Subset Of Dams Research Articles

Developmental metformin exposure does not rescue physiological impairments derived from early exposure to altered maternal metabolic state in offspring mice

ObjectiveThe incidence of gestational diabetes mellitus (GDM) and metabolic disorders during pregnancy are increasing globally. This has resulted in increased use of therapeutic interventions such as metformin to aid in glycemic control during pregnancy. Even though metformin can cross the placental barrier, its impact on offspring brain development remains poorly understood. As metformin promotes AMPK signaling, which plays a key role in axonal growth during development, we hypothesized that it may have an impact on hypothalamic signaling and the formation of neuronal projections in the hypothalamus, the key regulator of energy homeostasis. We further hypothesized that this is dependent on the metabolic and nutritional status of the mother at the time of metformin intervention. Using mouse models of maternal overnutrition, we aimed to assess the effects of metformin exposure on offspring physiology and hypothalamic neuronal circuits during key periods of development. MethodsFemale C57BL/6N mice received either a control diet or a high-fat diet (HFD) during pregnancy and lactation periods. A subset of dams was fed a HFD exclusively during the lactation. Anti-diabetic treatments were given during the first postnatal weeks. Body weights of male and female offspring were monitored daily until weaning. Circulating metabolic factors and molecular changes in the hypothalamus were assessed at postnatal day 16 using ELISA and Western Blot, respectively. Hypothalamic innervation was assessed by immunostaining at postnatal days 16 and 21. ResultsWe identified alterations in weight gain and circulating hormones in male and female offspring induced by anti-diabetic treatment during the early postnatal period, which were critically dependent on the maternal metabolic state. Furthermore, hypothalamic agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neuronal innervation outcomes in response to anti-diabetic treatment were also modulated by maternal metabolic state. We also identified sex-specific changes in hypothalamic AMPK signaling in response to metformin exposure. ConclusionWe demonstrate a unique interaction between anti-diabetic treatment and maternal metabolic state, resulting in sex-specific effects on offspring brain development and physiological outcomes. Overall, based on our findings, no positive effect of metformin intervention was observed in the offspring, despite ameliorating effects on maternal metabolic outcomes. In fact, the metabolic state of the mother drives the most dramatic differences in offspring physiology and metformin had no rescuing effect. Our results therefore highlight the need for a deeper understanding of how maternal metabolic state (excessive weight gain versus stable weight during GDM treatment) affects the developing offspring. Further, these results emphasize that the interventions to treat alterations in maternal metabolism during pregnancy need to be reassessed from the perspective of the offspring physiology.

Developmental Exposure to Flame Retardant Toxicants (PBDEs) Produces Autistic-Like Reprogramming of Behavior and Hypothalamic Oxytocin in a Thyroid- and Sex-Dependent Manner

