Associations between Maternal Iron Supplementation in Pregnancy and Changes in Offspring Size at Birth Reflect Those of Multiple Micronutrient Supplementation.

It was previously observed that in a population of a high-income country, dietary multiple micronutrient supplementation in pregnancy was associated with an increased risk of gestational diabetes (GDM) and increased offspring size at birth. In this follow-up study, we investigated whether similar changes are observed with dietary iron supplementation. For this we used the prospective Cambridge Baby Growth Study with records of maternal GDM status, nutrient supplementation, and extensive offspring birth size measurements. Maternal iron supplementation in pregnancy was associated with GDM development (risk ratio 1.67 (1.01-2.77), p = 0.048, n = 677) as well as offspring size and adiposity (n = 844-868) at birth in terms of weight (ß' = 0.078 (0.024-0.133); p = 0.005), head circumference (ß' = 0.060 (0.012-0.107); p = 0.02), body mass index (ß' = 0.067 (0.014-0.119); p = 0.01), and various skinfold thicknesses (ß' = 0.067-0.094; p = 0.03-0.003). In a subset of participants for whom GDM statuses were available, all these associations were attenuated by adjusting for GDM. Iron supplementation also attenuated the associations between multiple micronutrient supplementation and these same measures. These results suggest that iron supplementation may mediate the effects associated with multiple micronutrient supplementation in pregnancy in a high-income country, possibly through the increased risk of developing GDM.

Effects of Maternal Resveratrol Intake on the Metabolic Health of the Offspring.

Maternal nutritional imbalances, in addition to maternal overweight and obesity, can result in long-term effects on the metabolic health of the offspring, increasing the risk of common non-communicable disorders such as obesity, diabetes and cardiovascular disease. This increased disease risk may also be transmitted across generations. Unfortunately, lifestyle interventions have shown reduced compliancy and limited efficacy. Resveratrol is a natural polyphenolic compound reported to have pleiotropic beneficial actions including a possible protective effect against the metabolic programming induced by poor dietary habits during development. However, studies to date are inconclusive regarding the potential metabolic benefits of maternal resveratrol supplementation during pregnancy and lactation on the offspring. Moreover, the responses to metabolic challenges are suggested to be different in males and females, suggesting that the effectiveness of treatment strategies may also differ, but many studies have been performed only in males. Here we review the current evidence, both in humans and animal models, regarding the possible beneficial effects of maternal resveratrol intake on the metabolic health of the offspring and highlight the different effects of resveratrol depending on the maternal diet, as well as the differential responses of males and females.

High NOV/CCN3 expression during high-fat diet pregnancy in mice affects GLUT3 expression and the mTOR pathway.

We investigated the expression levels of nephroblastoma overexpressed [NOV or CCN3 (cellular communication network factor 3)] in the serum and placenta of pregnant women and of pregnant mice fed a high-fat diet (HFD), and its effect on placental glucose transporter 3 (GLUT3) expression, to examine its role in gestational diabetes mellitus (GDM). NOV/CCN3 expression was increased in the mouse serum during pregnancy. At gestational day 18, NOV/CCN3 protein expression was increased in the serum and placenta of the HFD mice compared with that of mice fed a normal diet. Compared with non-GDM patients, the patients with GDM had significantly increased serum NOV/CCN3 protein expression and placental NOV/CCN3 mRNA expression. Therefore, we hypothesized that NOV/CCN3 signaling may be involved in the pathogenesis of GDM. We administered NOV/CCN3 recombinant protein via intraperitoneal injections to pregnant mice fed HFD or normal diet. NOV/CCN3 overexpression led to glucose intolerance. Combined with the HFD, NOV/CCN3 exacerbated glucose intolerance and caused insulin resistance. NOV/CCN3 upregulates GLUT3 expression and affects the mammalian target of rapamycin (mTOR) pathway in the GDM environment in vivo and in vitro. In summary, our results demonstrate, for the first time, the molecular mechanism of NOV/CCN3 signaling in maternal metabolism to regulate glucose balance during pregnancy. NOV/CCN3 may be a potential target for detecting and treating GDM.NEW & NOTEWORTHY NOV/CCN3 regulates glucose homeostasis in mice during pregnancy. NOV/CCN3 upregulates GLUT3 expression and affects the mTOR pathway in the GDM environment in vivo and in vitro.

