Neuropeptides as neuroprotective agents: Oxytocin a forefront developmental player in the mammalian brain.

Oxytocin (OT) plays a major role in the establishment of social bonds. Social bonds are linked to the activation of cell signaling pathways that promote neurotrophic and synaptic maturation, plasticity and memory changes. Anti-social behavior is often associated with abnormalities of cell signaling pathways and/or defective function of brain neurotransmitters within behavioral CNS circuits due to unproper environmental and social factors, such as, diet, stress, chemical, air pollution, and noise, during gestational period or/and during early postnatal development. OT exerts an important regulatory functions in maternity and parental behaviors, lactation, attachment, bonding, trust, and sensorial functions such as: homeostatic cardiovascular control, satiety, touch, pain, analgesia and sexual behavior. Noteworthy, OT displays important neuroprotective properties against fetal programmed hypertension when administered during early postnatal life, added to its known anabolic properties shown in adult rats, e.g. body weight control, reduces blood pressure, and increases analgesia. This review focuses on the new evidences supporting OT's role as a major neuroprotective nonapeptide provided by its quality to reverse hypertension programmed in utero by undernutrition.

Maternal beef and postweaning herring diets increase bone mineral density and strength in mouse offspring.

The maternal diet during gestation and lactation affects the long-term health of the offspring. We sought to determine whether maternal and postweaning crossover isocaloric diets based on fish or meat affect the geometry, mineral density, and biomechanical properties of bone in mouse offspring in adulthood. During gestation and lactation, C57BL/6 dams were fed a herring- or beef-based diet. After weaning, half of the pups in each group were fed the same diet as their dams, and half were fed the other diet. Areal bone mineral density (aBMD) and bone mineral content (BMC) of the whole body and lumbar spine were measured in the offspring by dual X-ray absorptiometry at 9 and 21 weeks of age. At 22-26 weeks, tibia bone geometry (length, cortical volumetric (v) BMD, BMC, area and thickness) was analyzed by peripheral quantitative computed tomography, and the biomechanical properties of the tibia were analyzed by the three-point bending test. Plasma insulin-like growth factor-1 was analyzed at 12 weeks. In comparison to the maternal herring diet, the maternal beef diet increased aBMD and BMC in the whole body and lumbar spine of adult offspring, as well as cortical vBMD, BMC, bone area, and thickness at the mid-diaphyseal region of the tibia and the biomechanical properties of tibia strength. In contrast, a postweaning beef diet decreased aBMD in the lumbar spine and BMC in the whole body and lumbar spine compared with a postweaning herring diet, which instead increased plasma insulin-like growth factor-1 levels. The change from a maternal beef diet before weaning to a herring diet after weaning decreased body weight and increased the cortical area, vBMD, BMC, thickness, and strength of the tibia. These significant crossover effects indicate that a preweaning maternal beef diet and a postweaning herring diet are optimal for increasing BMC and bone strength in offspring in adulthood.

Determinants of vitamin D status in fair-skinned women of childbearing age at northern latitudes.

BACKGROUND AND OBJECTIVE: Poor vitamin D status during pregnancy has been associated with unfavorable outcomes for mother and child. Thus, adequate vitamin D status in women of childbearing age may be important. The aim of this study is to investigate the determinants of 25-hydroxyvitamin D (25(OH)D) serum concentrations in women of childbearing age living in Sweden, at latitude 57-58° north. METHOD: Eighty four non-pregnant, non-lactating, healthy, fair-skinned women aged between 25-40 years were included. All subjects provided blood samples, four day food records and answered questionnaires about sun exposure and lifestyle. Total serum 25(OH)D was analyzed using Roche Cobas® electrochemoluminiescent immunoassay. RESULTS: Mean 25(OH)D was 65.8±19.9 nmol/l and 23% of the subjects had concentrations <50 nmol/l. Only 1% had concentrations <25 nmol/l. Determinants of 25(OH)D concentrations were recent sunbed use, recent travel to southern latitude, season, estrogen contraceptive use and use of supplementary vitamin D (R(2) = 0.27). CONCLUSION: Every fifth woman had 25(OH)D concentrations <50 nmol/l. About 30% of the variation in vitamin D status was explained by sun exposure, use of vitamin D supplements and use of estrogen contraceptives. Cutaneous vitamin D synthesis seems to be a major contributor to vitamin D status, even at northern latitudes. Thus, recommendations on safe UV-B exposure could be beneficial for vitamin D status.

Determinants of vitamin D status in pregnant fair-skinned women in Sweden.