Introduction: The prevalence of psychosocial neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) is rising at an alarming rate. ASD etiology is multifactorial, resulting from sex-specific genetic susceptibilities that may interact with environmental toxicant exposures during critical developmental periods. In humans, PBDEs are thyroid-disrupting chemicals associated with altered socioemotional behavior, decreased IQ and hyperactivity. We have previously demonstrated autistic-like effects produced by perinatal exposure to PBDEs in female mice (Kozlova et al, 2022; PMID: 34687351). Maternal thyroid hormone (TH) status affects fetal brain development and has been linked to ASD. Since thyroid hormones regulate oxytocin (OXT) and/or vasopressin neuroendocrine systems critical for social behavior, PBDEs may produce autistic-like actions via disruption of the thyroid system. Therefore, this study tested the hypothesis that developmental exposure to PBDEs produce neurobehavioral and hypothalamic OXT deficits in a TH-dependent manner. Materials and Methods: C57BL/6N dams were exposed human relevant doses of the penta-PBDE mixture, DE-71, at 0.1 mg/kg/d (L-DE-71), 0.4 mg/kg/d (H-DE-71) or with corn oil vehicle control (VEH/CON) for 10 wks (pre-conception: 4 wk, gestation: 3 wk, lactation: 3 wk). A subset of dams was treated with levothyroxine, a synthetic analogue of thyroxine (T4) (8 μg/100 g bw; GD 12-PND 21). Other dams were administered the thyroid synthesis inhibitor, 6-propyl-2-thiouracil (PTU; 50 mg/L; GD 14-PND 21). Results: Compared to VEH/CON, T4 and insulin-like growth factor-1 were attenuated in L-DE-71 dams at PND 0 but normalized in L-DE-71 + T4. In contrast, dam plasma OXT was not altered by DE-71 and elevated by T4 supplementation. L-DE-71 adult male and female offspring showed deficient social novelty preference; maternal T4 supplementation prevented this only in females. In contrast, T4 supplementation was equally effective at normalizing exaggerated repetitive behavior in L-DE-71 male and female offspring. DE-71 reduced OXT immunofluorescence IOD in the paraventricular nucleus of the hypothalamus (PVH) in male (L- and H-DE-71) and female offspring (L-DE-71) and in supraoptic nucleus (SON) in male offspring (L-DE-71) at PND 30. T4 supplementation normalized OXT content in L-DE-71 female and H-DE-71 male PVH. DE-71 had no effect on plasma OXT but was upregulated in VEH/CON +T4 female and DE-71+T4 male offspring. RT-qPCR analysis performed at PND15-30 showed that L-DE-71 downregulated hypothalamic Trh and cortical Oatp1c1 and Dio3 in females and upregulated hypothalamic Dio2, Esr1 and Esr2 and cortical Oatp1c1 in males. PTU’s actions do not exactly mimic those of DE-71. Conclusions: These results suggest that PBDEs disrupt social behavior and central OXT in a TH-dependent and sex-dependent manner. We provide novel information about possible TH-responsive genes that may contribute to neurodevelopmental disorders such as ASD. This work is supported by a Society of Toxicology Syngenta Fellowship Award in Human Health Applications of New Technologies and University of California President's Pre-Professoriate Fellowship to E.V.K. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of prenatal and postnatal melatonin supplementation on overall performance, male reproductive performance, and testicular hemodynamics in beef cattle.

Melatonin has been documented to alleviate compromised pregnancies and enhance livestock performance traits. The objective of this study was to determine the effect of prenatal and postnatal melatonin supplementation on overall calf performance and dam milking traits in relation to calves, molecular factors involved in growth and metabolism of calves, along with testicular physiology and fertility traits in subsequent bulls. At day 190, 220 and 250 of gestation, dams (n = 60) were administered either 2 subdermal ear melatonin implants (preMEL) or no implants (preCON). After parturition, birth weights were recorded and calves were blocked based on prenatal treatment and sex. Calves received either melatonin implants (posMEL) or none (posCON) on day 0, 30, and 60 of age. At day 60 of lactation, a subset of dams (n= 32) were selected based on age, weight and calf sex for milk collection and analysis. At weaning, (day 210 postnatally) calf weight, morphometric data, liver samples, and loin samples were collected. At 12 months of age, bull (n = 30) scrotal circumference, scrotal temperature, and testicular artery measurements were recorded. Milk yield and fat percent from dams tended to decrease in the preMEL group (P < 0.07) compared with preCON group. Prenatal melatonin administration did not affect (P = 0.95) calf birth weight and similarly calf weaning weight was unaffected (P < 0.10) by prenatal or postnatal melatonin supplementation. Blood analysis demonstrated that plasma concentrations of melatonin were not different (P = 0.12) in dams; however, an increase (P < 0.001) in plasma concentrations of melatonin was observed in posMEL versus posCON calves. A tendency (P < 0.10) for decreased MYF5 and MYOD1 expression in loin muscle was observed in the posMEL calves. Prenatal and postnatal melatonin administration did not affect subsequent bull scrotal measurements or testicular hemodynamics (P ≥ 0.14). Administering supplemental melatonin via implants during the prenatal and postnatal phase did not alter performance characteristics in offspring. In this study, dams were implanted in winter months, whereas calves were implanted in the spring months. Seasonal differences involving photoperiod and ambient temperature might have attributed to a lack of differences in melatonin levels during the prenatal phase. In the postnatal period, the level of developmental plasticity appears to be too low for melatonin properties to be effective.