Evaluation of maternal high-fat diet and Quercetin-3-O-rutinoside treatment on the reproductive profile of diet naïve male offspring.

BACKGROUND: Male infertility and reproductive dysfunctions have become major global health problems. Although several causative factors have been attributed to this challenge, of importance are alterations in maternal-foetal environment, diet-induced transcriptional changes and dysregulation in chemical signaling via hypothalamic-gonadal axis. AIM: The present study investigated the impact of maternal high-fat diet (HFD) consumption and the putative role of Quercetin-3-O-rutinoside on reproductive functions of male offspring rats at critical developmental stages with a quest to unravel the underpinned molecular changes. MATERIALS AND METHODS: Fifty-six pregnant rats (previously fed normal diet ND) or 45% HFD) were maintained on supplemented chow (150 mg/kg QR) - ND/QR, HFD/QR throughout gestation. Subsequently, dams (n = 7) and offspring (n = 6) were sacrificed at post-natal day (PND) 21, 28 and 35, respectively, and the blood, placenta, hypothalamus (HT), and testicular samples were processed for molecular analysis of Gonadotropin-releasing hormone (GnRH), Luteinizing hormone (LH), testosterone, chemerin, chemokine-like receptor 1 (CMKLR1), tumour necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and nuclear factor kappa B (NF-κB). KEY FINDINGS: We observed a significant decrease in GnRH level in the HFD group at PND21 and PND28 in male offspring and treatment with QR significantly reduced GnRH. There was a significant reduction in LH levels in the HFD group at PND 21 in the male offspring accompanied by a significant decrease in testosterone level at PND 28 and PND35 which appears to be age dependent. In the HT, Chemerin and CMKLR1 was significantly upregulated in the HFD group at PND 21 and PND 35 respectively while CMKLR1 was significantly downregulated in the HFD group of the placenta and testis at PND 21. TNF-α, IL-1ß and NF-κB were also expressed in the placenta, HT and testis at PND 21. SIGNIFICANCE: Male fertility is affected by maternal HFD consumption while chemerin, CMKLR1 and TNF-α, may play a significant role in male steroidogenesis. Treatment with QR had little or no ameliorative effect on HFD induced alterations in male reproductive functions.

Effects of Maternal Fish Oil and/or 5-Methyl-Tetrahydrofolate Supplementation during Pregnancy on Offspring Brain Resting-State at 10 Years Old: A Follow-Up Study from the NUHEAL Randomized Controlled Trial.

Recent studies have shown that maternal supplementation with folate and long-chain polyunsaturated fatty acids (LC-PUFAs) during pregnancy may affect children's brain development. We aimed at examining the potential long-term effect of maternal supplementation with fish oil (FO) and/or 5-methyl-tetrahydrofolate (5-MTHF) on the brain functionality of offspring at the age of 9.5-10 years. The current study was conducted as a follow-up of the Spanish participants belonging to the Nutraceuticals for a Healthier Life (NUHEAL) project; 57 children were divided into groups according to mother's supplementation and assessed through functional magnetic resonance imaging (fMRI) scanning and neurodevelopment testing. Independent component analysis and double regression methods were implemented to investigate plausible associations. Children born to mothers supplemented with FO (FO and FO + 5-MTHF groups, n = 33) showed weaker functional connectivity in the default mode (DM) (angular gyrus), the sensorimotor (SM) (motor and somatosensory cortices) and the fronto-parietal (FP) (angular gyrus) networks compared to the No-FO group (placebo and 5-MTHF groups, n = 24) (PFWE < 0.05). Furthermore, no differences were found regarding the neuropsychological tests, except for a trend of better results in an object recall (memory) test. Considering the No-FO group, the aforementioned networks were associated negatively with attention and speed-processing functions. Mother's FO supplementation during pregnancy seems to be able to shape resting-state network functioning in their children at school age and appears to produce long-term effects on children´s cognitive processing.

Maternal hepcidin determines embryo iron homeostasis in mice.

