Ori Nevo

Hypospadias in Males With Intrauterine Growth Restriction Due To Placental Insufficiency: The Placental Role in the Embryogenesis of Male External Genitalia

Our aim was to define the association between early onset intra‐uterine growth restriction (IUGR) due to placental insufficiency and hypospadias in males. We prospectively studied a cohort of small‐for‐gestational age (SGA) male infants with hypospadias managed by a multidisciplinary team over a 5‐year period. Thirty SGA male infants were diagnosed with hypospadias/abnormal genitalia after birth, and four of them were diagnosed antenatally. Five cases occurred in the smaller pair of discordant IUGR twins, where the larger co‐twin had normal male genitalia. Serial ultrasounds demonstrated features of early‐onset IUGR in all cases at a median gestational age of 21 weeks (range 14–31weeks). Twenty‐one (70%) pregnancies were subsequently complicated by absent/reversed end‐diastolic flow in the umbilical arteries indicating severe IUGR, and 17 (57%) women developed severe pre‐eclampsia. There were 27 (90%) live births at a median gestational age of 31 weeks (range 27–37); 23 (77%) of the neonates had birth weights <3rd centile. All newborns had normal male karyotypes. In 62% (18/29) the hypospadias was severe. A correlation was found between the severity of the IUGR and the severity of hypospadias as significantly more infants with severe hypospadias were less than the 3rd centile compared to the mild–moderate hypospadias group: 94% (17/18) versus 55% (6/11), respectively (P = 0.02). In conclusion, SGA male newborns with hypospadias exhibit a high rate of early‐onset severe IUGR due to placental insufficiency. Early placental development likely influences male external genitalia formation. Careful sonographic evaluation of the genitalia is advised when early‐onset placentally mediated IUGR is found.

Aberrant TGFβ Signaling Contributes to Altered Trophoblast Differentiation in Preeclampsia.

TGFβ has been implicated in preeclampsia, but its intracellular signaling via phosphorylated mothers against decapentaplegic (SMADs) and SMAD-independent proteins in the placenta remains elusive. Here we show that TGFβ receptor-regulated SMAD2 was activated (Ser(465/467) phosphorylation) in syncytiotrophoblast and proliferating extravillous trophoblast cells of first-trimester placenta, whereas inhibitory SMAD7 located primarily to cytotrophoblast cells. SMAD2 phosphorylation decreased with advancing gestation, whereas SMAD7 expression increased and shifted to syncytiotrophoblasts toward term. Additionally, we found that the TGFβ SMAD-independent signaling via partitioning defective protein 6 (PARD6)/Smad ubiquitylation regulatory factor was activated at approximately 10-12 weeks of gestation in cytotrophoblast and extravillous trophoblast cells comprising the anchoring column. Placentae from early-onset, but not late-onset, preeclampsia exhibited elevated SMAD2 phosphorylation and SMAD7 levels. Whereas PARD6 expression increased and SMURF1 levels decreased in preeclamptic placentae, their association increased. SMAD2 phosphorylation by TGFβ in villous explants and BeWo cells resulted in a reduction of Glial cell missing-1 (GCM1) and fusogenic protein syncytin-1 while increasing cell cycle regulators cyclin E-1 (CCNE1) and cyclin-dependent kinase 4. SMAD7 abrogated the proliferative effects of TGFβ. CCNE1 levels were increased in preeclamptic placentae, whereas GCM1 was markedly reduced. In addition, TGFβ treatment increased the association of PARD6 and SMURF1 and down-regulated Ras homolog gene family, member A (RHOA) GTPase in JEG3 cells. In a wound assay, TGFβ treatment increased the association of PARD6 and SMURF1 and triggered JEG3 cell migration through increased cellular protrusions. Taken together, our data indicate that TGFβ signaling via both SMAD2/7 and PARD6/SMURF1 pathways plays a role in trophoblast growth and differentiation. Altered SMAD regulation of GCM1 and CCNE1 and aberrant expression/activation of PARD6/SMURF1 may contribute to the pathogenesis of preeclampsia by affecting cellular pathways associated with this disorder.