Toxicity of oxidized fish oil in pregnancy: a dose-response study in rats.

Fish oil (FO) supplements are consumed during pregnancy to increase dietary omega-3. However, FO is often oxidized past recommended limits. In rats, a large dose of highly oxidized FO substantially increased newborn mortality, but the effects of human-relevant doses of less oxidized oil are unknown. A dose-response study in rats was conducted to estimate the safe level of oxidation during pregnancy. Sprague-Dawley rat dams were mated, then individually housed and provided with a gel treatment on each day of pregnancy. Treatment groups differed only in the FO content of the gel; control (no oil), PV5, PV10, and PV40 [0.05 mL of FO oxidized to a peroxide value (PV) of 5, 10, or 40 meq/kg], or PV40(1 mL) (1 mL of PV40). A subset of dams was culled on gestational day 20 to enable sampling, and the remainder were allowed to give birth. Newborn mortality was recorded. Offspring were sampled on postnatal days 2 and 21, and dams on day 21. There were no signs of unwellness during pregnancy. However, there was markedly increased neonatal mortality affecting the PV40(1 mL) (12.8%) and PV40 (6.3%) groups, but not the control, PV5, or PV10 groups (1%-1.4%). Dietary-oxidized FO altered the expression of placental genes involved in antioxidant pathways and the production of free radicals. Highly oxidized FO was toxic in rat pregnancy leading to a marked increase in mortality even at a human-relevant dose. We observed no toxic effects of FOs with PV ≤10 meq/kg, suggesting that this is an appropriate maximum limit.

Lactational High Fat Diet in Mice Causes Insulin Resistance and NAFLD in Male Offspring Which Is Partially Rescued by Maternal Metformin Treatment.

Maternal metabolic disease and diet during pregnancy and lactation have important implications for the programming of offspring metabolic disease. In addition, high-fat diets during pregnancy and lactation can predispose the offspring to non-alcoholic fatty liver disease (NAFLD), a rising health threat in the U.S. We developed a model of maternal high-fat feeding exclusively during the lactation period. We previously showed that offspring from dams, given lactational high-fat diet (HFD), are predisposed to obesity, glucose intolerance, and inflammation. In separate experiments, we also showed that lactational metformin treatment can decrease offspring metabolic risk. The purpose of these studies was to understand the programming implications of lactational HFD on offspring metabolic liver disease risk. Dams were fed a 60% lard-based HFD from the day of delivery through the 21-day lactation period. A subset of dams was also given metformin as a co-treatment. Starting at weaning, the offspring were fed normal fat diet until 3 months of age; at which point, a subset was challenged with an additional HFD stressor. Lactational HFD led male offspring to develop hepatic insulin resistance. The post-weaning HFD challenge led male offspring to progress to NAFLD with more severe outcomes in the lactational HFD-challenged offspring. Co-administration of metformin to lactating dams on HFD partially rescued the offspring liver metabolic defects in males. Lactational HFD or post-weaning HFD had no impact on female offspring who maintained a normal insulin sensitivity and liver phenotype. These findings indicate that HFD, during the lactation period, programs the adult offspring to NAFLD risk in a sexually dimorphic manner. In addition, early life intervention with metformin via maternal exposure may prevent some of the liver programming caused by maternal HFD.

L-Citrulline supplementation during pregnancy improves perinatal and postpartum maternal vascular function in a mouse model of preeclampsia.