Iron disorders are associated with adverse pregnancy outcomes, yet iron homeostatic mechanisms during pregnancy are poorly understood. In humans and rodents, the iron-regulatory hormone hepcidin is profoundly decreased in pregnant mothers, which is thought to ensure adequate iron availability for transfer across placenta. However, the fetal liver also produces hepcidin, which may regulate fetal iron endowment by controlling placental iron export. To determine the relative contribution of maternal vs embryo hepcidin to the control of embryo iron endowment in iron-sufficient or iron-overloaded mice, we generated combinations of mothers and embryos that had or lacked hepcidin. We found that maternal, but not embryonic, hepcidin determined embryo and placental iron endowment in a healthy pregnancy. We further determined that inflammation can counteract pregnancy-dependent suppression of maternal hepcidin. To establish how essential maternal hepcidin suppression is for embryo iron homeostasis, we mimicked the range of maternal hepcidin activity by administering a hepcidin peptide mimetic to pregnant mice. This also allowed us to determine the effect of isolated maternal hepcidin excess on pregnancy, in the absence of other confounding effects of inflammation. Higher doses of hepcidin agonist caused maternal iron restriction and anemia, lower placenta and embryo weight, embryo anemia, and increased embryo mortality. Low agonist doses did not cause maternal anemia but still adversely affected the embryo, causing anemia, tissue iron deficiency (including in the brain), and decreased weight. Our studies demonstrate that suppression of maternal hepcidin during pregnancy is essential for maternal and embryo iron homeostasis and health.

Maternal Folic Acid Supplementation Mediates Offspring Health via DNA Methylation.

The clinical significance of periconceptional folic acid supplementation (FAS) in the prevention of neonatal neural tube defects (NTDs) has been recognized for decades. Epidemiological data and experimental findings have consistently been indicating an association between folate deficiency in the first trimester of pregnancy and poor fetal development as well as offspring health (i.e., NTDs, isolated orofacial clefts, neurodevelopmental disorders). Moreover, compelling evidence has suggested adverse effects of folate overload during perinatal period on offspring health (i.e., immune diseases, autism, lipid disorders). In addition to several single-nucleotide polymorphisms (SNPs) in genes related to folate one-carbon metabolism (FOCM), folate concentrations in maternal serum/plasma/red blood cells must be considered when counseling FAS. Epigenetic information encoded by 5-methylcytosines (5mC) plays a critical role in fetal development and offspring health. S-adenosylmethionine (SAM), a methyl donor for 5mC, could be derived from FOCM. As such, folic acid plays a double-edged sword role in offspring health via mediating DNA methylation. However, the underlying epigenetic mechanism is still largely unclear. In this review, we summarized the link across DNA methylation, maternal FAS, and offspring health to provide more evidence for clinical guidance in terms of precise FAS dosage and time point. Future studies are, therefore, required to set up the reference intervals of folate concentrations at different trimesters of pregnancy for different populations and to clarify the epigenetic mechanism for specific offspring diseases.

Maternal suppplementation with conjugated linoleic acid reduce anxiety and lipid peroxidation in the offspring brain.

BACKGROUND: Maternal consumption of fatty acids can alter neuronal membrane function, synaptic connections, and protect the brain from alterations caused by disturbances such as lipid peroxidation and anxiety in the offspring. We aimed to investigate how the maternal consumption of conjugated linoleic acid (CLA) interferes in anxiety behavior of the offspring and cerebral lipid peroxidation. METHODS: Three groups were formed: control (CG) - diet without CLA; CLA1 - diet containing 1% of CLA; and CLA3 - diet containing 3% of CLA. These diets were offered to the mothers from the 7th day of gestation until the end of lactation. The following behavioral tests were used: Elevated plus maze (EPM), Open Field (OF) and Light-dark Box (LDB). Levels of malondialdehyde (MDA) and glutathione were measured in the offspring's brains. Data were analyzed by ANOVA followed by the Holm-Sidak post-test or the Kruskal-Wallis test (p < 0.05). RESULTS: CLA1 and CLA3 showed higher number of entries in the open arms and time spent in the central area in EPM, they translocated and ambulated more in the clear area of the LDB and presented more rearing in the OF compared to CG (p < 0.05); moreover, they presented higher concentration of glutathione and lower MDA in brain tissue (p < 0.05). LIMITATIONS: We evaluated the effect of maternal consumption of CLA on anxiety and lipid peroxidation in rats' offspring, but a similar study should be performed in humans. CONCLUSIONS: Maternal intake of CLA induced a decrease in the parameters of anxiety and cerebral lipid peroxidation in the offspring.

Peripartum dietary supplementation of a small-molecule inhibitor of tryptophan hydroxylase 1 compromises infant, but not maternal, bone.

