Maternal protein restriction before pregnancy affects vital organs of offspring in Wistar rats

Epidemiologic studies indicate that undernutrition during fetal growth can have long-term effects on adult health. However, it is not known whether these effects are also associated with maternal undernutrition before conception. The objective of the present study was to examine the effect of dietary restriction before pregnancy on the vital organs and blood parameters of offspring at different time points. Wistar female rats in the restricted group were fed a diet consisting of 80 g protein/kg for 8 weeks before pregnancy and switched to 160 g protein/kg (control) from day 0 of pregnancy, while animals from the control group were fed 160 g protein/kg throughout life. The progeny were studied at birth (n = 71), at 94 days (n = 20), and at 180 days (n = 16). Weight gain during pregnancy was significantly lower (P <.01) for dams in the restricted group. At birth, relative weight for brain was lower (P 相似文献   

Opposite variations in maternal and neonatal thyroid function induced by iodine supplementation during pregnancy

Whereas the consequences of extremes in iodine intake are well described, much less is known about the effect of more moderate variations in maternal iodine intake on fetal thyroid function. The present study performed in Denmark with mild to moderate iodine deficiency dealt with the effect of maternal iodine supplementation on thyroid function in the mother at term and in the fetus/neonate. Serum was collected consecutively from pregnant women at term (n = 144) and from cord blood (n = 139). Forty-nine women had a regular intake of vitamin and mineral tablets with iodine (150 microg/day) during pregnancy, and 95 took no artificial iodine supplementation. Iodine supplementation (+I) induced opposite variations in thyroid function in the mother and the fetus. In +I mothers, TSH was 7.6% lower than in mothers with no supplementation (P < 0.05). In cord blood, on the contrary, TSH was 27.3% higher in the +I group (P < 0.05). The variations were caused by opposite shifts in TSH frequency distribution in mothers and neonates. The association between iodine supplementation and high serum TSH in the neonates was further substantiated by an inverse correlation between thyroglobulin and TSH in cord blood (P < 0.001), whereas no specific pattern was observed in the mothers. High serum thyroglobulin was a marker of low iodine intake in both mothers and neonates. The results suggest that the fetal thyroid, at least in areas of mild iodine deficiency, is more sensitive to the inhibitory effect of iodine than hitherto anticipated.     

Protein restriction during pregnancy induces hypertension and impairs endothelium-dependent vascular function in adult female offspring

Intrauterine undernutrition plays a role in the development of adult hypertension. Most studies are done in male offspring to delineate the mechanisms whereby blood pressure may be raised; however, the vascular mechanisms involved in female offspring are unclear. Female offspring of pregnant Sprague-Dawley rats fed either a control (C; 18%) or a low-protein (LP; 6%) diet during pregnancy were used. Birth weight and later growth were markedly lower in LP than in C offspring. LP offspring exhibited impaired estrous cyclicity with increased mean arterial pressure. Hypotensive response to acetylcholine (ACh) and the hypertensive response to phenylephrine (PE) were greater in LP than in C rats. N-nitro-L-arginine methyl ester (L-NAME) induced greater hypertensive responses in C than in LP rats. Endothelium-intact mesenteric arteries from LP offspring exhibited increased contractile responses to PE and reduced vasodilation in response to ACh. In endothelium-denuded arteries, relaxation responses to sodium nitroprusside were similar in both groups. Basal and ACh-induced increase in vascular nitrite/nitrate production was lower in LP than in C offspring. L-NAME or 1H-1,2,4-oxadiazolo-4,3-quinoxalin-1-one inhibited ACh relaxations and enhanced PE contractions in C offspring, but had minimal effect in LP rats. The decreased NO-mediated vascular response might explain the increased vascular contraction and arterial pressure in female offspring with low birth weight.     

Maternal melatonin: Effective intervention against developmental programming of cardiovascular dysfunction in adult offspring of complicated pregnancy

Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were divided into normoxic (N) or hypoxic (H, 10% O₂) pregnancy ± melatonin (M) treatment (5 μg·ml^?1.day^?1) in the maternal drinking water. Hypoxia ± melatonin treatment was from day 15–20 of gestation (term is ca. 22 days). To control for possible effects of maternal hypoxia-induced reductions in maternal food intake, additional dams underwent pregnancy under normoxic conditions but were pair-fed (PF) to the daily amount consumed by hypoxic dams from day 15 of gestation. In one cohort of animals from each experimental group (N, NM, H, HM, PF, PFM), measurements were made at the end of gestation. In another, following delivery of the offspring, investigations were made at adulthood. In both fetal and adult offspring, fixed aorta and hearts were studied stereologically and frozen hearts were processed for molecular studies. In adult offspring, mesenteric vessels were isolated and vascular reactivity determined by in-vitro wire myography. Melatonin treatment during normoxic, hypoxic or pair-fed pregnancy elevated circulating plasma melatonin in the pregnant dam and fetus. Relative to normoxic pregnancy, hypoxic pregnancy increased fetal haematocrit, promoted asymmetric fetal growth restriction and resulted in accelerated postnatal catch-up growth. Whilst fetal offspring of hypoxic pregnancy showed aortic wall thickening, adult offspring of hypoxic pregnancy showed dilated cardiomyopathy. Similarly, whilst cardiac protein expression of eNOS was downregulated in the fetal heart, eNOS protein expression was elevated in the heart of adult offspring of hypoxic pregnancy. Adult offspring of hypoxic pregnancy further showed enhanced mesenteric vasoconstrictor reactivity to phenylephrine and the thromboxane mimetic U46619. The effects of hypoxic pregnancy on cardiovascular remodelling and function in the fetal and adult offspring were independent of hypoxia-induced reductions in maternal food intake. Conversely, the effects of hypoxic pregnancy on fetal and postanal growth were similar in pair-fed pregnancies. Whilst maternal treatment of normoxic or pair-fed pregnancies with melatonin on the offspring cardiovascular system was unremarkable, treatment of hypoxic pregnancies with melatonin in doses lower than those recommended for overcoming jet lag in humans enhanced fetal cardiac eNOS expression and prevented all alterations in cardiovascular structure and function in fetal and adult offspring. Therefore, the data support that melatonin is a potential therapeutic target for clinical intervention against developmental origins of cardiovascular dysfunction in pregnancy complicated by chronic fetal hypoxia.     

Folate sufficient subjects do not accumulate additional folates during supplementation

In a double-blinded placebo-controlled trial of folic acid supplementation in 82 alcoholic subjects, it was found that whole blood folate levels, determined by a mass spectrometric method, do not increase in subjects whose baseline folate levels are above the third quartile (folate sufficiency). Since a state of folate sufficiency can now be identified, a recommended daily allowance (RDA) for folate can be determined using objective means.     

The antioxidant alpha-lipoic acid improves endothelial dysfunction induced by acute hyperglycaemia during OGTT in impaired glucose tolerance

