Search

Early-life malnutrition plays a critical role in foetal development and predisposes to metabolic diseases later in life, according to the concept of 'developmental programming'. Different types of early nutritional imbalance, including undernutrition, overnutrition and micronutrient deficiency, have been related to long-term metabolic disorders. Accumulating evidence has demonstrated that disturbances in nutrition during the period of preconception, pregnancy and primary infancy can affect mitochondrial function and epigenetic mechanisms. Moreover, even though multiple mechanisms underlying non-alcoholic fatty liver disease (NAFLD) have been described, in the past years, special attention has been given to mitochondrial dysfunction and epigenetic alterations. Mitochondria play a key role in cellular metabolic functions. Dysfunctional mitochondria contribute to oxidative stress, insulin resistance and inflammation. Epigenetic mechanisms have been related to alterations in genes involved in lipid metabolism, fibrogenesis, inflammation and tumorigenesis. In accordance, studies have reported that mitochondrial dysfunction and epigenetics linked to early-life nutrition can be important contributing factors in the pathogenesis of NAFLD. In this review, we summarise the current understanding of the interplay between mitochondrial dysfunction, epigenetics and nutrition during early life, which is relevant to developmental programming of NAFLD. [ABSTRACT FROM AUTHOR]

The developmental origins of health and disease (DOHaD) framework has highlighted the importance of the early life period on disease risk in later life with impacts that can span generations. A primary focus to date has been around maternal health and the 'First Thousand Days' as a key developmental window whereby an adverse environment can have lasting impacts on both mother and offspring. More recently, the impact of paternal health has gathered increasing traction as a key window for early life developmental programming. However, to date, adolescents, the next generation of parents, have attracted less attention as a key DOHaD window although many behavioural traits become entrained during adolescence and track into adulthood. This systematic review examined literature focused on identifying adolescent understanding of DOHaD concepts. Consistent across the eligible articles was that overall understanding of DOHaD-related concepts in adolescents was low. Three key themes emerged: 1. Individual-level awareness of DOHaD concepts (cognitive engagement and action of the adolescents themselves); 2. Interpersonal communication and social awareness of DOHaD concepts (cognitive engagement and communication of the DOHaD concepts to family and wider community); and 3. Health literacy and the promotion of adolescence as a key DOHaD life stage. These findings highlight the need to develop strategic approaches to increase DOHaD awareness that are not only appealing to adolescents but can also support sustained changes in health behaviour. Investment in today's adolescents has the potential to act as a NCD 'circuit breaker' and thus will yield significant dividends for future generations. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) involves changes in hepatic pathways, as lipogenesis, oxidative stress, endoplasmic reticulum (ER) stress, and macroautophagy. Maternal nicotine exposure exclusively during lactation leads to fatty liver (steatosis) only in the adult male offspring, not in females. Therefore, our hypothesis is that neonatal exposure to nicotine sex-dependently affects the signaling pathways involved in hepatic homeostasis of the offspring, explaining the hepatic lipid accumulation phenotype only in males. For this, between postnatal days 2 and 16, Wistar rat dams were implanted with osmotic minipumps, which released nicotine (NIC; 6 mg/Kg/day) or vehicle. The livers of offspring were evaluated at postnatal day 180. Only the male offspring that had been exposed to nicotine neonatally showed increased protein expression of markers of unfolded protein response (UPR), highlighting the presence of ER stress, as well as disruption of the activation of the macroautophagy repair pathway. These animals also had increased expression of diacylglycerol O-acyltransferase 1 and 4-hydroxynonenal, suggesting increased triglyceride esterification and oxidative stress. These parameters were not altered in the female offspring that had been neonatally exposed to nicotine, however they exhibited increased phospho adenosine monophosphate-activated protein kinase pAMPK expression, possibly as a protective mechanism. Thus, the disturbance in the hepatic homeostasis by UPR, macroautophagy, and oxidative stress modifications seem to be the molecular mechanisms underlying the liver steatosis in the adult male offspring of the nicotine-programming model. This highlights the importance of maternal smoking cessation during breastfeeding to decrease the risk of NAFLD development, especially in males. [ABSTRACT FROM AUTHOR]