Long-term effects of breastfeeding on maternal bone are not fully understood. Excessive maternal bone loss stimulated by serotonin signaling during lactation may increase bone fragility later in life. We hypothesized that inhibiting nonneuronal serotonin activity by feeding a small-molecule inhibitor of the rate-limiting enzyme in serotonin synthesis [tryptophan hydroxylase 1 (TPH1)] would preserve maternal bone postweaning without affecting neonatal bone. Chow supplemented with the small-molecule TPH1 inhibitor LP778902 (~100 mg/kg) or control chow was fed to C57BL/6 dams throughout pregnancy and lactation, and blood was collected on days 1 and 21 of lactation. Dams returned to a common diet postweaning and were aged to 3 or 9 mo postweaning. Pups were euthanized at weaning. The effect of TPH1 inhibition on dam and pup femoral bone was determined by micro-computed tomography. Peripartum dietary supplementation with LP778902 decreased maternal serum serotonin concentrations ( P = 0.0007) and reduced bone turnover, indicated by serum NH2-terminal propeptide of type I collagen ( P = 0.01) and COOH-terminal collagen cross-links ( P = 0.02) concentrations, on day 21 of lactation. Repressed bone turnover from TPH1 inhibition was not associated with structural changes in maternal femur at 3 or 9 mo postweaning. By contrast, neonates exposed to peripartum LP778902 demonstrated differences in trabecular and cortical femoral bone compared with pups from control dams, with fewer ( P = 0.02) and thinner ( P = 0.001) trabeculae as well as increased trabecular spacing ( P = 0.04). Additionally, cortical porosity was increased ( P = 0.007) and cortical tissue mineral density was decreased ( P = 0.005) in pups of LP778902-treated dams. Small-molecule TPH1 inhibitors should be carefully considered in pregnant and lactating women, given potential risks to neonatal bone development.

Dietary supplementation of n-3 polyunsaturated fatty acid alters endometrial expression of genes involved in prostaglandin biosynthetic pathway in breeding sows (Sus scrofa).

The present investigation was designed to study the effect of dietary supplementation of omega-3 (n-3) PUFA on endometrial expression of fertility-related genes in breeding sows. Sixteen crossbred sows were randomized to receive diets containing 4% (wt/wt) flaxseed oil as n-3 PUFA source (TRT group) or iso-nitrogenous, iso-caloric standard control diet (CON group), starting from the first day of estrus up to 40 days and were artificially bred on the second estrus. Endometrial samples were collected during days 10-11 and 15-16 post-mating for studying relative expression profile of candidate genes viz. Prostaglandin F Synthase (PGFS), microsomal Prostaglandin E Synthase-1 (mPGES-1) and Carbonyl Reductase-1 (CBR-1) using quantitative Real-Time PCR. Expression level of mPGES-1 gene transcript was 2.1-fold higher (P < 0.05) during 10-11 days of pregnancy and 1.4-fold higher (P > 0.05) during 15-16 days of pregnancy in TRT group as compared to CON group. Relative expression of PGFS gene transcript was significantly lower (P < 0.05) during 10-11 days of pregnancy in TRT group while there was no significant effect (P > 0.05) of dietary supplementation during 15-16 days of pregnancy. Endometrial mRNA level of CBR1 was significantly lower (P < 0.05) with 3.93-fold decrease in TRT group during 10-11 days of pregnancy whereas 2.82-fold reduction in expression (P > 0.05) was observed subsequently during 15-16 days of pregnancy as compared to CON group. Collectively, these results indicate that dietary n-3 PUFA supplementation can modulate gene expression of key enzymes in prostaglandin biosynthetic pathway during early gestation, which in turn might have beneficial impact on overall reproductive response in breeding sows. These findings partly support strategic dietary supplementation of plant-based source of n-3 PUFA with an aim to improve overall reproductive performance in sows.

Prenatal fish oil supplementation and early childhood development in the Upstate KIDS Study.

