Placenta Defects and Embryonic Lethality Resulting from Disruption of Mouse Hydroxysteroid (17-β) Dehydrogenase 2 Gene

Abstract

Hydroxysteroid (17-beta) dehydrogenase 2 (HSD17B2) is a member of aldo-keto reductase superfamily, known to catalyze the inactivation of 17beta-hydroxysteroids to less active 17-keto forms and catalyze the conversion of 20alpha-hydroxyprogesterone to progesterone in vitro. To examine the role of HSD17B2 in vivo, we generated mice deficient in Hsd17b2 [HSD17B2 knockout (KO)] by a targeted gene disruption in embryonic stem cells. From the homozygous mice carrying the disrupted Hsd17b2, 70% showed embryonic lethality appearing at the age of embryonic d 11.5 onward. The embryonic lethality was associated with reduced placental size measured at embryonic d 17.5. The HSD17B2KO mice placentas presented with structural abnormalities in all three major layers: the decidua, spongiotrophoblast, and labyrinth. Most notable was the disruption of the spongiotrophoblast and labyrinthine layers, together with liquid-filled cysts in the junctional region and the basal layer. Treatments with an antiestrogen or progesterone did not rescue the embryonic lethality or the placenta defect in the homozygous mice. In hybrid background used, 24% of HSD17B2KO mice survived through the fetal period but were born growth retarded and displayed a phenotype in the brain with enlargement of ventricles, abnormal laminar organization, and increased cellular density in the cortex. Furthermore, the HSD17B2KO mice had unilateral renal degeneration, the affected kidney frequently appearing as a fluid-filled sac. Our results provide evidence for a role for HSD17B2 enzyme in the cellular organization of the mouse placenta.

Fetal Loss and Hyposulfataemia in Pregnant NaS1 Transporter Null Mice

“…Enlargement of the spongiotrophoblast layer in mouse placentae has been observed in several mouse models with decreased fetal survival, including over-expression of epidermal growth factor receptor [32], trisomy 15 syndrome [33] and hydroxysteroid 17β dehydrogenase 2 null mice [34]. This is relevant to the enlarged spongiotrophoblast layer in placentae from pregnant Nas1 -/-mice, which have enhanced mid-gestational fetal loss.…”

“…In addition, since impaired IGF1 expression can reduce fecundity and placental nutrient exchange [31], it is possible that low levels of IGF1 in Nas1 -/-mice [15] may be a contributing factor to the reduced fecundity and/or altered placental morphometry in pregnant Nas1 -/-mice. To our knowledge, this is the first study to show increased fetal reabsorption and altered placental morphology in a model of maternal hyposulfataemia.Enlargement of the spongiotrophoblast layer in mouse placentae has been observed in several mouse models with decreased fetal survival, including over-expression of epidermal growth factor receptor [32], trisomy 15 syndrome [33] and hydroxysteroid 17β dehydrogenase 2 null mice [34]. This is relevant to the enlarged spongiotrophoblast layer in placentae from pregnant Nas1 -/-mice, which have enhanced mid-gestational fetal loss.…”

The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

“…However, the placentas of HSD17B2KO mice displayed histological malformations, while no signs of thrombosis were observed. Furthermore, the treatment of pregnant female mice with an anti-estrogen or with progesterone did not prevent the foetal loss of the HSD17B2KO mice (Rantakari et al 2008). Thus, the cause of embryonic deaths in the HSD17B2KO mice is likely not due to the lack of progesterone or due to an increased action of estrogens.…”

17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: Protein structures, functions, and recent progress in inhibitor development

“…Transgenic mice expressing human 17␤-HSD2 (HSD17B2TG) [31,123] showed growth retardation, delayed eye opening and disrupted spermatogenesis. Since part of these effects could be rescued by a synthetic retinoic acid receptor agonist, it can be speculated that 17␤-HSD2 plays a role in the action of retinoids.…”