Low maternal vitamin D status during pregnancy may have negative consequences for both mother and child. There are few studies of vitamin D status and its determinants in pregnant women living at northern latitudes. Thus, the present study investigates vitamin D status and its determinants during the third trimester of women living in Sweden (latitudes 57-58°N). A total of ninety-five fair-skinned pregnant women had blood taken between gestational weeks 35 and 37. The study included a 4 d food diary and questionnaires on dietary intake, supplement use, sun exposure, skin type, travels to southern latitudes and measure of BMI. Serum 25-hydroxyvitamin D (25(OH)D) was analysed using the chemiluminescence immunoassay. In the third trimester of pregnancy, mean serum concentration of 25(OH)D was 47.4 (sd 18.1) nmol/l (range 10-93 nmol/l). In total, 65% of women had serum 25(OH)D < 50 nmol/l and 17 % < 30 nmol/l. During the winter, 85% of the pregnant women had serum 25(OH)D < 50 nmol/l and 28 % < 30 nmol/l. The main determinants of vitamin D status were as follows: season; use of vitamin D supplements; travels to southern latitudes. Together, these explained 51% of the variation in 25(OH)D. In conclusion, during the winter, the majority of fair-skinned pregnant women had serum 25(OH)D < 50 nmol/l in their third trimester and more than every fourth woman < 30 nmol/l. Higher vitamin D intake may therefore be needed during the winter for fair-skinned pregnant women at northern latitudes to avoid vitamin D deficiency.

Calcium economy in human pregnancy and lactation.

Pregnancy and lactation are times of additional demand for Ca. Ca is transferred across the placenta for fetal skeletal mineralisation, and supplied to the mammary gland for secretion into breast milk. In theory, these additional maternal requirements could be met through mobilisation of Ca from the skeleton, increased intestinal Ca absorption efficiency, enhanced renal Ca retention or greater dietary Ca intake. The extent to which any or all of these apply, the underpinning biological mechanisms and the possible consequences for maternal and infant bone health in the short and long term are the focus of the present review. The complexities in the methodological aspects of interpreting the literature in this area are highlighted and the inter-individual variation in the response to pregnancy and lactation is reviewed. In summary, human pregnancy and lactation are associated with changes in Ca and bone metabolism that support the transfer of Ca between mother and child. The changes generally appear to be independent of maternal Ca supply in populations where Ca intakes are close to current recommendations. Evidence suggests that the processes are physiological in humans and that they provide sufficient Ca for fetal growth and breast-milk production, without relying on an increase in dietary Ca intake or compromising long-term maternal bone health. Further research is needed to determine the limitations of the maternal response to the Ca demands of pregnancy and lactation, especially among mothers with marginal and low dietary Ca intake, and to define vitamin D adequacy for reproductive women.

Maternal serum concentrations of insulin-like growth factor (IGF)-I and IGF binding protein-1 before and during pregnancy in relation to maternal body weight and composition and infant birth weight.

Maternal nutritional status, e.g. body weight and composition, is associated with fetal growth. It has been suggested that the insulin-like growth factor (IGF) system may be a mediator of this relationship. In twenty-three healthy Swedish women, we studied (1) the relationships before and during pregnancy between maternal serum concentrations of IGF-I and IGF binding protein-1 (IGFBP-1) and maternal body weight and composition; (2) interactions between serum concentrations of IGF-I (before and in early pregnancy) and maternal nutritional status in relation to infant birth weight. We found that serum IGF-I during pregnancy was positively correlated with maternal body weight (r 0.47-0.56) and fat-free body weight (r 0.61-0.65), whereas serum IGFBP-1 was negatively correlated with maternal body weight (r - 0.44 to - 0.69) and body fat (r - 0.64 to - 0.76) before and during pregnancy. Women with a lower body fat content (%) before pregnancy had greater increases in serum IGFBP-1 during pregnancy than women with a higher prepregnant body fat content (%). In addition, significant fractions of the variation in corrected infant birth weight were explained by variables related to the maternal nutritional status when these were combined with serum concentrations of IGF-I in gestational week 14 (adjusted r2 0.25-0.44, P = 0.001-0.021), but not when they were combined with such concentrations before pregnancy (adjusted r2 0.11-0.12, P = 0.105-0.121). These results suggest mechanisms by which the IGF system may be a mediator between maternal nutritional status and fetal growth.

Body fat, insulin resistance, energy expenditure and serum concentrations of leptin, adiponectin and resistin before, during and after pregnancy in healthy Swedish women.

Healthy human pregnancy is associated with changes in food intake, body fatness, energy expenditure and insulin resistance. However, available knowledge is limited regarding the physiological basis of these changes. Published evidence suggests that so-called adipokines (i.e. leptin, adiponectin and resistin) have significant roles when such changes are established. We explored, throughout a complete pregnancy, relationships between total body fat (TBF), energy expenditure, insulin resistance (homeostasic model of insulin resistance, HOMA-IR) and serum concentrations of leptin, adiponectin and resistin. Such concentrations were assessed before pregnancy in gestational weeks 8, 14, 20, 32 and 35, and 2 weeks postpartum in twenty-three healthy women. TBF, BMR (n 23) and HOMA-IR (n 17) were assessed before pregnancy in gestational weeks 14 and 32 and 2 weeks postpartum. TBF (%) was correlated with HOMA-IR (r 0.68-0.79, P < 0.01) and with serum leptin (r 0.85-0.88, P < 0.001) before and during pregnancy. Serum leptin was correlated with HOMA-IR (r 0.53-0.70, P < 0.05) before and during pregnancy. Serum adiponectin was inversely correlated with HOMA-IR in gestational week 32 (r - 0.52, P < 0.05). When HOMA-IR was regressed on TBF (%), the slope of the regression line was 0.046 before pregnancy, which was significantly (P < 0.05) different from the corresponding value, 0.111, in gestational week 32. The results indicate that pregnancy has an enhancing effect on the relationship between body fatness and insulin resistance. This effect, possibly mediated by leptin, may represent a mechanism by which offspring size is regulated in response to the nutritional situation of the mother.

Changes in bone mineral status and bone size during pregnancy and the influences of body weight and calcium intake.

BACKGROUND: Calcium may be mobilized from the maternal skeleton during pregnancy, which may be influenced by several factors. OBJECTIVE: The objective was to investigate changes in bone mineral status and size during pregnancy and to consider the influences of body weight and calcium intake. DESIGN: Thirty-four British women were studied before pregnancy and 2 wk postpartum (Preg). Eighty-four nonpregnant, nonlactating (NPNL) women were studied over a corresponding time. Bone mineral content (BMC), bone area (BA), areal bone mineral density (aBMD), and BA-adjusted BMC of the whole-body, lumbar spine, radius, and hip were measured by dual-energy X-ray absorptiometry. RESULTS: The Preg group experienced significant decreases in BMC, aBMD, and BA-adjusted BMC at the whole-body, spine, and total hip of between 1% and 4%. Whole-body BMC increased in the NPNL group, and aBMD and BA-adjusted BMC decreased at the spine and hip by 0.5% to 1%. Whole-body BMC decreased in the Preg group by -2.16 +/- 0.46%, equivalent to -2.71 +/- 0.43% relative to the NPNL group (P < or = 0.001). Weight change was a positive predictor of skeletal change at the spine, hip, and radius in both groups. Differences between the Preg and NPNL groups in change in BA-adjusted BMC, after correction for weight change and other influences, were as follows (P < or = 0.01): whole-body, -1.70 +/- 0.25%; spine, -3.03 +/- 0.72%; and total hip, -1.87 +/- 0.60%. Calcium intake was not a significant predictor of skeletal change in either group. CONCLUSIONS: Pregnancy is associated with decreases in whole-body and regional bone mineral status sufficient to make a sizeable contribution to maternal and fetal calcium economy. Calcium intake is not a significant predictor of the skeletal response to pregnancy in well-nourished women.

A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats.

A 28-day repeated dose study in rats (OECD407) enhanced for endocrine and immune parameters was performed with hexabromocyclododecane (HBCD). Rats were exposed by daily gavage to HBCD dissolved in corn oil in 8 dose groups with doses ranging between 0 and 200 mg/kg bw per day (mkd). Evaluation consisted of dose-response analysis with calculation of a benchmark dose at the lower 95% one-sided confidence bound (BMDL) at predefined critical effect sizes (CESs) of 10-20%. The most remarkable findings were dose-related effects on the thyroid hormone axis, that is, decreased total thyroxin (TT4, BMDL 55.5 mkd at CES--10%), increased pituitary weight (29 mkd at 10%) and increased immunostaining of TSH in the pituitary, increased thyroid weight (1.6 mkd at 10%), and thyroid follicle cell activation. These effects were restricted to females. Female rats also showed increased absolute liver weights (22.9 mkd at 20%) and induction of T4-glucuronyl transferase (4.1 mkd at 10%), suggesting that aberrant metabolization of T4 triggers feedback activation of the thyroid hormone system. These effects were accompanied by possibly secondary effects, including increased cholesterol (7.4 mkd at 10%), increased tibial bone mineral density (> 49 mkd at 10%), both in females, and decreased splenocyte counts (0.3-6.3 mkd at 20%; only evaluated in males). Overall, female rats appeared to be more sensitive to HBCD than male rats, and an overall BMDL is proposed at 1.6 mkd, based on a 10% increase of the thyroid weight, which was the most sensitive parameter in the sequence of events.

Maternal body composition in relation to infant birth weight and subcutaneous adipose tissue.

