Abstract
Placental mitochondrial dysfunction plays a central role in the pathogenesis of preeclampsia. Since preeclampsia is a hyperandrogenic state, we hypothesized that elevated maternal testosterone levels induce damage to placental mitochondria and decrease bioenergetic profiles. To test this hypothesis, pregnant Sprague–Dawley rats were injected with vehicle or testosterone propionate (0.5 mg/kg/day) from gestation day (GD) 15 to 19. On GD20, the placentas were isolated to assess mitochondrial structure, copy number, ATP/ADP ratio, and biogenesis (Pgc-1α and Nrf1). In addition, in vitro cultures of human trophoblasts (HTR-8/SVneo) were treated with dihydrotestosterone (0.3, 1.0, and 3.0 nM), and bioenergetic profiles using seahorse analyzer were assessed. Testosterone exposure in pregnant rats led to a 2-fold increase in plasma testosterone levels with an associated decrease in placental and fetal weights compared with controls. Elevated maternal testosterone levels induced structural damage to the placental mitochondria and decreased mitochondrial copy number. The ATP/ADP ratio was reduced with a parallel decrease in the mRNA and protein expression of Pgc-1α and Nrf1 in the placenta of testosterone-treated rats compared with controls. In cultured trophoblasts, dihydrotestosterone decreased the mitochondrial copy number and reduced PGC-1α, NRF1 mRNA, and protein levels without altering the expression of mitochondrial fission/fusion genes. Dihydrotestosterone exposure induced significant mitochondrial energy deficits with a dose-dependent decrease in basal respiration, ATP-linked respiration, maximal respiration, and spare respiratory capacity. In summary, our study suggests that the placental mitochondrial dysfunction induced by elevated maternal testosterone might be a potential mechanism linking preeclampsia to feto-placental growth restriction.
Highlights
Preeclampsia (PE) is a severe pregnancy-specific multi-system disorder characterized by the new onset of hypertension, proteinuria, edema, and a series of other systematic dysfunctions after 20 weeks of gestation [1,2]
We examined the mRNA expression of Pgc-1α and Nrf-1, the two genes that regulate mitochondrial biogenesis and replication
This study identified that elevated T levels, as observed in PE pregnancies, induced disruption in structure and the number of placental mitochondria with a parallel decrease in placental and fetal weights
Summary
Preeclampsia (PE) is a severe pregnancy-specific multi-system disorder characterized by the new onset of hypertension, proteinuria, edema, and a series of other systematic dysfunctions after 20 weeks of gestation [1,2]. Mitochondria are the main energy producers in the cell They consume oxygen and produce ATP by electron transport and oxidative phosphorylation. The mitochondrial structure was found to be disorganized with the disappearance of cristae in trophoblast cells of PE placenta [10,11]. The incidence of PE is higher in the family with mitochondrial dysfunction [13]. Together, these findings suggest that mitochondrial function plays an important role in the pathogenesis of PE. The finding that endothelial cells incubated with plasma from PE women result in a significant decrease in mitochondrial function [14] suggests that circulatory factors/hormones have the ability to impair mitochondrial bioenergetics
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