Preeclampsia is a spontaneously occurring pregnancy complication diagnosed by new-onset hypertension and end-organ dysfunction with or without proteinuria. This pregnancy-specific syndrome contributes to maternal morbidity and mortality and can have detrimental effects on fetal outcomes. Preeclampsia is also linked to increased risk of maternal cardiovascular disease throughout life. Despite intense investigation of this disorder, few treatment options are available. The aim of this study was to investigate the potential therapeutic effects of maternal l-citrulline supplementation on pregnancy-specific vascular dysfunction in the male C57BL/6J × female C57BL/6J C1q-/- preeclampsia-like mouse model. l-Citrulline is a nonessential amino acid that is converted to l-arginine to promote smooth muscle and blood vessel relaxation and improve nitric oxide (NO)-mediated vascular function. To model a preeclampsia-like pregnancy, female C57BL/6J mice were mated to C1q-/- male mice, and a subset of dams was supplemented with l-citrulline throughout pregnancy. Blood pressure, systemic vascular glycocalyx, and ex vivo vascular function were investigated in late pregnancy, and postpartum at 6 and 10 mo of age. Main findings show that l-citrulline reduced blood pressure, increased vascular glycocalyx volume, and rescued ex-vivo vascular function at gestation day 17.5 in this preeclampsia-like model. The vascular benefit of l-citrulline also extended postpartum, with improved vascular function and glycocalyx measures at 6 and 10 mo of age. l-Citrulline-mediated vascular improvements appear, in part, attributable to NO pathway signaling. Taken together, l-citrulline supplementation during pregnancy appears to have beneficial effects on maternal vascular health, which may have translational implications for improved maternal cardiovascular health.

The Effect of Melatonin Supplementation on Dam Milking Traits and Calf Performance in Beef Cattle

Abstract Melatonin has been documented to alleviate compromised pregnancies and enhance livestock performance traits. The objective of this study was to determine the effect of melatonin supplementation on milking traits in beef cattle dams and subsequent influence on calf performance. Cows (n = 60) were blocked based on embryo transfer donor and sire, potential calf breed and embryo grade. At d190, 220 and 250 of gestation, dams were administered either 2 subdermal ear melatonin implants (preMEL) or no implants (preCON). After parturition, birth weights were recorded and calves randomly received either melatonin implants (posMEL) or none (posCON) on approximately d 0, 30, and 60. At approximately d 60 of lactation, a subset of dams (n = 32) were selected based on age, weight and calf sex for milk collection and analysis. At weaning, calf weight and morphometric data were collected and adjusted according to weaning age. Prenatal melatonin administration did not change calf birth weight (P = 0.956). Milk yield tended to decrease in the preMEL group (P = 0.054) at 2.368 kg ± 0.11 compared to preCON at 2.054 kg ± 0.11. Milk fat percent tended to decrease (P = 0.07) in preMEL at 3.25 ± 0.19 versus preCON at 3.92 ± 0.19. There were no differences in prenatal treatment in respect to milk protein, lactose, solid non-fats, somatic cell count, and urea nitrogen (P &amp;gt; 0.16). At weaning, calf head circumference decreased (P &amp;lt; 0.031) in the preMEL group at 77.92cm ± 0.42 versus preCON at 79.31cm ± 0.45. Otherwise, there were no prenatal or postnatal treatment differences in respect to weaning weight, crown-rump length, hip height and head length (P &amp;gt; 0.12). Previous studies show crown-to-rump length and ponderal index differences. Our lack of differences might be attributed to geographical locations that impact day length or endogenous melatonin status.

Postpartum fluoxetine increased maternal inflammatory signalling and decreased tryptophan metabolism: Clues for efficacy