Fetal liver tissue collected from a nonhuman primate (NHP) baboon model of maternal nutrient reduction (MNR) at four gestational time points (90, 120, 140, and 165 days gestation [dG], term in the baboon is ∼185 dG) was used to quantify MNR effects on the fetal liver transcriptome. 28 transcripts demonstrated different expression patterns between MNR and control livers during the second half of gestation, a developmental period when the fetus undergoes rapid weight gain and fat accumulation. Differentially expressed transcripts were enriched for fatty acid oxidation and RNA splicing-related pathways. Increased RNA splicing activity in MNR was reflected in greater abundances of transcript splice variant isoforms in the MNR group. It can be hypothesized that the increase in splice variants is deployed in an effort to adapt to the poor in utero environment and ensure near-normal development and energy metabolism. This study is the first to study developmental programming across four critical gestational stages during primate fetal liver development and reveals a potentially novel cellular response mechanism mediating fetal programming in response to MNR. [ABSTRACT FROM AUTHOR]

Maternal protein restriction is often associated with structural and functional sequelae in offspring, particularly affecting growth and renal-cardiovascular function. However, there is little understanding as to whether hypertension and kidney disease occur because of a primary nephron deficit or whether controlling postnatal growth can result in normal renal-cardiovascular phenotypes. To investigate this, female Sprague-Dawley rats were fed either a low-protein (LP, 8.4% protein) or normal-protein (NP, 19.4% protein) diet prior to mating and until offspring were weaned at postnatal day (PN) 21. Offspring were then fed a non 'growth' (4.6% fat) which ensured that catch-up growth did not occur. Offspring growth was determined by weight and dual energy X-ray absorptiometry. Nephron number was determined at PN21 using the disector-fractionator method. Kidney function was measured at PN180 and PN360 using clearance methods. Blood pressure was measured at PN360 using radio-telemetry. Body weight was similar at PN1, but by PN21 LP offspring were 39% smaller than controls (Pdiet < 0.001). This difference was due to proportional changes in lean muscle, fat, and bone content. LP offspring remained smaller than NP offspring until PN360. In LP offspring, nephron number was 26% less in males and 17% less in females, than NP controls (Pdiet < 0.0004). Kidney function was similar across dietary groups and sexes at PN180 and PN360. Blood pressure was similar in LP and NP offspring at PN360. These findings suggest that remaining on a slow growth trajectory after exposure to a suboptimal intrauterine environment does not lead to the development of kidney dysfunction and hypertension. [ABSTRACT FROM AUTHOR]

Prenatal hypoxia is a common complication of pregnancy and is associated with detrimental health outcomes, such as impaired cardiac and vascular function, in adult offspring. Exposure to prenatal hypoxia reportedly impacts the reproductive system of female offspring. Whether exposure to prenatal hypoxia influences pregnancy adaptations and outcomes in these female offspring is unknown. We hypothesised that prenatal hypoxia impairs uterine artery adaptations in pregnancies of the adult offspring. Pregnancy outcomes and uterine artery function were assessed in 14–16 weeks old non-pregnant and late pregnant (gestational day 20; term = 22 days) adult female offspring born to rats exposed to prenatal normoxia (21% oxygen) or hypoxia (11% oxygen, between days 15–21 of gestation). Compared with normoxia controls, prenatal hypoxia was associated with pregnant adult offspring having reduced placental weights in their litters, and uterine artery circumferential stress that increased with pregnancy. Overall, prenatal hypoxia adversely, albeit mildly, compromised pregnancies of adult offspring. [ABSTRACT FROM AUTHOR]

