Dexamethasone induces germ cell apoptosis in the human fetal ovary.
BACKGROUND
The 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia. Pregnant women presenting a risk of genetic transmission may be treated with synthetic glucocorticoids such as dexamethasone (DEX) to prevent female fetus virilization.


OBJECTIVE
The aim of this study was to assess the potential deleterious effects of DEX exposure on fetal ovarian development.


METHODS
Human fetal ovaries, ranging from 8-11 weeks after fertilization, were harvested from material available after legally induced abortions. They were cultured in the absence or presence of DEX (2, 10, or 50 μm) over 14 d, and histological analyses were performed.


RESULTS
The glucocorticoid receptor NR3C1 was present and the signaling pathway active in the fetal ovary as demonstrated by the expression of NR3C1 target genes, such as PLZF and FKBP5, in response to DEX exposure. DEX decreased germ cell density at the 10 and 50 μm doses. Exposure to DEX, even at the highest dose, did not change oogonial proliferation as monitored by 5-bromo-2'-deoxyuridine incorporation and significantly increased the apoptotic rate, detected with cleaved caspase 3 staining. Interestingly, the expression of the prosurvival gene KIT was significantly decreased in the presence of DEX during the course of the culture.


CONCLUSIONS
We have demonstrated for the first time that in vitro exposure to high doses of DEX impairs human fetal oogenesis through an increase in apoptosis. These data are of high importance, and additional epidemiological studies are required to investigate the female fertility of those women who have been exposed to DEX during fetal life.
Laboratoire de Développement des Gonades Batiment 05 Porte A011B Commissariat à l'Energie Atomique-DSV/iRCM/SCSR/LDG Route du Panorama, 92265 Fontenay-aux-Roses, France.
Marine
M
Poulain
Nelly
N
Frydman
Clotilde
C
Duquenne
Thierry
T
N'Tumba-Byn
Alexandra
A
Benachi
René
R
Habert
Virginie
V
Rouiller-Fabre
Gabriel
G
Livera
D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy*; D017209:Apoptosis / Q000187:drug effects*; D002452:Cell Count; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005333:Fetus / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D009867:Oogonia / Q000166:cytology / Q000187:drug effects*; D009924:Organ Culture Techniques; D010053:Ovary / Q000166:cytology* / Q000187:drug effects*; D011247:Pregnancy; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D014770:Virilism / Q000517:prevention & control
D005938:Glucocorticoids; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D019009:Proto-Oncogene Proteins c-kit