Infant birth weight has increased recently, representing an obstetric and potentially a public health problem since high birth weight involves a risk of obesity later in life. Maternal nutritional status is important for fetal growth and therefore relationships between maternal body weight and composition v. birth weight and infant subcutaneous adipose tissue were investigated in twenty-three healthy women and their newborn infants using multiple and simple linear regression analysis. Furthermore, using previously published data for nineteen infants, it was demonstrated that an anthropometric method could provide useful estimates of the amount of subcutaneous adipose tissue. Birth weight was correlated with the maternal content of total body fat (TBF) both before pregnancy and in gestational week 32 and, together with gestational age at birth, TBF (%) before pregnancy explained 45% of the variation in birth weight. This figure was not increased when gestational gains in weight or TBF were added to the model. Furthermore, in infants, birth weight correlated with the amount of their subcutaneous adipose tissue. Together maternal TBF (%) and amount of subcutaneous adipose tissue in infants explained 61-63% of the variation in birth weight while the amount of infant subcutaneous adipose tissue alone explained only 55%. The maternal TBF content is likely to be important for the recent increase in birth weight. This factor probably causes a general augmentation in fetal growth rather than a specific stimulation of adipose tissue growth.

Changes in basal metabolic rate during pregnancy in relation to changes in body weight and composition, cardiac output, insulin-like growth factor I, and thyroid hormones and in relation to fetal growth.

BACKGROUND: The total energy cost of pregnancy is largely due to an elevated basal metabolic rate (BMR). Large variations in the BMR response to pregnancy have been reported, but the factors associated with this variability are incompletely known. OBJECTIVE: The objective was to identify factors associated with variability in the BMR response to pregnancy. DESIGN: In 22 healthy women, BMR, body weight (BW), total body fat (TBF), fat-free mass (FFM), circulatory variables, serum concentrations of insulin-like growth factor I (IGF-I), and thyroid hormones were measured before pregnancy and in gestational weeks 14 and 32. BMR and BW were also measured in gestational weeks 8, 20, and 35. Fetal weight was estimated in gestational week 31. RESULTS: In gestational week 14, the increase in BMR correlated significantly with the corresponding increase in BW and with the prepregnancy percentage of TBF. Together these variables explained approximately 40% of the variability in the BMR response. In gestational week 32, the increase in BMR correlated significantly with the corresponding changes in BW, TBF, FFM, IGF-I, cardiac output, and free triiodothyronine. The increase in BW in combination with fetal weight or with the elevated concentration of IGF-I in serum explained approximately 60% of the variability in the increase in BMR. CONCLUSIONS: Weight gain and the prepregnancy percentage of TBF-ie, factors related to the maternal nutritional situation-are important factors with regard to the variability in the BMR response to pregnancy. Thus, it is important to consider the nutritional situation before and during gestation when assessing pregnancy energy requirements.

Postnatal oxytocin alleviates adverse effects in adult rat offspring caused by maternal malnutrition.

Repeated oxytocin administration to adult rats causes a long-term decrease of plasma levels of corticosterone and blood pressure and stimulates growth and fat retention. Maternal undernutrition increases blood pressure and plasma corticosterone in adult offspring. We hypothesized that oxytocin treatment early in life would alleviate adverse effects of intrauterine food restriction. Male pups from ad libitum-fed and food-restricted (fed 60% of ad libitum intake) dams were injected with oxytocin or saline in days 1-14 after birth. At 4 mo, blood pressure, plasma levels of corticosterone, and adiposity were assessed. Oxytocin treatment decreased blood pressure independently of nutrition, whereas the increased plasma levels of corticosterone were lowered to normal levels in food-restricted offspring. Blood pressure and adiposity were not affected by in utero food restriction, whereas birth and adult weight were. In conclusion, postnatal events may alleviate adverse effects caused by in utero food restriction. In contrast to more severe food restriction, a moderate general food restriction during gestation had no effect on blood pressure in the offspring.

Oxytocin treatment during early life influences reproductive performance in ad libitum fed and food-restricted female rats.

Oxytocin treatment may permanently alter endocrine axes resulting in anti-stress and anabolic effects. However, the nutritional status influences the effects of oxytocin. The specific aims of this study were to investigate the effects of postnatal oxytocin treatment on reproductive performance in adult life, by studying maternal weight gain, adiposity, plasma levels of IGF-I as well as fetal and placental weights in the following groups of animals: (1) Ad libitum fed dams coming from ad libitum fed mothers. (2) Ad libitum fed dams coming from food-restricted mothers. (3) Food-restricted dams coming from ad libitum fed mothers. (4) Food-restricted dams coming from food-restricted mothers. Oxytocin treatment postnatally had long-term effects and increased adiposity in pregnant dams and stimulated placental and fetal growth relative to saline-treated dams. However, if the dams themselves had been exposed to food restriction during fetal life, the effect of postnatal oxytocin treatment changed. The oxytocin-treated mothers were still fatter but had smaller fetuses. In conclusion, postnatal oxytocin treatment influences reproductive performance in later life but is dependent on the mother's previous and current nutritional experience.