Maternal obesity programs the offspring to metabolic diseases later in life; however, the mechanisms of programming are yet unclear, and no strategies exist for addressing its detrimental transgenerational effects. Obesity has been linked to dipeptidyl peptidase IV (DPPIV), an adipokine, and treatment of obese individuals with DPPIV inhibitors has been reported to prevent weight gain and improve metabolism. We hypothesized that DPPIV plays a role in maternal obesity-mediated programming. We measured plasma DPPIV activity in human maternal and cord blood samples from normal-weight and obese mothers at term. We found that maternal obesity increases maternal and cord blood plasma DPPIV activity but only in male offspring. Using two non-human primate models of maternal obesity, we confirmed the activation of DPPIV in the offspring of obese mothers. We then created a mouse model of maternal high-fat diet (HFD)-induced obesity, and found an early-life increase in plasma DPPIV activity in male offspring. Activation of DPPIV preceded the progression of obesity, glucose intolerance and insulin resistance in male offspring of HFD-fed mothers. We then administered sitagliptin, DPPIV inhibitor, to regular diet (RD)- and HFD-fed mothers, starting a week prior to breeding and continuing throughout pregnancy and lactation. We found that sitagliptin treatment of HFD-fed mothers delayed the progression of obesity and metabolic diseases in male offspring and had no effects on females. Our findings reveal that maternal obesity dysregulates plasma DPPIV activity in males and provide evidence that maternal inhibition of DPPIV has potential for addressing the transgenerational effects of maternal obesity. [ABSTRACT FROM AUTHOR]

Previous studies in rodents suggest that mismatch between fetal and postnatal nutrition predisposes individuals to metabolic diseases. We hypothesized that in nonhuman primates (NHP), fetal programming of maternal undernutrition (MUN) persists postnatally with a dietary mismatch altering metabolic molecular systems that precede standard clinical measures. We used unbiased molecular approaches to examine response to a high fat, high-carbohydrate diet plus sugar drink (HFCS) challenge in NHP juvenile offspring of MUN pregnancies compared with controls (CON). Pregnant baboons were fed ad libitum (CON) or 30% calorie reduction from 0.16 gestation through lactation; weaned offspring were fed chow ad libitum . MUN offspring were growth restricted at birth. Liver, omental fat, and skeletal muscle gene expression, and liver glycogen, muscle mitochondria, and fat cell size were quantified. Before challenge, MUN offspring had lower body mass index (BMI) and liver glycogen, and consumed more sugar drink than CON. After HFCS challenge, MUN and CON BMIs were similar. Molecular analyses showed HFCS response differences between CON and MUN for muscle and liver, including hepatic splicing and unfolded protein response. Altered liver signaling pathways and glycogen content between MUN and CON at baseline indicate in utero programming persists in MUN juveniles. MUN catchup growth during consumption of HFCS suggests increased risk of obesity, diabetes, and cardiovascular disease. Greater sugar drink consumption in MUN demonstrates altered appetitive drive due to programming. Differences in blood leptin, liver glycogen, and tissue-specific molecular response to HFCS suggest MUN significantly impacts juvenile offspring ability to manage an energy rich diet.

While metabolic disorders such as obesity and diabetes are costly and deadly to the current population, they are also extremely detrimental to the next generation. Much of the current literature focuses on the negative impact of poor maternal choices on offspring disease, while there is little work examining maternal behaviors that may improve offspring health. Research has shown that voluntary maternal exercise in mouse models improves metabolic function in offspring. In this study, we hypothesized that controlled maternal exercise in a mouse model will effect positive change on offspring obesity and glucose homeostasis. Female mice were separated into three groups: home cage, sedentary, and exercise. The sedentary home cage group was not removed from the home cage, while the sedentary wheel group was removed from the cage and placed in an immobile wheel apparatus. The exercise group was removed from the home cage and run on the same wheel apparatus but with the motor activated at 5–10 m/min for 1 h/d prior to and during pregnancy. Offspring were subjected to oral glucose tolerance testing and body composition analysis. There was no significant difference in offspring glucose tolerance or body composition as a consequence of the maternal exercise intervention compared to the sedentary wheel group. There were no marked negative consequences of the maternal controlled exercise intervention. Further research should clarify the potential advantages of the controlled exercise model and improve experimental techniques to facilitate translation of this research to human applications. [ABSTRACT FROM AUTHOR]