Perinatal depression (PND) affects approximately 15% of women, and de novo postpartum depression affects approximately 40% of PND cases. Selective serotonin reuptake inhibitors (SSRIs) are a common class of antidepressants prescribed to treat PND. However, the safety and efficacy of SSRIs have been questioned in both clinical and preclinical research. Here, using a preclinical rodent model of de novo postpartum depression, we aim to better understand neuroinflammatory cytokines and tryptophan mechanisms that may be related to SSRI efficacy. Rat dams were treated with high corticosterone (CORT; 40 mg/kg, s.c.) for 22 days in the postpartum period to simulate a depressive-like endophenotype. Concurrently, a subset of dams was treated with the SSRI, fluoxetine (FLX; 10 mg/kg, s.c.), in the postpartum period. We showed, consistent with previous studies, that although maternal FLX treatment prevented CORT-induced disturbances in maternal care behavior during the early postpartum, it failed to prevent the expression of CORT-induced passive coping behavior in the late postpartum. Furthermore, FLX treatment, regardless of CORT treatment, increased maternal hippocampal IL-1β, plasma CXCL1, and decreased maternal plasma tryptophan, 4′-pyridoxic acid, and pyridoxal concentrations. Maternal CORT treatment reduced maternal hippocampal IFN-γ, and both hippocampal and plasma TNF-α. Our work suggests that the limited efficacy of FLX in the late postpartum may be associated with elevated levels of the proinflammatory cytokine IL-1β in the maternal hippocampus, elevated plasma CXCL1, decreased plasma tryptophan concentration, and changes in vitamin B6 dependent tryptophan-kynurenine pathway. These findings suggest novel pathways for improving SSRI efficacy in alleviating perinatal depression.

High 5MTHF, but Not Folic Acid During Pregnancy, Alters Hypothalamic Regulatory Pathways and Associates with Post-Partum Weight-Gain in Wistar Rat Mothers

Abstract Objectives 5-methyltetrahydrofolate (5MTHF), the bioactive folate form, has been proposed an alternative supplement to folic acid (FA) due to direct cellular uptake and utilization. In North America, 5MTHF is incorporated into prenatal supplements at the equivalent high dose (1000 µg) as FA and discussion has been raised of its formation into baby formula. Our lab was the first to compare the dose (1X vs high, 5X) and form (FA vs 5MTHF) effects of folate during pregnancy on later-life metabolic health of the Wistar rat mother. Contrary to our hypothesis, 5MTHF diets, independent of dose, led to mothers with 40% greater body weight-gain and higher food intake post-birth compared to FA. The objective of this study was to identify differentially expressed genes and related hypothalamic pathways of mothers fed FA vs 5MTHF diets during pregnancy. Methods Pregnant Wistar rats were fed an AIN-93 G diet with recommended (1X, control, 2 mg/kg diet) or high (5X) FA or equimolar levels of 5MTHF. At birth, a subset of dams were terminated and RNA-seq analysis was performed in the arcuate nucleus of the hypothalamus (ARC), a key regulator of body weight and food intake, in dams fed the high FA and MTHF diets. Results Over 350 differentially expressed genes were identified in the ARC of dams fed high 5MTHF vs FA diets. Combining differential gene expression patterns with reported GO function terms and Kegg pathway analyses, four candidate genes (prolactin hormone receptor, corticotropin releasing hormone receptor, KISS1 peptide and dopamine receptor) were validated by qPCR thus far as plausible contributors to higher body weight-gain and food intake in 5MTHF dams. These genes correspond to neuroactive ligand-receptor interaction pathway (path: hsa04080), associated with metabolic diseases including leptin deficiency and genetic obesity. Other significantly enriched pathways included the retrograde endocannabinoid signalling and morphine addiction pathway. Conclusions High 5MTHF supplementation during pregnancy alters expression of central feeding regulatory pathways in the hypothalamus of the mother, potentially programming post-partum body-weight gain. 5MTHF, at the equivalent dose of FA, may not be the preferred folate form during pregnancy. Funding Sources CIHR-INMD; EP supported by NSERC-CGS D.

Fetal growth outcomes following peri-implantation exposure of Long-Evans rats to noise and ozone differ by sex

