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MHR’s highlight for November 2013 

This highlight covers the issue rather than a particular study since all eight papers relate to pregnancy. As summarized in their Editorial ‘MHR welcomes high quality basic reproductive research around pregnancy’ MHR Associate Editors Professor Jane Norman and Associate professor Stephen Tong welcome the fact that MHR’s interest does not stop at implantation, but straddles all of pregnancy.

Five of the articles focus on molecular regulation in the placenta in health and disease. 

Chang et al explore placental cell fusion and demonstrate that the endogenous histone de-acetytylase inhibitor HDAC5 co-localises with Glial Cell Missing 1 (GCM1, the upstream regulator of syncytin) to facilitate GCM1 deacetylation and repress transcriptional activity.

Goldman-Wohl et al add to our understanding of how the syncytiotrophoblast manages to simultaneously present a vast surface area of 12m3 (required for nutrient transport) without being overwhelmed by protein production. The answer is that expression of small nuclear RNA is down regulated in trophoblast under fusion conditions.

Dordea et al demonstrate that differences in PKD mediated myofilament Ca2+ desensitization leads to attenuation in the response of placental arteries to endothelial dependent relaxing agents in comparison with myometrial arteries. These data are likely to be important in developing therapies to treat disorders associated with inadequate placental perfusion, including pre-eclampsia and intrauterine growth retardation.

Andreasen et al use Sanger sequencing to show that no deleterious mutations were demonstrated in the genes NLRP7 or KHDC3L in women with recurrent miscarriage and hydatidiform mole, androgenetic recurrent hydatidiform mole or diploid androgenetic hydatidiform mole in combination with a relative with a hydatidiform mole. These data contrast with published literature on diploid biparental molar pregnancy and imply that familiar diploid biparental moles have a different monogenetic aetiology from the other conditions of reproductive failure.

Schrey et al, used the natural human experiment of severely growth-discordant monochorionic twins. They demonstrate that placental mRNA expression of leptin, fms-like tyrosine kinase 1, and endoglin are upregulated in the growth restricted twin. Increased leptin expression was associated with increased DNA methylation, implying an epigenetic mechanism in the regulation of fetal growth. Whether these changes were a cause or effect of the underlying growth disorder is unclear.

The three remaining articles focus on the pregnancy complication associated with the greatest mortality and morbidity for the baby – that of preterm birth.

Using a mouse model, Wakabayashi et al demonstrate that an anti-IL-6 antibody significantly decreased LPS induced preterm birth, prolonging pregnancy without any adverse effect on pups. These data support the rationale for trials of tocilizumab as a therapeutic agent for the treatment of preterm labour if concerns about potential unwanted fetal effects of the drug can be allayed.

Around 25% of preterm births are iatrogenic, and pre-eclampsia is one of the commonest causes. PAPP-A2 is emerging as a potential biomarker but until now, there have been no robust assays to quantify protein levels. Kloverpris et al provide validation for their recently developed monoclonal antibody ELISA, with a CV of 20% and a sensitivity down to 0.08ng/ml. Further work is required to determine the sensitivity and specificity of this new PAPPA-A2 assay for pre-eclampsia prediction and diagnosis.

Lastly, Sharp and colleagues review the use of computer modeling to understand the mechanism of uterine activation at labour, and as in silico human models to test novel drug therapies (such as tocilizumab) prior to human testing.

 

Read the November 2013 issue of MHR : basic Science of Reproductive Medicine here.


L. Andreasen, O.B. Christiansen, I. Niemann, L. Bolund and L. Sunde. NLRP7 or KHDC3L genes and the etiology of molar pregnancies and recurrent miscarriage Mol. Hum. Reprod. first published online August 19, 2013 doi:10.1093/molehr/gat056
Ching-Wen Chang, Mei-Leng Cheong, Geen-Dong Chang, Ming-Song Tsai and Hungwen Chen. Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in the regulation of placental cell fusion Mol. Hum. Reprod. first published online July 18, 2013 doi:10.1093/molehr/gat050
A.C. Dordea, M. Sweeney, J. Taggart, J. Lartey, H. Wessel, S.C. Robson and M.J. Taggart. Differential vasodilation of human placental and myometrial arteries related to myofilament Ca2+-desensitization and the expression of Hsp20 but not MYPT1 Mol. Hum. Reprod. first published online June 16, 2013 doi:10.1093/molehr/gat045
Debra Goldman-Wohl, Caryn Greenfield, Iris Eisenberg-Loebl, Galia Skarzinski, Ronit Haimov-Kochman, Tal Imbar, Ilana Ariel and Simcha Yagel. snRNAs are reduced in the syncytiotrophoblast: a possible mechanism for regulation of human placental protein production Mol. Hum. Reprod. first published online July 18, 2013 doi:10.1093/molehr/gat049 (8 pages)
S. Kløverpris, E. Gaidamauskas, L.C.V. Rasmussen, M.T. Overgaard, C. Kronborg,U.B. Knudsen,M. Christiansen, A. Kumarand C. Oxvig. A robust immunoassay for pregnancy-associated plasma protein-A2 based on analysis of circulating antigen: establishment of normal ranges in pregnancy Mol. Hum. Reprod. first published online June 25, 2013 doi:10.1093/molehr/gat047
S. Schrey, J. Kingdom, D. Baczyk, B. Fitzgerald, S. Keating, G. Ryan and S. DrewloLeptin is differentially expressed and epigenetically regulated across monochorionic twin placenta with discordant fetal growth Mol. Hum. Reprod. first published online July 4, 2013 doi:10.1093/molehr/gat048
G.C. Sharp, P.T.K. Saunders and J.E. Norman. Computer models to study uterine activation at labour Mol. Hum. Reprod. first published online June 17, 2013 doi:10.1093/molehr/gat043
Atsuko Wakabayashi, Kenjiro Sawada, Masahiro Nakayama, Aska Toda, Akihito Kimoto, Seiji Mabuchi, Yasuto Kinose, Koji Nakamura, Kazuhiro Takahashi, Hirohisa Kurachi and Tadashi Kimura.Targeting interleukin-6 receptor inhibits preterm delivery induced by inflammation Mol. Hum. Reprod. first published online August 22, 2013 doi:10.1093/molehr/gat057