Evidence suggests that maternal prepregnancy body mass index (BMI) is associated with offspring cardiometabolic risk factors. This study was aimed at assessing the association of maternal prepregnancy BMI with offspring cardiometabolic risk factors in adolescence and adulthood. We also evaluated whether offspring BMI was a mediator in this association. The study included mother–offspring pairs from three Pelotas birth cohorts. Offspring cardiometabolic risk factors were collected in the last follow-up of each cohort [mean age (in years) 30.2, 22.6, 10.9]. Blood pressure was measured using an automatic device, cholesterol by using an enzymatic colorimetric method, and glucose from fingertip blood, using a portable glucose meter. In a pooled analysis of the cohorts, multiple linear regression was used to control for confounding. Mediation analysis was conducted using G-computation formula. In the adjusted model, mean systolic blood pressure of offspring from overweight and obese mothers was on average 1.25 (95% CI: 0.45; 2.05) and 2.13 (95% CI: 0.66; 3.59) mmHg higher than that of offspring from normal-weight mothers; for diastolic blood pressure, the means were 0.80 (95% CI: 0.26; 1.34) and 2.60 (95% CI: 1.62; 3.59) mmHg higher, respectively. Non-HDL cholesterol was positively associated with maternal BMI, whereas blood glucose was not associated. Mediation analyses showed that offspring BMI explained completely the association of maternal prepregnancy BMI with offspring systolic and diastolic blood pressure, and non-HDL cholesterol. Our findings suggest that maternal prepregnancy BMI is positively associated with offspring blood pressure, and blood lipids, and this association is explained by offspring BMI. [ABSTRACT FROM AUTHOR]

In many human populations, especially those living in regions with pronounced climatic differences between seasons, the most sensitive (prenatal and neonatal) developmental stages occur in contrasting conditions depending on the season of conception. The difference in prenatal and postnatal environments may be a factor significantly affecting human development and risk for later life chronic diseases. Factors potentially contributing to this kind of developmental programming include nutrition, outdoor temperature, infectious exposures, duration of sunlight, vitamin D synthesis, etc. Month of birth is commonly used as a proxy for exposures which vary seasonally around the perinatal period. Season-of-birth patterns have been identified for many chronic health outcomes. In this review, the research evidence for the seasonality of birth in adult-life disorders is provided and potential mechanisms underlying the phenomenon of early life seasonal programming of chronic disease and longevity are discussed. [ABSTRACT FROM AUTHOR]

Microvascular health is a main determinant of coronary blood flow reserve and myocardial vascular resistance. Extracardiac capillary abnormality has been reported in subjects at increased coronary heart disease risk, such as prehypertension, hypertension, diabetes, hyperlipidemia, and atherosclerosis. We have reported cardiovascular dysfunction in a cohort of maternal nutrient reduction (MNR)-induced intrauterine growth restriction (IUGR) baboon offspring. Here we test the hypothesis that there is oral capillary rarefaction associated with MNR-induced IUGR. Capillary density was quantified using in vivo high-power capillaroscopy on seven middle-aged (~10.7 yr; human equivalent ~40 yr) male IUGR baboons and seven male age-matched controls in the lateral buccal and inferior labial mucosa. While no difference was found between groups in either area by fraction area or optical density for these vascular beds derived from fetal preductal vessels, further studies are needed on post-ductal vascular beds, retina, and function. [ABSTRACT FROM AUTHOR]

Experimental studies have demonstrated the effects of maternal fructose consumption during pregnancy and lactation on metabolic alterations in their offspring, especially male offspring. However, few studies have focused on female offspring after providing fructose in food to dam rats. Here, we studied whether offspring of both sexes were differentially affected by a maternal high-fructose diet (HFD). For this purpose, Sprague-Dawley rats were fed during pregnancy and lactation with a standard diet (SD) or a HFD (50% w/w). After weaning, offspring were fed an SD; 3 days later, dams were sacrificed, and their offspring were sacrificed on postnatal day 90. Body weight (BW), food and water intake (only for dams), and various biomarkers of metabolic syndrome were measured. When compared to the SD-fed dams, HFD-fed dams had a reduction in BW and food and water intake. Conversely, adiposity, liver weight, liver lipids, and plasma levels of glucose, insulin, cholesterol, triglycerides, and uric acid were increased in HFD-fed dams. Moreover, the BW, food consumption, weight of retroperitoneal fat pads, and liver lipids increased in female and male offspring of HFD-fed dams. Interestingly, the pups of HFD-fed mothers showed increased levels of leptin and insulin resistance and decreased levels of adiponectin which were more pronounced in male offspring than in female offspring. In contrast, a higher increase in BW was shown earlier in female offspring. Thus, high-fructose consumption by dams during pregnancy and lactation led to sex-specific developmental programming of the metabolic syndrome phenotype in adult offspring. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVD) are important consequences of adverse perinatal conditions such as fetal hypoxia and maternal malnutrition. Cardiac magnetic resonance imaging (CMR) can produce a wealth of physiological information related to the development of the heart. This review outlines the current state of CMR technologies and describes the physiological biomarkers that can be measured. These phenotypes include impaired ventricular and atrial function, maladaptive ventricular remodeling, and the proliferation of myocardial steatosis and fibrosis. The discussion outlines the applications of CMR to understanding the developmental pathways leading to impaired cardiac function. The use of CMR, both in animal models of developmental programming and in human studies, is described. Specific examples are given in a baboon model of intrauterine growth restriction (IUGR). CMR offers great potential as a tool for understanding the sequence of dysfunctional adaptations of developmental origin that can affect the human cardiovascular system. [ABSTRACT FROM AUTHOR]

