RESUMEN
Prenatal overexposure to glucocorticoids (GC) can lead to behavioral changes in adulthood. We aimed to explore the effects of gestational administration of vitamin D on the behavioral responses of dams and their offspring prenatally exposed to dexamethasone (DEX). Vitamin D (500UI) was given daily during the whole pregnancy (VD group). Half of the groups that received vitamin D were treated with DEX (0.1 mg/kg, VD + DEX group) daily between the 14th and 19th days of pregnancy. The corresponding control groups of progenitors were assigned (CTL and DEX groups, respectively). Maternal care and the dam's behaviors were evaluated during lactation. The offspring had developmental and behavioral parameters evaluated during lactation and at 3, 6, and 12 months of age. Gestational administration of vitamin D increased maternal care and had an anxiolytic-like effect on the dams, but the latter was blocked in DEX-treated dams. Prenatal DEX partially impaired neural development and caused an anxiety-like phenotype in the male and female offspring at 6 months, which was prevented by gestational administration of vitamin D. As well, gestational vitamin D improved memory just in the male offspring, but this response was suppressed by prenatal DEX. We concluded that gestational vitamin D could prevent anxiety-like behavior in adult male and female rats prenatally exposed to DEX, which might be, in part, a result of the maternal care improvement.
Asunto(s)
Dexametasona , Efectos Tardíos de la Exposición Prenatal , Embarazo , Ratas , Femenino , Masculino , Animales , Humanos , Ratas Wistar , Dexametasona/farmacología , Vitamina D/farmacología , Glucocorticoides/toxicidad , Ansiedad/tratamiento farmacológico , Ansiedad/prevención & control , Vitaminas , Efectos Tardíos de la Exposición Prenatal/prevención & controlRESUMEN
Overexposure to glucocorticoids during gestation can lead to long-term mental disorders. Given the higher prevalence of depression in females, we investigated whether late gestational administration of dexamethasone could generate a depressive-like phenotype in the adult female offspring and if vitamin D could have a neuroprotective effect in this context. Pregnant rats received vitamin D (VitD, 500 IU/day) or vehicle (CTL) during gestation. Other pregnant rats received dexamethasone (Dex 0.1 mg/kg/ - 14th to the 19th gestational day) or dexamethasone + vitamin D (DexVitD). The offspring were tested for anhedonia (sucrose preference) and depressive-like behavior (forced swimming test) at postnatal months (PNM) 3, 6 and 12. Components of the serotonergic system, as well as glucocorticoids' receptors, were evaluated in the dorsal raphe nucleus at PNM 6 and 12. Prenatal vitamin D and dexamethasone increased sucrose preference at PNM 12. Prenatal vitamin D had an antidepressant-like effect at PNM 3 in rats overexposed to dexamethasone. However, at PNM 12, this effect was blunted in the DexVitD group. Prenatal dexamethasone reduced the protein content of SERT, TPH, and 5-HT1A receptors in the dorsal raphe nucleus at 6 but not at 12 PNM. The glucocorticoids' receptors expression was similar in all groups. We concluded that prenatal overexposure to dexamethasone does not change emotional behaviors in females, but it blunts the antidepressant-like effect of gestational vitamin D in an age-dependent manner. The antidepressant-like activity of vitamin D in the offspring was not related either to alterations of the serotonergic system or the glucocorticoids' receptors expression in the dorsal raphe nucleus.
Asunto(s)
Dexametasona , Glucocorticoides , Efectos Tardíos de la Exposición Prenatal , Vitamina D , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Dexametasona/efectos adversos , Dexametasona/farmacología , Femenino , Glucocorticoides/efectos adversos , Glucocorticoides/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Ratas Wistar , Receptores de Glucocorticoides , Sacarosa , Vitamina D/metabolismo , Vitamina D/farmacologíaRESUMEN
PURPOSE: The overexposure to synthetic glucocorticoids (GC) during pregnancy can predispose to metabolic diseases during adulthood. Vitamin D is not only crucial for fetal development, but also exerts direct effects on the GC sensitivity and down-regulates GC receptors. Given the vitamin D effects on glucocorticoid-related parameters, we aimed to investigate a possible protective role of maternal vitamin D administration on the glucose homeostasis of rats exposed to dexamethasone in utero. METHODS: Pregnant rats received dexamethasone (0.1 mg/kg, Dex) daily between the 14th and 19th days of pregnancy. A subgroup of dexamethasone-treated dams received oral administration of vitamin D (500UI, DexVD) during the whole gestation. The corresponding control groups of dams were included (CTL and VD groups, respectively). Male and female offspring were evaluated at 3, 6 and 12 months of age. RESULTS: Prenatal exposure to dexamethasone caused metabolic disruption in an age and sex-dependent manner being the older male offspring more susceptible to insulin resistance, fatty liver and beta-cell mass expansion than females. Furthermore, we demonstrated that prenatal GC led to glucose intolerance in male and female offspring in an age-dependent manner. Maternal vitamin D administration did not influence glucose intolerance but attenuated the insulin resistance, liver lipid accumulation and prevented the beta-cell mass expansion caused by prenatal dexamethasone in the male offspring. CONCLUSION: Maternal vitamin D administration mitigates metabolic disturbances that occur later in life in male rats exposed to GC in utero. Moreover, our data suggest vitamin D as an important nutritional supplement for pregnant overexposed to GC during gestation.