Fish oil contains omega-3 fatty acids, which play a vital role in fetal growth and development. In utero exposure to omega-3 fatty acids is exclusively dependent on maternal nutrition. Previous studies have suggested that prenatal fish oil supplementation has positive impacts on child neurodevelopment later in life. This study examines the associations between fish oil supplementation both before pregnancy and throughout pregnancy and subsequent child development. Mother-child pairs from the Upstate KIDS Study, a birth cohort consisting of children born between 2008 and 2010, were included. Self-reported prenatal fish oil supplementation data were available for 5845 children (3807 singletons and 2038 twins). At multiple time points, from 4 months to 3 years of age, child development was reported by the parents on the Ages and Stages Questionnaire (ASQ). Five developmental domains were assessed: fine motor, gross motor, communication, personal-social functioning and problem solving. Generalized linear mixed models were used to estimate odds ratios (OR) while adjusting for covariates. Primary analyses showed that the risk of failing the ASQ problem-solving domain was significantly lower among children of women who took fish oil before pregnancy (OR 0.40, 95% confidence intervals (CI) 0.18-0.89) and during pregnancy (OR 0.43, 95% CI 0.22-0.83). Gender interaction was not statistically significant, although stratified results indicated stronger associations among girls. Similarly, associations were primarily among singletons. Prenatal fish oil supplementation may be beneficial in regards to neurodevelopment. Specifically, it is associated with a lower risk of failing the problem-solving domain up to 3 years of age.

Effects of Maternal Linseed Oil Supplementation on Metabolic Parameters in Cafeteria Diet-induced Obese Rats.

Because linseed oil may influence maternal and fetal metabolisms, we investigated its role in the modulation of lipid metabolism in cafeteria diet-induced obese rats and their offspring. Female Wistar rats were fed control or cafeteria food, which were either supplemented or not supplemented with linseed oil (5%) for 1 month before and during gestation. At parturition, serum and tissue lipids and enzyme activities were analyzed. Cafeteria diet induced adverse metabolic alterations in both mothers and offspring. Linseed oil improved metabolic status. In conclusion, linseed oil displayed health benefits by modulating tissue enzyme activities in both obese mothers and their newborns.

Maternal methyl donors supplementation during lactation prevents the hyperhomocysteinemia induced by a high-fat-sucrose intake by dams.

Maternal perinatal nutrition may program offspring metabolic features. Epigenetic regulation is one of the candidate mechanisms that may be affected by maternal dietary methyl donors intake as potential controllers of plasma homocysteine levels. Thirty-two Wistar pregnant rats were randomly assigned into four dietary groups during lactation: control, control supplemented with methyl donors, high-fat-sucrose and high-fat-sucrose supplemented with methyl donors. Physiological outcomes in the offspring were measured, including hepatic mRNA expression and global DNA methylation after weaning. The newborns whose mothers were fed the obesogenic diet were heavier longer and with a higher adiposity and intrahepatic fat content. Interestingly, increased levels of plasma homocysteine induced by the maternal high-fat-sucrose dietary intake were prevented in both sexes by maternal methyl donors supplementation. Total hepatic DNA methylation decreased in females due to maternal methyl donors administration, while Dnmt3a hepatic mRNA levels decreased accompanying the high-fat-sucrose consumption. Furthermore, a negative association between Dnmt3a liver mRNA levels and plasma homocysteine concentrations was found. Maternal high-fat-sucrose diet during lactation could program offspring obesity features, while methyl donors supplementation prevented the onset of high hyperhomocysteinemia. Maternal dietary intake also affected hepatic DNA methylation metabolism, which could be linked with the regulation of the methionine-homocysteine cycle.

Effect of exogenous melatonin on embryo viability and uterine environment in undernourished ewes.

The effect of exogenous melatonin on embryo viability in undernourished ewes was investigated. At lambing, 24 ewes were treated (+MEL) or not (-MEL) with a melatonin implant. After 45 days, both groups were fed to provide 1.5 (Control, C) or 0.5 (Low, L) times daily maintenance requirements, so that experimental groups were: C-MEL, C+MEL, L-MEL and L+MEL. Ewes were mated (Day 0) and on Day 5 embryos were recovered and classified according to their developmental stage and morphology. Ovaries were used for in vitro fertilization and uterine horns were processed to study progesterone and oestrogen receptor (PR and ERα) expression by inmunohistochemistry. After 21 days, groups L-MEL and L+MEL had an average weight loss of 10kg (P<0.001). Number of viable embryos per CL from L+MEL (0.50±0.2) was higher than from other groups (P<0.05). Overall, the melatonin effect was particularly evident in undernourished ewes, increasing both viability (L+MEL: 65%; L-MEL: 25%; P<0.05) and pregnancy rates (L+MEL: 66.6%; L-MEL: 16.6%; P<0.05). Neither nutrition and melatonin nor their interaction had a significant effect on the in vitro oocyte development. Melatonin treatment tended to increase the percentage of positive cells to PR in deep glandular epithelium, independently of diet (P=0.09), and the greatest staining intensity of PR was observed in the luminal and superficial glandular epithelia (P<0.0001). In conclusion, melatonin implants at lambing during the breeding season improve the viability of embryos recovered from undernourished ewes, although this effect seems not to be mediated at the oocyte competence level.