Optimal placental function is critical for fetal development, and therefore a crucial consideration for understanding the developmental origins of health and disease (DOHaD). The structure of the fetal side of the placental vasculature is an important determinant of fetal growth and cardiovascular development. There are several imaging modalities for assessing feto-placental structure including stereology, electron microscopy, confocal microscopy, micro-computed tomography, light-sheet microscopy, ultrasonography and magnetic resonance imaging. In this review, we present current methodologies for imaging feto-placental vasculature morphology ex vivo and in vivo in human and experimental models, their advantages and limitations and how these provide insight into placental function and fetal outcomes. These imaging approaches add important perspective to our understanding of placental biology and have potential to be new tools to elucidate a deeper understanding of DOHaD. [ABSTRACT FROM AUTHOR]

Overconsumption of fructose time dependently induces the development of non-alcoholic fatty liver disease (NAFLD). We investigated whether ursolic acid (UA) intake by new-born rats would protect against fructose-induced NAFLD. One hundred and seven male and female Sprague Dawley rat pups were randomly grouped and gavaged (10 ml/kg body weight) with either 0.5% dimethylsulphoxide (vehicle control), 0.05% UA, 50% fructose mixed with UA (0.05%) or 50% fructose alone, from postnatal day 6 (P6) to P20. Post-weaning (P21–P69), the rats received normal rat chow (NRC) and water to drink. On P70, the rats in each group were continued on water or 20% fructose to drink, as a secondary high fructose diet during adulthood. After 8 weeks, body mass, food and fluid intake, circulating metabolites, visceral adiposity, surrogate markers of liver function and indices of NAFLD were determined. Food intake was reduced as a result of fructose feeding in both male and female rats (p < 0.0001). Fructose consumption in adulthood significantly increased fluid intake and visceral adiposity in female rats (p < 0.05) and had no apparent effects in male rats (p > 0.05). In both sexes of rats, fructose had no significant (p > 0.05) effects on body mass, circulating metabolites, total calorie intake and surrogate markers of hepatic function. Fructose consumption in both early life and adulthood in female rats promoted hepatic lipid accumulation (p < 0.001), hypertrophy, microvesicular and macrovesicular steatosis (p < 0.05). Early-life UA intake significantly (p < 0.001) reduced fructose-induced hepatic lipid accumulation in both male and female rats. Administration of UA during periods of developmental plasticity shows prophylactic potential against dietary fructose-induced NAFLD. [ABSTRACT FROM AUTHOR]

The mechanism through which developmental programming of offspring overweight/obesity following in utero exposure to maternal overweight/obesity operates is unknown but may operate through biologic pathways involving offspring anthropometry at birth. Thus, we sought to examine to what extent the association between in utero exposure to maternal overweight/obesity and childhood overweight/obesity is mediated by birth anthropometry. Analyses were conducted on a retrospective cohort with data obtained from one hospital system. A natural effects model framework was used to estimate the natural direct effect and natural indirect effect of birth anthropometry (weight, length, head circumference, ponderal index, and small-for-gestational age [SGA] or large-for-gestational age [LGA]) for the association between pre-pregnancy maternal body mass index (BMI) category (overweight/obese vs normal weight) and offspring overweight/obesity in childhood. Models were adjusted for maternal and child socio-demographics. Three thousand nine hundred and fifty mother–child dyads were included in analyses (1467 [57.8%] of mothers and 913 [34.4%] of children were overweight/obese). Results suggest that a small percentage of the effect of maternal pre-pregnancy BMI overweight/obesity on offspring overweight/obesity operated through offspring anthropometry at birth (weight: 15.5%, length: 5.2%, head circumference: 8.5%, ponderal index: 2.2%, SGA: 2.9%, and LGA: 4.2%). There was a small increase in the percentage mediated when gestational diabetes or hypertensive disorders were added to the models. Our study suggests that some measures of birth anthropometry mediate the association between maternal pre-pregnancy overweight/obesity and offspring overweight/obesity in childhood and that the size of this mediated effect is small. [ABSTRACT FROM AUTHOR]

