Adverse effect of dexamethasone on development of the fetal rat ovary

Abstract

Dexamethasone (Dx) is often used in obstetric practice to promote fetal lung maturation and to prevent respiratory distress syndrome when the risk of preterm delivery persists. This therapy enables survival of the newborn, but also is associated with deleterious effects on the offspring, such as reproductive disorders. The aim of this study was to determine specifically whether prenatal exposure to Dx disturbs the physiological balance between proliferation and apoptosis of germinative cells (GC) in the ovary of 19- and 21-day-old fetuses and thus induces developmental programming of the female reproductive system. Pregnant Wistar rats (n = 10/group), separated into control (vehicle) and Dx-treated (0.5 mg/kg body mass) groups, received injections on gestational days 16, 17, and 18. Exposure to Dx lowered the volume of the fetal ovary by 30% (P < 0.05) in 21-day-old fetuses, as well as the total number of GC in the ovary by 21% (P < 0.05). When compared to the controls, in Dx-exposed fetuses, the total number of PCNA-positive GC was 27% lower at 19 days and 71% lower at 21 days old (P < 0.05), while total numbers of caspase-3-positive GC were 2.3-fold and 34% higher, respectively (P < 0.05). Our results demonstrate that prenatal exposure to Dx diminished proliferation but increased the rate of germinative cell apoptosis, with consequently reduced total germinative cell number and ovary volume. Impairment of fetal oogenesis and fewer GC in the fetal ovary compromise the oogonial stock and thus may constitute a risk of female fertility.

Developmental toxicity and programming alterations of multiple organs in offspring induced by medication during pregnancy

“…Intrauterine organ development is vulnerable to adverse environments such as prenatal drug use, and many different kinds of drugs have been shown to damage the development of the same organ ( Table 1 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ). The liver is the crucial organ for the metabolism of many exogenous compounds, including drugs.…”

“…Hippocampal, bone, and gonadal development are also vulnerable to a variety of drugs. Anesthetics 28 , 29 , 30 , 31 , 32 , antipsychotics 33 , 34 , 35 , 36 , and synthetic glucocorticoids 37 have been shown to affect hippocampal development; synthetic glucocorticoids 38 , 39 , antibiotics 12 , 40 , anticancer drugs 41 , 42 , antimalarials 43 , antiviral drugs 44 , NSAIDs 45 , and synthetic estrogen 46 have been shown to affect bone development and chondrogenesis; NSAIDs 47 , 48 , 49 , antipyretic-analgesic drugs 50 , 51 , synthetic glucocorticoids 52 , 53 , synthetic estrogens 54 , 55 , and hypoglycemic agents 56 can affect testicular or ovarian development. It is not difficult to find that studies on drug-induced organ developmental toxicity are mainly based on animal models.…”

“… Fetal rat limb deformity 43 Antiviral agent Tenofovir 一 Lower bone mineral content in human newborn 44 NSAID Indomethacin 10 −5 mol/L for 24 h Proliferation suppression and increased cell death of fetal rat chondrocytes 45 Ketorolac 10 −5 mol/L for 24 h Proliferation suppression and increased cell death of fetal rat chondrocytes 45 Diclofenac 10 −5 mol/L for 24 h Proliferation suppression and increased cell death of fetal rat chondrocytes 45 Piroxicam 10 −5 mol/L for 24 h Proliferation suppression and increased cell death of fetal rat chondrocytes 45 Synthetic estrogen Diethylstilbestrol 10 μg/kg·day, GD9–16, s.c. Shorter femurs in female offspring mice 46 Gonad NSAID Indomethacin 10 μmol/L for 24 h Decreased testosterone secretion in fetal rat testes 47 Ibuprofen 10 −5 mol/L for 72 h/10 μmol/L for 7 days Decreased testosterone production in human fetal testes/Increased cell apoptosis and necrosis in human fetal ovaries 48 , 49 Antipyretic-analgesic drug Acetaminophen 60 mg/kg·day for 7 days, p.o. /10 μmol/L for 7 days Decreased testosterone production in human fetal testis xenografts/Reduced germ cells in human fetal ovaries 50 , 51 Synthetic glucocorticoids Dexamethasone 0.2 mg/kg·day, GD9–20, s.c./0.5 mg/kg·day, GD16–18, s.c. Abnormal morphology and decreased testosterone production of offspring rats/Decreased volume and increased germ cell apoptosis of fetal rat ovaries 52 , 53 …”

Disruption of Circadian Rhythms: A Crucial Factor in the Etiology of Infertility

“…In the uterus, it was described that an increase of GCs causes a reduction of embryos implantation rate [58]. Ovaries exposed to GCs treatment undergo several damages such as steroidogenesis alteration, histological impairment [59], and reduction of the total number of germ cells and ovarian volume [60]. In oocytes, GCs impair their reproductive competence, inducing oocytes apoptosis [61].…”

Stress, Sex, and Sugar: Glucocorticoids and Sex-Steroid Crosstalk in the Sex-Specific Misprogramming of Metabolism

“…One study showed that maternal stress in guinea pigs increased T levels in female offspring during adulthood [ 212 ], whereas prenatal DEX led to reduced circulating follicle-stimulating hormone and luteinizing hormone in peripubertal rats [ 213 ] and lower serum E2 in adult female offspring [ 214 ]. The most consistent results reported in female offspring were alterations in the onset of puberty and variations in the length of estrus stages [ 215-220 ] as well as decreased numbers of healthy primordial follicles [ 221 , 222 ], likely due to the proapoptotic action of DEX reported on human and rat fetal ovaries [ 223 , 224 ]. Thus, developmental GC overexposure has the ability to disrupt later-life processes in female offspring that depend on sex-steroid action.…”