Objective Impaired glucose tolerance (IGT) is considered a transitional phase in the development of type 2 diabetes, and is also independently associated with the occurrence of cardiovascular disease. Endothelial dysfunction (ED) represents a very early step in the development of atherosclerosis. The aim of the present study was to examine ED in the fasting state and after a glucose challenge as well as after administration of an antioxidant agent. Patients and methods The study subjects included 42 IGT patients and 26 healthy individuals (control group). The IGT patients were randomly divided into two groups, 21 in each group (the alpha‐lipoic acid group and the placebo group). In the alpha‐lipoic acid group, 300 mg of alpha‐lipoic acid was administrated before an oral glucose tolerance test (OGTT); in the placebo group, 250 ml of 0·9% sodium chloride was administrated before the OGTT. In addition, 250 ml of 0·9% sodium chloride was also administrated to the control subjects before the OGTT (control group), and then vascular function was examined in the fasting state and repeated 1 and 2 h after the glucose load. High‐resolution ultrasound was used to measure flow‐mediated endothelium‐dependent arterial dilation (FMD) and glyceryltrinitrate (GTN)‐induced endothelium‐independent arterial dilation. Results In the fasting state, and at 60 and 120 min, FMD in both the placebo and alpha‐lipoic acid groups was significantly lower than in the controls (P < 0·01). In the control group, FMD tended to decrease at 60 min after glucose loading and returned to the baseline levels at 120 min (P > 0·05). In the placebo group, FMD decreased significantly at 60 min after glucose loading (P < 0·01) and increased markedly from 60 to 120 min (P < 0·01). The alpha‐lipoic acid‐treated patients showed FMD values intermediate between the control subjects and the IGT patients treated with placebo, at both 60 and 120 min, and the differences were significant (P < 0·01). In multiple regression analysis, FMD was significantly correlated to fasting blood glucose (FBG), low density lipoprotein cholesterol (LDL‐C), lipoprotein (a) [Lp(a)], C‐reactive protein (CRP), thiobarbituric acid reactive substances (TBARS) and age in IGT patients at baseline (P < 0·01). Spearman's analysis showed a significant negative correlation between FMD and plasma glucose levels, and between FMD and TBARS during the OGTT in IGT patients (placebo group) (P < 0·01). There was also a significant correlation between FMD and plasma glucose levels, and between FMD and TBARS during the OGTT in IGT patients treated with alpha‐lipoic acid (P < 0·05), although the power of association decreased. Conclusion In subjects with IGT, FMD was impaired both in the fasting state and after a glucose challenge, probably through increased production of oxygen‐derived free radicals. The ED observed after a glucose challenge is related to the extent of hyperglycaemia and TBARS, and an antioxidant agent can improve the impairment of endothelial function induced by acute hyperglycaemia.     

Acute keratoconus induced by hypothyroxinemia during pregnancy

Keratoconus is a bilateral non-inflammatory corneal ectasia with an incidence of approximately 1 per 2000 in the general population. The etiology of keratoconus is multifactorial, although not completely understood. Several clinical observations suggest that thyroid gland dysfunction is associated with keratoconus pathophysiology. Pregnancy represents a major alteration in the maternal endocrinologic status characterized by modified function of the thyroid gland. We report on a 33-yr-old pregnant women suffering from keratoconus, who presented simultaneously with a remarkable deterioration of the disease during gestation and with thyroid gland dysfunction. Acute keratoconus in this patients coincided with the lowest plasma T4 level reached during pregnancy. During the third trimester of gestation, the keratoconus receded significantly. Here we provide direct evidence in support of a possible linkage between keratoconus and thyroid gland dysfunction, assumed by previous clinical observations. This case report is the first to suggest that changes in maternal thyroid hormone levels during pregnancy can aggravate the progression of keratoconus.     

Vitamin D deficiency and supplementation during pregnancy

Objective  Vitamin D is essential for skeletal health and prolonged deficiency results in infantile rickets and adult osteomalacia. The aim of this study is to determine the vitamin D status in pregnancy and to evaluate the effects of daily and of single-dose vitamin D supplementation.
Design  A prospective randomized study at St Mary's Hospital London.
Patients A total of 180 women (Indian Asian, Middle Eastern, Black and Caucasian) were recruited at 27 weeks gestation and randomized into three treatment groups: a single oral dose of 200 000 IU vitamin D, a daily supplement of 800 IU vitamin D from 27 weeks until delivery and a no treatment group.
Measurements  Vitamin D (25-hydroxyvitamin D), PTH and corrected calcium levels in mothers at 27 weeks and at delivery and cord 25-hydroxyvitamin D and corrected calcium levels.
Results  The final maternal 25-hydroxyvitamin D levels were significantly higher in the supplemented group [daily dose (median) 42 (IQR 31–76) nmol/l, stat dose (median) 34 (IQR 30–46) nmol/l vs. median 27 (IQR 27–39) nmol/l in the no treatment; P  < 0·0001] and significantly fewer women with secondary hyperparathyroidism in the supplemented group (10% in daily dose vs. 12% in stat dose vs. 27% in the no treatment; P  < 0·05). Cord 25-hydroxyvitamin D levels were significantly higher with supplementation [daily dose median 26 (IQR 17–45) nmol/l, stat dose median 25 (IQR 18–34) nmol/l vs. median 17 (IQR 14–22) nmol/l in no treatment; P  = 0·001].
Conclusion  Single or daily dose improved 25-hydroxyvitamin D levels significantly. However, even with supplementation, only a small percentage of women and babies were vitamin D sufficient. Further research is required to determine the optimal timing and dosing of vitamin D in pregnancy.     