An adverse early life environment is associated with increased cardiovascular disease in offspring. Work in animal models has shown that maternal undernutrition (UN) during pregnancy leads to hypertension in adult offspring, with effects thought to be mediated in part via altered renal function. We have previously shown that growth hormone (GH) treatment of UN offspring during the pre-weaning period can prevent the later development of cardiometabolic disorders. However, the mechanistic basis for these observations is not well defined. The present study examined the impact of GH treatment on renal inflammatory markers in adult male offspring as a potential mediator of these reversal effects. Female Sprague-Dawley rats were fed either a chow diet fed ad libitum (CON) or at 50% of CON intake (UN) during pregnancy. All dams were fed the chow diet ad libitum during lactation. CON and UN pups received saline (CON-S/UN-S) or GH (2.5 µg/g/day; CON-GH/UN-GH) from postnatal day 3 until weaning (p21). Post-weaning males were fed a standard chow diet for the remainder of the study (150 days). Histological analysis was performed to examine renal morphological characteristics, and gene expression of inflammatory and vascular markers were assessed. There was evidence of renal hypotrophy and reduced nephron number in the UN-S group. Tumour necrosis factor-α, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecular-1 and vascular cell adhesion molecule-1 gene expression was increased in UN-S offspring and normalized in the UN-GH group. These findings indicate that pre-weaning GH treatment has the potential to normalize some of the adverse renal and cardiovascular sequelae that arise as a consequence of poor maternal nutrition. [ABSTRACT FROM AUTHOR]

Exposure to maternal over-nutrition in utero is linked with developmental programming of obesity, metabolic syndrome and cardiovascular disease in offspring, which may be exacerbated by postnatal high-fat (HF) diet. Skeletal muscle mitochondrial function contributes to substrate metabolism and is impaired in metabolic disease. We examined muscle mitochondrial respiration in male and female mice exposed to maternal HF diet in utero , followed by postweaning HF diet until middle age. After in utero exposure to maternal control (Con) or HF diet (45% kcal fat; 39.4% lard, 5.5% soybean oil), offspring were weaned to Con or HF, creating four groups: Con/Con (male/female (m/f), n =8/8), Con/HF (m/f, n =7/4), HF/Con (m/f, n =9/6) and HF/HF (m/f, n =4/4). Oxidative phosphorylation (OXPHOS) and electron transfer system (ETS) capacity were measured in permeabilized gastrocnemius bundles. Maternal HF diet increased fasting glucose and lean body mass in males and body fat percentage in both sexes (P ⩽0.05). Maximal adenosine diphosphate-stimulated respiration (complex I OXPHOS) was decreased by maternal HF diet in female offspring (−21%, P =0.053), but not in male (−0%, P >0.05). Sexually divergent responses were exacerbated in offspring weaned to HF diet. In females, OXPHOS capacity was lower (−28%, P =0.041) when weaned to high-fat (HF/HF) v. control diet (HF/Con). In males, OXPHOS (+33%, P =0.009) and ETS (+42%, P =0.016) capacity increased. Our data suggest that maternal lard-based HF diet, rich in saturated fat, affects offspring skeletal muscle respiration in a sex-dependent manner, and these differences are exacerbated by HF diet in adulthood. [ABSTRACT FROM AUTHOR]

Growth restriction caused by postnatal undernutrition increases risk for cardiovascular disease in adulthood with the potential to induce arrhythmogenesis. Thus, the purpose was to determine if undernutrition during development produced arrhythmias at rest and when stressed with dobutamine in adulthood. Mouse dams were fed (CON: 20% protein), or low-protein (LP: 8%) diet before mating. A cross-fostering model was used where pups nursed by dams fed LP diet in early [EUN; postnatal day (PN) 1–10], late (LUN; PN11–21) and whole (PUN; 1–21) phases of postnatal life. Weaned pups were switched to CON diets for the remainder of the study (PN80). At PN80, body composition (magnetic resonance imaging), and quantitative electrocardiogram (ECG) measurements were obtained under 1% isoflurane anesthesia. After baseline ECG, an IP injection (1.5 µg/g body weight) of dobutamine was administered and ECG repeated. Undernutrition significantly (P <0.05) reduced body weight in LUN (22.68±0.88 g) and PUN (19.96±0.32 g) but not in CON (25.05±0.96 g) and EUN (25.28±0.9207 g). Fat mass decreased in all groups compared with controls (CON: 8.00±1.2 g, EUN: 6.32±0.65 g, LUN: 5.11±1.1 g, PUN: 3.90±0.25 g). Lean mass was only significantly reduced in PUN (CON: 17.99±0.26 g, EUN: 17.78±0.39 g, LUN: 17.34±0.33 g, PUN: 15.85±0.28 g). Absolute heart weights were significantly less from CON, with PUN having the smallest. ECG showed LUN had occurrences of atrial fibrillation; EUN had increases of 1st degree atrioventricular block upon stimulation, and PUN had increased risk for ventricular depolarization arrhythmias. CON did not display arrhythmias. Undernutrition in early life resulted in ventricular arrhythmias under stressed conditions, but undernutrition occurring in later postnatal life there is an increased incidence of atrial arrhythmias. [ABSTRACT FROM AUTHOR]

With brown adipose tissue (BAT) becoming a possible therapeutic target to counteract obesity, the prenatal environment could represent a critical window to modify BAT function and browning of white AT. We investigated if levels of uncoupling protein 1 (UCP1) and UCP1-mediated thermogenesis are altered in offspring exposed to prenatal obesity. Female CD-1 mice were fed a high-fat (HF) or standard-fat (SF) diet for 3 months before breeding. After weaning, all pups were placed on SF. UCP1 mRNA and protein levels were quantified using quantitative real-time PCR and Western blot analysis, respectively, in brown (BAT), subcutaneous (SAT) and visceral (VAT) adipose tissues at 6 months of age. Total and UCP1-dependent mitochondrial respiration were determined by high-resolution respirometry. A Student’s t -test and Mann–Whitney test were used (significance: P <0.05). UCP1 mRNA levels were not different between the HF and SF offspring. UCP1 protein levels, total mitochondrial respiration and UCP1-dependent respiration were significantly higher in BAT from HF males (P =0.02, P =0.04, P =0.005, respectively) and females (P =0.01, P =0.04, P =0.02, respectively). In SAT, the UCP1 protein was significantly lower in HF females (P =0.03), and the UCP1-dependent thermogenesis was significantly lower from HF males (P =0.04). In VAT, UCP1 protein levels and UCP1-dependent respiration were significantly lower only in HF females (P =0.03, P =0.04, respectively). There were no differences in total respiration in SAT and VAT. Prenatal exposure to maternal obesity leads to significant increases in UCP1 levels and function in BAT in offspring with little impact on UCP1 levels and function in SAT and VAT. [ABSTRACT FROM AUTHOR]

The immune system not only provides protection against infectious disease but also contributes to the etiology of neoplastic, atopic, and cardiovascular and metabolic diseases. Prenatal and postnatal nutritional and microbial environments have lasting effects on multiple aspects of immunity, indicating that immune processes may play important roles in the developmental origins of disease. The objective of this study is to evaluate the association between birth weight and the distribution of leukocyte (white blood cell) subsets in peripheral blood in young adulthood. Postnatal microbial exposures were also considered as predictors of leukocyte distribution. Participants (n=486; mean age=20.9 years) were drawn from a prospective birth cohort study in the Philippines, and analyses focused on the following cell types: CD4 T lymphocytes, CD8 T lymphocytes, B lymphocytes, natural killer cells, monocytes, granulocytes. Higher birth weight was a strong predictor of higher proportion of CD4 T lymphocytes (B=0.12, s.e.=0.041, P=0.003), lower proportion of CD8 T lymphocytes (B=−0.874, s.e.=0.364, P=0.016), higher CD4:CD8 ratio (B=1.964, s.e.=0.658, P=0.003), and higher B lymphocytes (B=0.062, s.e.=0.031, P=0.047). Measures of microbial exposure in infancy were negatively associated with proportions of B lymphocytes and granulocytes, and lower CD4:CD8 ratio. Leukocytes are the key regulators and effectors of innate and specific immunity, but the origins of variation in the distribution of cell type across individuals are not known. Our findings point toward nutritional and microbial exposures in infancy as potentially important determinants of immune-phenotypes in adulthood, and they suggest that leukocyte distribution is a plausible mechanism through which developmental environments have lasting effects on disease risk in adulthood. [ABSTRACT FROM PUBLISHER]