Echium oil and linseed oil as alternatives for fish oil in the maternal diet: Blood fatty acid profiles and oxidative status of sows and piglets.

Echium oil (source of stearidonic acid) and linseed oil (source of α-linolenic acid) were evaluated as alternatives for fish oil in the diet of sows to increase the docosahexaenoic acid (DHA) status of the offspring. The hypothesis was that echium oil would be more efficient than linseed oil to increase the DHA concentration, as it bypasses the enzyme Δ6-desaturase. In addition, it was determined whether adding PUFA to the diet affected the plasma oxidative status. Sows were fed either a palm oil diet or a diet containing 1% linseed oil, echium oil, or fish oil from d 73 of gestation and during lactation (n = 16 per dietary treatment). Total oil concentrations in the diets were similar among dietary treatments. Blood samples were taken for fatty acid analysis and oxidative status of sows on d 73 and 93 of gestation and at parturition and the lightest and heaviest piglet per litter at birth and weaning. Colostrum was also sampled. No effect of diet was observed on total number of piglets born (13.7 ± 0.4), number of weaned piglets (10.8 ± 0.4), and gestation length (114.8 ± 0.2 d). Piglets from sows fed fish oil had lighter birth weights (1.41 ± 0.03 kg) than piglets from the linseed oil diet (1.54 ± 0.03 kg; P = 0.006), with no difference between the palm oil (1.45 ± 0.03 kg) and echium oil diet (1.49 ± 0.03 kg). Daily BW gain until weaning was less for piglets from sows fed the fish oil diet (214 ± 5 g) compared with piglets from sows fed the echium oil (240 ± 5 g; P < 0.001) or linseed oil diet (234 ± 5 g; P = 0.02). Compared with the palm oil diet, echium and linseed oil in the maternal diet increased the DHA concentration in the colostrum and the sow and piglet plasma to the same extent (1.1 to 1.4-fold; P < 0.001). On the fish oil diet, 20.7-fold, 10-fold, and 2.4-fold increases in DHA in colostrum, sow, and piglet plasma, respectively, were observed (P < 0.001). At 1% in the maternal diet, echium oil had, thus, no benefit over linseed oil and resulted in a twofold less DHA concentration in the plasma of piglets compared with fish oil. Including n-3 PUFA in the maternal diet did not affect oxidative status of the mother or the offspring.

The effect of feeding a low iron diet prior to and during gestation on fetal and maternal iron homeostasis in two strains of rat.

BACKGROUND: Iron deficiency anaemia during pregnancy is a global problem, with short and long term consequences for maternal and child health. Animal models have demonstrated that the developing fetus is vulnerable to maternal iron restriction, impacting on postnatal metabolic and blood pressure regulation. Whilst long-term outcomes are similar across different models, the commonality in mechanistic events across models is unknown. This study examined the impact of iron deficiency on maternal and fetal iron homeostasis in two strains of rat. METHODS: Wistar (n=20) and Rowett Hooded Lister (RHL, n=19) rats were fed a control or low iron diet for 4 weeks prior to and during pregnancy. Tissues were collected at day 21 of gestation for analysis of iron content and mRNA/protein expression of regulatory proteins and transporters. RESULTS: A reduction in maternal liver iron content in response to the low iron diet was associated with upregulation of transferrin receptor expression and a reduction in hepcidin expression in the liver of both strains, which would be expected to promote increased iron absorption across the gut and increased turnover of iron in the liver. Placental expression of transferrin and DMT1+IRE were also upregulated, indicating adaptive responses to ensure availability of iron to the fetus. There were considerable differences in hepatic maternal and fetal iron content between strains. The higher quantity of iron present in livers from Wistar rats was not explained by differences in expression of intestinal iron transporters, and may instead reflect greater materno-fetal transfer in RHL rats as indicated by increased expression of placental iron transporters in this strain. CONCLUSIONS: Our findings demonstrate substantial differences in iron homeostasis between two strains of rat during pregnancy, with variable impact of iron deficiency on the fetus. Whilst common developmental processes and pathways have been observed across different models of nutrient restriction during pregnancy, this study demonstrates differences in maternal adaptation which may impact on the trajectory of the programmed response.

