Placental effects of systemic tumour necrosis factor-α in an animal model of gestational diabetes mellitus.
BACKGROUND
Gestational diabetes mellitus (GDM) may adversely affect fetoplacental interaction. Numerous reports demonstrate that GDM women have increased circulating tumour necrosis factor-α (TNF), a pro-apoptotic peptide.


OBJECTIVE
To examine whether implantation site apoptosis is increased by exogenous TNF in mice heterozygous for a defective leptin receptor (db/+), a GDM animal model.


METHODS
Implantation sites were studied at gestational day (gd)18.5 in 3 groups: saline-treated wild-type (wt) and db/+ mice, and TNF-treated db/+ mice. Saline or TNF (total dose 4 μg) was administered by miniosmotic pump from gd11.5. Immunostaining for cleaved caspase-3, PAS and cytokeratin was performed for quantification of apoptotic cells, uterine natural killer (uNK) cells, and trophoblast invasion, respectively. The mRNA expression of TNF and TNF-induced apoptotic markers in placenta and mesometrial triangle (MT) was measured by quantitative RT-PCR.


RESULTS
The implantation sites from saline-treated wt and db/+ mice showed comparable numbers of apoptotic cells and uNK cells. Compared with the saline-treated groups, TNF-treated db/+ dams had less fetuses; the placental labyrinth and trophospongium contained more apoptotic cells; and the MT contained a higher total number of uNK cells including more cells intensely stained for cleaved caspase-3 as well as cells with negative staining. Trophoblast invasion was shallower in db/+ than in wt mice (14% and 30% of total invasion into MT, respectively) but this was not affected by TNF. The mRNA expression of TNF and apoptotic markers was comparable in the 3 groups.


CONCLUSIONS
TNF treatment in db/+ mice raises the number of apoptotic cells in the placenta, and appears to increase the retention of uNK cells in the MT. Db/+ mice demonstrate shallower trophoblast invasion which is unaffected by exogenous TNF.
Department of Obstetrics and Gynecology, Health Campus Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, Leuven, Belgium.
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RA
Bobadilla
R
R
van Bree
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L
Vercruysse
R
R
Pijnenborg
J
J
Verhaeghe
D000818:Animals; D017209:Apoptosis; D016640:Diabetes, Gestational / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D010064:Embryo Implantation; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha