Gender-related effects of prenatal administration of estrogen and progesterone receptor antagonists on VEGF and surfactant-proteins and on alveolarisation in the developing piglet lung.
BACKGROUND
Vascular endothelial growth factor (VEGF) is essential for embryonic lung development and has been shown to be regulated by estradiol (E2) and progesterone (P).


OBJECTIVE
To investigate the effects of prenatal E2 and P withdrawal by specific receptor antagonists on the mRNA expression of VEGF, surfactant proteins (SP-B and SP-C) and on alveolarisation in lung tissue of male and female pig fetuses.


METHODS
Fetuses from 10 sows were randomized to receive either both an intramuscular injection of the E2 receptor blocker ICI 182.780 and the P receptor blocker RTI 3021-022 (ICI+RTI, n=5) or a placebo injection (n=5) at 90 days of gestation (DOG, 115=term). After delivery by cesarean section on 114 DOG, tissue of the left lingula of the piglet's lung (28 placebo, 26 ICI+RTI) was obtained to determine the mRNA expression of VEGF, SP-B and SP-C. Lungs from 15 placebo and 14 ICI+RTI group piglets were removed and alveolar counts performed.


RESULTS
The ICI+RTI group showed significantly lower SP-C mRNA expression and alveolar counts compared to the placebo group (p=0.04 and 0.03, respectively). Diminished alveolarisation in the ICI+RTI group was mainly due to the reduction of alveolar counts in male piglets (p=0.02). Within the placebo group VEGF and SP-B mRNA expression in male piglets were significantly lower compared to female piglets (p=0.01 and 0.004, respectively). ICI+RTI treatment abolished this gender-related difference.


CONCLUSIONS
Estradiol and P antagonism affected gender-related differences of key proteins for pulmonary function and development and especially in males was associated with diminished alveolarisation.
Trotter
Andreas
A
Section of Neonatology, Center for Perinatal Medicine, Children's Hospital, University of Bonn, Bonn, Germany. andreas.trotter@web.de
Hilgendorff
Anne
A
Kipp
Markus
M
Beyer
Cordian
C
Kueppers
Eva
E
Kiossis
Evangelos
E
Stuplich
Judith
J
Pohlandt
Frank
F
Thome
Ulrich
U
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage*; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000196:embryology; D008297:Male; D018811:Maternal Exposure; D010919:Placebos; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000196:embryology*; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics*; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors*; D012737:Sex Factors; D013552:Swine / Q000196:embryology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D017931:DNA Primers; D020847:Estrogen Receptor Modulators; D010919:Placebos; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D042461:Vascular Endothelial Growth Factor A