Asunto(s)
Dexametasona/efectos adversos , Glucocorticoides/efectos adversos , Enfermedades Metabólicas/tratamiento farmacológico , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Vitamina D/uso terapéutico , Vitaminas/uso terapéutico , Animales , Femenino , Células Secretoras de Insulina/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Intercambio Materno-Fetal , Enfermedades Metabólicas/sangre , Enfermedades Metabólicas/inducido químicamente , Enfermedades Metabólicas/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/sangre , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas Wistar , Caracteres Sexuales , Triglicéridos/sangre , Triglicéridos/metabolismo , Vitamina D/farmacología , Vitaminas/farmacologíaRESUMEN
Administration of dexamethasone (DEX) during late gestation is a model to study growth restriction in rodents, but the pup's mortality index can be high, depending on DEX dosage, and little is known about the effects of DEX on maternal care (MC). Considering that an inadequate MC can also contribute to pup's mortality in this model, we evaluated the effects of DEX on dams' behavior and its consequences on offspring survival. We also investigated whether the cross-fostering of pups from dams treated or not with DEX could improve pup's survival. Wistar rats were treated with DEX (14th to 19th day of gestation -0.2 mg/kg, B.W, in the drinking water). Nest building, MC and responses in the elevated plus-maze, forced swimming and object recognition tests were evaluated. DEX reduced gestational weight gain and impaired neonatal development, reducing pup's survival to 0% by the 3rd postnatal day. DEX-treated dams reduced the expression of typical MC and increased anxiety-like behaviors. After cross-fostering, DEX-treated mothers behaved similarly to controls, indicating that a healthy offspring is crucial to induce adequate MC. Cross-fostering increased the survival index from zero to 25% in the DEX offspring. Postnatal development of the DEX offspring was comparable to controls after cross-fostering. We concluded that exposure to DEX during late gestation causes behavioral changes that compromise the maternal emotional state, disrupting the expression of MC. Although it does not seem to be the main cause of pup's mortality, our data indicate that an adequate MC improves pup's survival in this model.
Asunto(s)
Antiinflamatorios/toxicidad , Dexametasona/toxicidad , Conducta Materna/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/mortalidad , Animales , Animales Recién Nacidos , Antiinflamatorios/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Masculino , Conducta Materna/fisiología , Conducta Materna/psicología , Embarazo , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Ratas Wistar , Tasa de Supervivencia/tendenciasRESUMEN
AIMS: After menopause, women are more responsive to stress and more prone to exhibit hypertension, which elevates the risk of cardiac diseases. This vulnerability is due, in part, to the decline of ovarian steroids plasma levels. The 4-vinylciclohexane diepoxide (VCD) causes a gradual depletion of ovarian follicles causing loss of the normal ovarian function and a hormonal profile comparable to menopause in humans. We aimed to verify whether the ovarian failure (OF) worsens the cardiovascular autonomic response to stress. MAIN METHODS: Rats were treated with VCD (160â¯mg/kg) or oil for 15â¯days, exposed to chronic unpredictable stress (CUS) for 10â¯days and studied 80 and 180â¯days after VCD treatment. KEY FINDINGS: 80â¯days after VCD-treatment, stressed rats showed increased sympathetic nerve activity, reduced parasympathetic activity and an increase in the overall spontaneous baroreflex sensitivity (BRS). 180â¯days after VCD treatment, BRS was impaired and the vascular sympathetic activity was increased, independently of stress exposure. SIGNIFICANCE: Neither 80 nor 180â¯days after the onset of VCD-treatment the hypertensive effects of stress were enhanced in rats. However, OF led to a worsening on different aspects of the cardiovascular response to stress, which can cause cardiovascular complications when associated with ovarian aging.
Asunto(s)
Sistema Cardiovascular/fisiopatología , Insuficiencia Ovárica Primaria/fisiopatología , Estrés Psicológico/fisiopatología , Animales , Sistema Nervioso Autónomo/fisiopatología , Barorreflejo/fisiología , Ciclohexenos/farmacología , Modelos Animales de Enfermedad , Ciclo Estral , Femenino , Menopausia , Folículo Ovárico , Ovario , Perimenopausia , Insuficiencia Ovárica Primaria/inducido químicamente , Ratas , Ratas Wistar , Estrés Psicológico/metabolismo , Compuestos de Vinilo/farmacologíaRESUMEN
After menopause, hypertension elevates the risk of cardiac diseases, one of the major causes of women's morbidity. The gradual depletion of ovarian follicles in rats, induced by 4-vinylcyclohexene diepoxide (VCD), is a model for studying the physiology of menopause. 4-Vinylcyclohexene diepoxide treatment leads to early ovarian failure (OF) and a hormonal profile comparable to menopause in humans. We have hypothesized that OF can compromise the balance between sympathetic and parasympathetic tones of the cardiovascular system, shifting toward dominance of the former. We aimed to study the autonomic modulation of heart and blood vessels and the cardiovascular reflexes in rats presenting short-term (80 days) or long-term (180 days) OF induced by VCD. Twenty-eight-day-old Wistar rats were submitted to VCD treatment (160 mg/kg, intraperitoneally) or vehicle (control) for 15 consecutive days and experiments were conducted at 80 or 180 days after the onset of treatment. Long-term OF led to an increase in the sympathetic activity to blood vessels and an impairment in the baroreflex control of the heart, evoked by physiological changes in arterial pressure. Despite that, long-term OF did not cause hypertension during the 180 days of exposure. Short-term OF did not cause any deleterious effect on the cardiovascular parameters analyzed. These data indicate that long-term OF does not disrupt the maintenance of arterial pressure homeostasis in rats but worsens the autonomic cardiovascular control. In turn, this can lead to cardiovascular complications, especially when associated with the aging process seen during human menopause.