Differential modulation of dibenzo[def,p]chrysene transplacental carcinogenesis: maternal diets rich in indole-3-carbinol versus sulforaphane.

Cruciferous vegetable components have been documented to exhibit anticancer properties. Targets of action span multiple mechanisms deregulated during cancer progression, ranging from altered carcinogen metabolism to the restoration of epigenetic machinery. Furthermore, the developing fetus is highly susceptible to changes in nutritional status and to environmental toxicants. Thus, we have exploited a mouse model of transplacental carcinogenesis to assess the impact of maternal dietary supplementation on cancer risk in offspring. In this study, transplacental and lactational exposure to a maternal dose of 15mg/Kg B.W. of dibenzo[def,p]chrysene (DBC) resulted in significant morbidity of offspring due to an aggressive T-cell lymphoblastic lymphoma. As in previous studies, indole-3-carbinol (I3C, feed to the dam at 100, 500 or 1000ppm), derived from cruciferous vegetables, dose-dependently reduced lung tumor multiplicity and also increased offspring survival. Brussels sprout and broccoli sprout powders, selected for their relative abundance of I3C and the bioactive component sulforaphane (SFN), respectively, surprisingly enhanced DBC-induced morbidity and tumorigenesis when incorporated into the maternal diet at 10% wt/wt. Purified SFN, incorporated in the maternal diet at 400ppm, also decreased the latency of DBC-dependent morbidity. Interestingly, I3C abrogated the effect of SFN when the two purified compounds were administered in equimolar combination (500ppm I3C and 600ppm SFN). SFN metabolites measured in the plasma of neonates positively correlated with exposure levels via the maternal diet but not with offspring mortality. These findings provide justification for further study of the safety and bioactivity of cruciferous vegetable phytochemicals at supplemental concentrations during the perinatal period.

Metabolic and mitochondrial dysfunction in early mouse embryos following maternal dietary protein intervention.

Dietary supply of nutrients, both periconception and during pregnancy, influence the growth and development of the fetus and offspring and their health into adult life. Despite the importance of research efforts surrounding the developmental origins of health and disease hypothesis, the biological mechanisms involved remain elusive. Mitochondria are of major importance in the oocyte and early embryo, particularly as a source of ATP generation, and perturbations in their function have been related to reduced embryo quality. The present study examined embryo development following periconception exposure of females to a high-protein diet (HPD) or a low-protein diet (LPD) relative to a medium-protein diet (MPD; control), and we hypothesized that perturbed mitochondrial metabolism in the mouse embryo may be responsible for the impaired embryo and fetal development reported by others. Although the rate of development to the blastocyst stage did not differ between diets, both the HPD and LPD reduced the number of inner cell mass cells in the blastocyst-stage embryo. Furthermore, mitochondrial membrane potential was reduced and mitochondrial calcium levels increased in the 2-cell embryo. Embryos from HPD females had elevated levels of reactive oxygen species and ADP concentrations, indicative of metabolic stress and, potentially, the uncoupling of oxidative phosphorylation, whereas embryos from LPD females had reduced mitochondrial clustering around the nucleus, suggestive of an overall quietening of metabolism. Thus, although periconception dietary supply of different levels of protein is permissive of development, mitochondrial metabolism is altered in the early embryo, and the nature of the perturbation differs between HPD and LPD exposure.

Future health implications of prenatal and early-life vitamin D status.

Current or recent low vitamin D status (or proxy measures such as dietary intake or ambient ultraviolet radiation) is linked to several chronic diseases, including osteoporosis, cancers, and cardiovascular and autoimmune diseases. Low prenatal vitamin D status may also increase susceptibility to such diseases in later life via specific target organ effects and/or through changes to the developing immune system. Maternal vitamin D supplementation during pregnancy could be an important public health measure to decrease risk of a range of chronic diseases, but further research is required to clarify beneficial and adverse effects of high prenatal vitamin D.