BackgroundExposure to air pollution and high levels of noise have both been independently associated with the development of adverse pregnancy outcomes including low birth weight. However, exposure to such environmental stressors rarely occurs in isolation and is often co-localized, especially in large urban areas.MethodsThe purpose of this study was to compare the effects of combined exposure to noise (N) or ozone (O3), compared to either exposure alone. Long-Evans dams were exposed to air or 0.4 ppm ozone for 4 h on gestation day (GD) 5 and 6, coinciding with implantation receptivity. A subset of dams from each exposure group was further exposed to intermittent white noise (~ 85 dB) throughout the dark cycle following each inhalation exposure (n = 14 − 16/group). Uterine artery ultrasound was performed on GD 15 and 21. Fetal growth characteristics and indicators of placental nutrient status were measured at GD 21.ResultsExposure to ozone + quiet (O3 + Q) conditions reduced uterine arterial resistance at GD 15 compared to air + quiet (A + Q) exposure, with no further reduction by GD 21. By contrast, exposure to air + noise (A + N) significantly increased uterine arterial resistance at both GD 15 and 21. Notably, while peri-implantation exposure to O3 + Q conditions reduced male fetal weight at GD 21, this effect was not observed in the air + noise (A + N) or the ozone + noise (O3 + N) exposure groups. Fetal weight in female offspring was not reduced by ozone exposure alone (O3 + Q), nor was it affected by air + noise (A + N) or by combined ozone + noise (O3 + N) exposure.ConclusionsThese data indicate that exposure to ozone and noise differentially impact uterine blood flow, particularly at mid-gestation, with only ozone exposure being associated with sex-dependent fetal growth retardation in male offspring.

Effects of maternal nutrient restriction during early or mid-gestation without realimentation on maternal physiology and foetal growth and development in beef cattle

The aim of this study is to determine the effects of early and mid-gestation nutrient restriction on maternal metabolites and foetal growth. Primiparous Angus cows were synchronized and inseminated with semen from one sire. Dietary treatments were: control to gain 1 kg/week (CON) or 0.55% maintenance energy and CP requirements (nutrient restricted; NR). A subset of dams was fed NR (n=8) or CON (n=8) from days 30 to 110 of gestation. Another group was fed CON (n=8), days 30 to 190; NR (n=7), days 30 to 110 followed by CON days 110 to 190; or CON, (n=7) days 30 to 110 followed by NR days 110 to 190. Cows were harvested at days 110 or 190 of gestation, when foetal measurements and samples were collected. Cows that were NR during days 30 to 110 or 110 to 190 of gestation lost significant BW and body condition score (P<0.001), this was associated with reduced plasma glucose during NR (P<0.002). Foetal weights, empty foetal weights, abdominal and thoracic circumferences were all reduced (P<0.03) in day 110 NR animals. Foetal perirenal adipose as a percentage of empty foetal weight was increased (P=0.01) in NR day 110 female foetuses compared with CON foetus. Maternal serum triglycerides at day 110 of gestation were decreased (P<0.05) in NR dams, whereas foetal serum triglycerides were increased (P<0.05) in response to maternal NR. Foetal weights tended to be reduced (P=0.08) in NR/CON and CON/NR v. CON/CON cattle at day 190 of gestation. Empty foetal weights, abdominal and thoracic circumferences were reduced (P⩽0.03) in NR/CON and CON/NR v. CON/CON cattle. Brain weight as a percentage of empty foetal weight was increased (P<0.001) in NR/CON and CON/NR v. CON/CON cattle. Foetal perirenal adipose as a percentage of empty foetal weight was increased (P=0.003) in NR/CON and CON/NR v. CON/CON cattle. Maternal serum triglycerides at day 190 of gestation were decreased (P<0.05) in association with maternal NR. Foetal serum triglycerides at day 190 of gestation were increased (P<0.05) in response to maternal NR during early gestation but decreased by NR in mid gestation compared with CON foetuses. The data show that maternal nutrient restriction during early or mid-gestation cause’s asymmetrical foetal growth restriction, regardless if the restriction is preceded or followed by a period of non-restriction.

The effect of farrowing induction on colostrum and piglet serum immunocrits is dependent on parity.

