uses a non-toxic biodegradable agent (d-glucose) and thus has a potential for rapid translation to human studies of placental disorders.

Figure 1:

(A) The experimental diagram: every acquisition block (1min) consists of five S1 images and one S0 image, which was repeated for 25 mins; and the D-glucose was infused at 5 min via the tail vein. (B) T2-weighted abdominal MRI of a coronal section of a pregnant mouse on embryonic day 17, with the placentae outlined in yellow. The inset shows the manually defined maternal and fetal parts of one placenta. (C) Comparison of an onVDMP labeled image (S1) in comparison with a nonlabeled reference image (S0).

Figure 2:

Time-resolved dynamics of the normalized signal change (ΔS_N, %) over the 25min DGE experiment in all individual placentae in (A) the PBS-exposed control group (n=6 from 3 dams), and (B) the LPS-exposed group (n=10 from 4 dams). (C) Averages of the normalized signals in the PBS (blue) and LPS-exposed (red) groups. Shaded regions present the standard deviation of the curves. AUC_15min was calculated as the area under the curve between 10–15 min from the start (time points between the black dashed lines). Green dashed lines indicate the time points, at which, ΔS_N was significantly lower in the LPS group compared to the PBS group (p<0.05, t-test followed by FDR correction).

Figure 3:

Voxelwise maps of the normalized signal change (ΔS_N, %) in a placenta acquired at every minute during the DGE experiment, in the PBS-exposed group (A, corresponding to placenta 5 in Figure 2A) or LPS-exposed group (B, corresponding to placenta 4 in Figure 2B). (C) Voxelwise AUC_15min maps of a PBS-exposed placenta and a LPS-exposed placenta, corresponding to the ones shown in (A) and (B), respectively. (D) Group analysis showing significantly lower AUC_15min in the LPS-exposed placentae compared to the PBS placentae (p<0.01). (E) Further analysis of AUC_15min in the maternal and fetal parts of the placenta showed significant group difference in the fetal part (p<0.01, two-way ANOVA followed by post-hoc t-test with Bonferroni correction).

Figure 4:

At the mRNA level GLUT1 was significantly increased in the PBS+glucose group compared to PBS+PBS and LPS+glucose groups (p<0.05, one-way ANOVA followed by pairwise post-hoc t-test).