Streptozotocin diabetes in the pregnant rat induces cardiovascular dysfunction in adult offspring

Summary Severe diabetes in pregnant rats produces persistent metabolic consequences in adult offspring. This study investigated whether diabetes in pregnant rats could also lead to cardiovascular abnormalities in the adult offspring. Blood pressure, heart rate and in vitro vascular reactivity of small arteries were evaluated in female adult offspring of control rats and of rats rendered diabetic with streptozotocin. Rise in blood pressures were similar in both groups of offspring but heart rate was lower in the diabetic offspring (p < 0.05). The rise in blood pressure associated with infusion of a nitric oxide synthase inhibitor was similar in both groups, but the associated decrease in heart rate was more pronounced in diabetic offspring (p < 0.01). Small mesenteric arteries from this group showed enhanced sensitivity to noradrenaline (p < 0.05) and abnormal endothelium-dependent relaxation to acetylcholine (p < 0.01) and bradykinin (p < 0.05). Reduction in acetylcholine induced relaxation, reflected reduced synthesis of nitric oxide or a cyclooxygenase product and was not attributable to an endothelium-derived hyperpolarizing factor. Sensitivity to exogenous nitric oxide was normal. A subgroup of pups born to diabetic dams were suckled by control maternal dams and a subgroup of those born to controls by diabetic dams. Suckling was an important determinant of impaired growth; offspring of diabetic rats suckled by their own mother and those of control rats by diabetic dams showed impaired growth rates whereas growth of offspring of diabetic rats suckled by control dams paralleled those of control rats suckled by their own mother. [Diabetologia (1999) 42: 81–89] Received: 29 May 1998 and in final form: 28 July 1998     

Vitamin D supplementation during pregnancy and the risk of wheezing in offspring: a systematic review and dose-response meta-analysis

Background: In the past few years, growing evidence supports a preventive role of vitamin D supplementation during pregnancy for wheezing or asthma in offspring. However, the optimal dose of vitamin D intake is unclear. We conducted a meta-analysis to examine the linear and nonlinear dose-response pattern of vitamin D intake during pregnancy and asthma or wheezing in offspring. Questions/purposes: The purpose of this study was to answer the following question: Which dose of vitamin D is more effective in preventing wheezing in offspring? Method: We identified relevant studies by searching PubMed, EMBASE and CENTRAL up to December 2017 and by hand-searching reference lists. Meta-analysis and subgroup analysis were performed. Fixed or random effects model linear trends analyses were conducted based on the heterogeneity test. Then, if the data did not show linear trends, we considered a nonlinear trend analysis instead. Results: A total of 6068 participants were included in the study. Our analysis showed an inverse relationship between the intake of vitamin D during pregnancy and the occurrence of wheezing in offspring (pooled OR?=?0.68, 95% CI?=?0.55–0.83, I²?= 24%, Z statistic?=?3.64, p?<?0.01). We found a nonlinear U-shaped association between vitamin D supplementation during pregnancy and asthma or wheezing in offspring, with the lowest risk at approximately 800?IU/d. Publication bias was shown in a funnel plot without Egger’s test. Conclusions: Vitamin D intake during pregnancy is inversely related to wheezing or asthma in offspring. Furthermore, the trend analysis indicates that offspring may benefit from approximately 800?IU/d vitamin D intake during pregnancy.     

Folate treatment of pregnant rat dams abolishes metabolic effects in female offspring induced by a paternal pre-conception unhealthy diet

Aims/hypothesis

Paternal high-fat diet prior to mating programmes impaired glucose tolerance in female offspring. We examined whether the metabolic consequences in offspring could be abolished by folate treatment of either the male rats before mating or the corresponding female rats during pregnancy.

Methods

Male F0 rats were fed either control diet or high-fat, high-sucrose and high-salt diet (HFSSD), with or without folate, before mating. Male rats were mated with control-diet-fed dams. After mating, the F0 dams were fed control diet with or without folate during pregnancy.