Farrowing induction is a common practice among swine producers to manage timing of farrowing and the labor associated with farrowing. In this experiment, the effect of induction of labor using cloprostenol on Day 114 of gestation ( = 88) was compared to our standard farrowing protocol at USMARC (natural farrowing with induction using cloprostenol on Day 116 if needed, = 82) in gilts and sows up to fourth parity. In a subset of dams ( = 10 each treatment), colostrum was collected within 30 min of birth of the first piglet, and at 4, 8, 12, and 24 h. Colostrum samples were measured for immunoglobulin G (IgG) using the immunoglobulin immunocrit and porcine IgG specific ELISA, and for total protein. Blood samples were collected from each live piglet on d 1 of age and measured using the immunocrit assay, and average immunocrit was calculated for each litter. Total piglets born and born alive, birth and weaning weights, and the stillbirth rate and preweaning mortality rate were also recorded for each litter. Results indicated that induction of farrowing by cloprostenol treatment on d 114 reduced average gestation length by 0.5 to 1 d depending on parity ( < 0.05), and reduced overall colostrum immunocrit, IgG and total protein ( < 0.05). Colostrum immunocrits and IgG concentrations were well correlated ( = 0.89; < 0.01) but IgG was curvilinearly related to total protein. Litter average immunocrits were similar in gilts between treatments, but were reduced in later parity sows induced to farrow using cloprostenol on d 114 of gestation. Total born, born alive, birth and weaning weights, and stillbirth and preweaning mortality rates were unaffected by treatments. In conclusion, induction of farrowing using cloprostenol injection on d 114 reduced colostrum IgG concentrations in dams, but this was reflected in a reduction in litter average immunocrit only in later parity sows. This reduction in litter average immunocrit was not sufficient to influence preweaning mortality, but other effects are possible given the reported influence of colostrum on growth and reproductive traits.

Reproductive and developmental outcomes, and influence on maternal and offspring tissue mineral concentrations, of (−)-epicatechin, (+)-catechin, and rutin ingestion prior to, and during pregnancy and lactation in C57BL/6J mice

Maternal nutrition can have a significant effect on developmental processes during pregnancy and lactation. While certain flavonoids have been postulated to be beneficial for health, little is known about the effects of ingestion during pregnancy and lactation on the mother and progeny. We report on the effects of maternal consumption of high levels of certain flavonoids on reproductive and developmental outcomes in a mouse model. C57BL/6J female mice were fed a control diet (CT), the CT diet supplemented with 1% or 2% of a mix of epicatechin and catechin (EC1, EC2), or rutin (RU1, RU2) prior to, during pregnancy, and lactation. A subset of dams was killed on gestation day (GD) 18.5 to evaluate fetal outcomes and the remainder was allowed to deliver to evaluate offspring. Maternal food intake, body and tissue weight did not differ among groups. The number of resorptions, implantations, litter size, postnatal survival, body weight, and skeletal development were also similar. Alterations in maternal and offspring liver mineral concentrations were observed. The current results indicate that consumption of high amounts of epicatechin, catechin, and rutin during gestation and lactation is not associated with any marked developmental effects, although changes in liver mineral concentrations were noted.

Adverse Fetal and Neonatal Outcomes Associated with a Life-Long High Fat Diet: Role of Altered Development of the Placental Vasculature

Maternal obesity results in a number of obstetrical and fetal complications with both immediate and long-term consequences. The increased prevalence of obesity has resulted in increasing numbers of women of reproductive age in this high-risk group. Since many of these obese women have been subjected to hypercaloric diets from early childhood we have developed a rodent model of life-long maternal obesity to more clearly understand the mechanisms that contribute to adverse pregnancy outcomes in obese women. Female Sprague Dawley rats were fed a control diet (CON - 16% of calories from fat) or high fat diet (HF - 45% of calories from fat) from 3 to 19 weeks of age. Prior to pregnancy HF-fed dams exhibited significant increases in body fat, serum leptin and triglycerides. A subset of dams was sacrificed at gestational day 15 to evaluate fetal and placental development. The remaining animals were allowed to deliver normally. HF-fed dams exhibited a more than 3-fold increase in fetal death and decreased neonatal survival. These outcomes were associated with altered vascular development in the placenta, as well as increased hypoxia in the labyrinth. We propose that the altered placental vasculature may result in reduced oxygenation of the fetal tissues contributing to premature demise and poor neonatal survival.