Abstract
It is well known that maternal folate deficiency results in adverse pregnancy outcomes. In addition to aspects in embryonic development, maternal uterine receptivity and the decidualization of stromal cells is also very important for a successful pregnancy. In this study, we focused on endometrium decidualization and investigated whether apoptosis, which is essential for decidualization, was impaired. Flow cytometry and TUNEL detection revealed that apoptosis of mouse endometrium decidual cells was suppressed in the dietary folate-deficient group on Days 7 and 8 of pregnancy (Day 1 = vaginal plug) when decidua regression is initiated. The endometrium decidual tissue of the folate deficiency group expressed less Bax compared to the normal diet group while they had nearly equal expression of Bcl2 protein. Further examination revealed that the mitochondrial transmembrane potential (ΔΨm) decreased, and the fluorescence of diffuse cytoplasmic cytochrome c protein was detected using laser confocal microscopy in normal decidual cells. However, no corresponding changes were observed in the folate-deficient group. Western blotting analyses confirmed that more cytochrome c was released from mitochondria in normal decidual cells. Taken together, these results demonstrated that folate deficiency could inhibit apoptosis of decidual cells via the mitochondrial apoptosis pathway, thereby restraining decidualization of the endometrium and further impairing pregnancy.
Highlights
Numerous studies have examined the effect of folate deficiency on birth defects, and folate deficiency has been acknowledged to be a vital risk factor of neural tube defects (NTD) [1]
For a morphological comparison of the endometrium decidual cells between folate-deficient mice and control mice, transmission electron microscopy (TEM) was employed to observe differences in the organelles related to programmed cell death
Compared with the control mice, the number of transferase-mediated dUTP nick end labeling (TUNEL)-positive cells was much less in the folate-deficient diet mice, and the results of the flow cytometric analysis showed that in normal Day 7 (D7) and Day 8 (D8) pregnant mice decidual cells, the percentage of early apoptotic cells were 12.80% and 12.79% and the percentages of late apoptotic cells were 60.98%
Summary
Numerous studies have examined the effect of folate deficiency on birth defects, and folate deficiency has been acknowledged to be a vital risk factor of neural tube defects (NTD) [1]. Our previous study revealed that there was no effect of folate deficiency on embryo implantation, and both the expression of uterine receptivity marker genes and the number of implantation sites showed no significant difference between the folate deficiency group and control group [4]. The outcomes of the folate-deficient pregnant mice were not favorable, and we found a lower birth rate and more embryo loss in folate-deficient pregnant mice (unpublished data). It remains an outstanding question of whether folate deficiency plays a role in the process of decidualization after embryo implantation. We investigated maternal uterine endometrium decidualization under folate-deficient conditions
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