Results

Male, but not female offspring of HFSSD-fed founders were heavier than those of control-diet-fed counterparts (p?<?0.05 and p?=?0.066 in males and females, respectively). Both male and female offspring of HFSSD-fed founders were longer compared with control (p?<?0.01 for both sexes). Folate treatment of the pregnant dams abolished the effect of the paternal diet on the offspring’s body length (p ? 0.05). Female offspring of HFSSD-fed founders developed impaired glucose tolerance, which was restored by folate treatment of the dams during pregnancy. The beta cell density per pancreatic islet was decreased in offspring of HFSSD-fed rats (?20% in male and ?15% in female F1 offspring, p ? 0.001 vs controls). Folate treatment significantly increased the beta cell density (4.3% and 3.3% after folate supplementation given to dams and founders, respectively, p ? 0.05 vs the offspring of HFSSD-fed male rats). Changes in liver connective tissue of female offspring of HFSSD-fed founders were ameliorated by treatment of dams with folate (p ? 0.01). Hepatic Ppara gene expression was upregulated in female offspring only (1.51-fold, p ? 0.05) and was restored in the female offspring by folate treatment (p ? 0.05). We observed an increase in hepatic Lcn2 and Tmcc2 expression in female offspring born to male rats exposed to an unhealthy diet during spermatogenesis before mating (p ? 0.05 vs controls). Folate treatment of the corresponding dams during pregnancy abolished this effect (p ? 0.05). Analysis of DNA methylation levels of CpG islands in the Ppara, Lcn2 and Tmcc2 promoter regions revealed that the paternal unhealthy diet induced alterations in the methylation pattern. These patterns were also affected by folate treatment. Total liver DNA methylation was increased by 1.52-fold in female offspring born to male rats on an unhealthy diet prior to mating (p ? 0.05). This effect was abolished by folate treatment during pregnancy (p ? 0.05 vs the offspring of HFSSD-fed male rats).

Conclusions/interpretation

Folate treatment of pregnant dams restores effects on female offspring’s glucose metabolism induced by pre-conception male founder HFSSD.

     

Moderate calorie restriction improves cardiac remodeling and diastolic dysfunction in the Dahl-SS rat

Caloric restriction extends longevity and reduces the onset of chronic disease in many animal models. Recently, caloric restriction was shown in humans to be associated with lower blood pressure, decreased systemic inflammation, and improved cardiac diastolic parameters. However, the causation and mechanisms of caloric restriction were obscured by the varied diet composition of the participants. The Dahl salt-sensitive rat which develops gradual, hypertension-associated diastolic dysfunction was used in this study to assess the impact of caloric restriction upon decompensated pressure-overload hypertrophy. Male Dahl salt-sensitive rats were provided either a low-salt diet or a high-salt diet to initiate heart failure progression. A further subset of high-salt rats underwent 15% calorie restriction, with salt load held constant. Parameters measured included serial systolic blood pressure, body weight, and changes of left ventricular systolic and diastolic parameters and ventricular geometry by echocardiography. After 18 weeks, fasting glucose, blood lipids, heart weight, kidney weight, lung weight, plasma interleukin-6 and TNF-alpha, and cardiac lipid peroxidation were measured. Low-salt rats did not develop heart failure. While high-salt rats displayed features of decompensated pressure-overload hypertrophy, moderate calorie restriction remarkably reduced morbidity. Compared to the high-salt fed group, the high-salt, calorie-restricted group showed reduced blood pressure, delayed onset of cachexia, lower fasting hyperlipidemia, lower cardiac, renal and lung weight, less plasma IL-6 and TNF-alpha, less cardiac oxidative damage, and improved diastolic chamber function and cardiac index. Modest calorie restriction, independent of salt intake, reduced pathogenesis in this well described model of decompensated pressure-overload hypertrophy.     

