Gestational diabetes mellitus alters apoptotic and inflammatory gene expression of trophobasts from human term placenta.
OBJECTIVE
Increased placental growth secondary to reduced apoptosis may contribute to the development of macrosomia in GDM pregnancies. We hypothesize that reduced apoptosis in GDM placentas is caused by dysregulation of apoptosis related genes from death receptors or mitochondrial pathway or both to enhance placental growth in GDM pregnancies.


METHODS
Newborn and placental weights from women with no pregnancy complications (controls; N=5), or with GDM (N=5) were recorded. Placental villi from both groups were either fixed for TUNEL assay, or snap frozen for gene expression analysis by apoptosis PCR microarrays and qPCR.


RESULTS
Maternal, placental and newborn weights were significantly higher in the GDM group vs. Controls. Apoptotic index of placentas from the GDM group was markedly lower than the Controls. At a significant threshold of 1.5, seven genes (BCL10, BIRC6, BIRC7, CASP5, CASP8P2, CFLAR, and FAS) were down regulated, and 13 genes (BCL2, BCL2L1, BCL2L11, CASP4, DAPK1, IκBκE, MCL1, NFκBIZ, NOD1, PEA15, TNF, TNFRSF25, and XIAP) were unregulated in the GDM placentas. qPCR confirmed the consistency of the PCR microarray. Using Western blotting we found significantly decreased placental pro-apoptotic FAS receptor and FAS ligand (FASL), and increased mitochondrial anti-apoptotic BCL2 post GDM insult. Notably, caspase-3, which plays a central role in the execution-phase of apoptosis, and its substrate poly (ADP-ribose) polymerase (PARP) were significantly down regulated in GDM placentas, as compared to non-diabetic Control placentas.


CONCLUSIONS
Maternal GDM results in heavier placentas with aberrant placental apoptotic and inflammatory gene expression that may account, at least partially, for macrosomia in newborns.
Department of Obstetrics and Gynecology, Perinatal Research Laboratories, David Geffen School of Medicine at University of California in Los Angeles, Los Angeles, CA, USA; Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA; Department of Health and Life Sciences at Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA.
Thomas R
TR
Magee
Department of Obstetrics and Gynecology, Perinatal Research Laboratories, David Geffen School of Medicine at University of California in Los Angeles, Los Angeles, CA, USA; Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
Michael G
MG
Ross
Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
Lauren
L
Wedekind
Department of Obstetrics and Gynecology, Perinatal Research Laboratories, David Geffen School of Medicine at University of California in Los Angeles, Los Angeles, CA, USA; Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
Mina
M
Desai
Department of Obstetrics and Gynecology, Perinatal Research Laboratories, David Geffen School of Medicine at University of California in Los Angeles, Los Angeles, CA, USA.
Siri
S
Kjos
Department of Obstetrics and Gynecology, Perinatal Research Laboratories, David Geffen School of Medicine at University of California in Los Angeles, Los Angeles, CA, USA; Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA. Electronic address: lbelkacemi1@gmail.com.
Louiza
L
Belkacemi
D000328:Adult; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001724:Birth Weight; D016640:Diabetes, Gestational / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005320:Fetal Macrosomia / Q000209:etiology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010920:Placenta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010929:Placentation; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047929:Term Birth
D051017:Apoptosis Regulatory Proteins; D018836:Inflammation Mediators; D012333:RNA, Messenger
Apoptosis; Apoptotic gene microarray; Gestational diabetes; Placenta