Genistein supplementation and estrogen replacement therapy improve endothelial dysfunction induced by ovariectomy in rats

BACKGROUND: We investigated the effect of genistein, a phytoestrogen derived from a soy diet with a flavonoid chemical structure, on endothelial dysfunction induced by estrogen deficiency in rats. METHODS: Female mature Sprague-Dawley rats were subjected to a bilateral ovariectomy (OVX rats). Sham-operated animals (Sham OVX rats) were used as controls. Three weeks after surgery animals were randomized to the following treatments: genistein (0.2 mg/kg/day, s.c. for 4 weeks), 17 beta-estradiol (20 micrograms/kg/day, s.c. for 4 weeks) or their respective vehicles. Mean arterial blood pressure (MAP), heart rate (HR), total plasma cholesterol, plasma estradiol, plasma genistein levels and uterine weights were studied. Furthermore, we investigated acetylcholine (ACh 10 nM-10 microM) and sodium nitroprusside: (SN 15-30 nM) induced relaxation of aortic rings as well as NG-L-arginine (L-NMA: 10-100 microM) induced vasoconstriction in phenylephrine precontracted aortic segments and calcium-dependent nitric oxide synthase (cNOS) activity in homogenates of lungs taken from both sham OVX and OVX rats. RESULTS: Untreated OVX rats had, compared with sham OVX animals, unchanged body weight, MAP, HR and plasma cholesterol. In contrast ovariectomy impaired endothelial responses, blunted L-NMA induced contraction (L-NMA 100 microM: Sham OVX = 2.1 +/- 0.2 g/mg tissue; OVX = 1.7 +/- 0.4 g/mg tissue) and reduced cNOS activity. Treatment with 17 beta-estradiol increased the hormone plasma levels, reverted the endothelial dysfunction and increased cNOS activity in lung homogenates. Genistein supplementation enhanced the circulating levels of the phytoestrogen and affected NOS activity and endothelial dysfunction to the same extent. CONCLUSIONS: Our data suggest that genistein and 17 beta-estradiol show overlapping effects on experimental endothelial dysfunction.     

Idebenone improves learning and memory impairment induced by cholinergic or serotonergic dysfunction in rats

The effects of idebenone, a cerebral metabolic enhancer, on learning and memory impairment in two rat models with central cholinergic or serotonergic dysfunction were investigated using positively reinforced learning tasks. A delayed alternation task using a T maze was employed to test the effect of idebenone on short-term memory impairment induced by a cholinergic antagonist, scopolamine. A correct response, defined as a turn toward the arm opposite to that in the forced run, was rewarded with food pellets. Scopolamine (0.2 and 0.5 mg/kg, i.p.) significantly decreased the correct responses to the chance level in the 60-s-delayed alternation task. The scopolamine (0.2 mg/kg, i.p.)-induced impairment of short-term memory was improved by idebenone (3-30 mg/kg, i.p.) or an acetylcholinesterase inhibitor, physostigmine (0.1 and 0.2 mg/kg, i.p.), administered simultaneously. The central serotonergic dysfunction model was produced by giving rats a diet deficient in tryptophan, a precursor of serotonin. The rats fed on a tryptophan-deficient diet (TDD) showed a slower learning process in the operant brightness discrimination task (mult V115 EXT) than did rats fed on a normal diet. Idebenone (60 mg/kg/day) admixed with the TDD decreased the number of lever-pressing responses emitted during the extinction periods. The percentage of correct responses was significantly higher in the idebenone-treated group than in the control TDD group. These results suggest that idebenone may improve both the impairment of short-term memory induced by a decreased cholinergic activity and the retardation of discrimination learning induced by central serotonergic dysfunction.     

Medical treatment of cardiovascular disorders during pregnancy

Medical treatment in pregnancy presents a number of problems for the physician. Does the prescribed medication pose a potential threat by having a teratogenic effect on the fetus if taken early in pregnancy? Could it cause functional disturbances during delivery if taken late in pregnancy? Could the drug interfere with the mother during the normal course of pregnancy, and cause functional disturbances during labor? There are several cardiovascular diseases to which women are prone both before and during pregnancy, the most common being systemic hypertension, rheumatic heart disease with the complications of congestive heart failure and arrhythmias, and to a lesser extent congenital heart disease, primary pulmonary hypertension, cardiomyopathies, and other conditions. The frequency and treatment of these diseases during pregnancy have been reviewed.^1–3 This report deals with the direct actions and side effects of various cardiovascular pharmacologic preparations administered during pregnancy.