Intrauterine growth restriction in animal models reduces heart size and cardiomyocyte number at birth. Such incomplete cardiomyocyte endowment is believed to increase susceptibility toward cardiovascular disease in adulthood, a phenomenon referred to as developmental programming. We have previously described a mouse model of impaired myocardial development leading to a 25% reduction of cardiomyocyte number in neonates. This study investigated the response of these hypoplastic hearts to pressure overload in adulthood, applied by abdominal aortic constriction (AAC). Echocardiography revealed a similar hypertrophic response in hypoplastic hearts compared with controls over the first 2 weeks. Subsequently, control mice develop mild left ventricular (LV) dilation, wall thinning and contractile dysfunction 4 weeks after AAC, whereas hypoplastic hearts fully maintain LV dimensions, wall thickness and contractility. At the cellular level, controls exhibit increased cardiomyocyte crosssectional area after 4 weeks pressure overload compared with sham operated animals, but this hypertrophic response is markedly attenuated in hypoplastic hearts. AAC mediated induction of fibrosis, apoptosis or cell cycle activity was not different between groups. Expression of fetal genes, indicative of pathological conditions, was similar in hypoplastic and control hearts after AAC. Among various signaling pathways involved in cardiac hypertrophy, pressure overload induces p38 MAP-kinase activity in hypoplastic hearts but not controls compared with the respective sham operated animals. In summary, based on themousemodel used in this study, our data indicates that adult hearts after neonatal cardiac hypoplasia show an altered growth response to pressure overload, eventually resulting in better functional outcome compared with controls. [ABSTRACT FROM AUTHOR]

Obesity is a global epidemic, affecting both developed and developing countries. The related metabolic consequences that arise from being overweight or obese are a paramount global health concern, and represent a significant burden on healthcare systems. Furthermore, being overweight or obese during pregnancy increases the risk of offspring developing obesity and other related metabolic complications in later life, which can therefore perpetuate a transgenerational cycle of obesity. Obesity is associated with a chronic state of low-grade metabolic inflammation. However, the role of maternal obesity-mediated alterations in inflammatory processes as a mechanism underpinning developmental programming in offspring is less understood. Further, the use of anti-inflammatory agents as an intervention strategy to ameliorate or reverse the impact of adverse developmental programming in the setting of maternal obesity has not been well studied. This review will discuss the impact of maternal obesity on key inflammatory pathways, impact on pregnancy and offspring outcomes, potential mechanisms and avenues for intervention. [ABSTRACT FROM PUBLISHER]

Fructose (C 6 H 12 O 6 ) is acutely obesogenic and is a risk factor for hypertension, cardiovascular disease, and nonalcoholic fatty liver disease. However, the possible long-lasting effects of early-life fructose consumption have not been studied. We tested for effects of early-life fructose and/or wheel access (voluntary exercise) in a line of selectively bred High Runner (HR) mice and a non-selected Control (C) line. Exposures began at weaning and continued for 3 weeks to sexual maturity, followed by a 23-week "washout" period (equivalent to ∼17 human years). Fructose increased total caloric intake, body mass, and body fat during juvenile exposure, but had no effect on juvenile wheel running and no important lasting effects on adult physical activity or body weight/composition. Interestingly, adult maximal aerobic capacity (VO 2 max) was reduced in mice that had early-life fructose and wheel access. Consistent with previous studies, early-life exercise promoted adult wheel running. In a 3-way interaction, C mice that had early-life fructose and no wheel access gained body mass in response to 2 weeks of adult wheel access, while all other groups lost mass. Overall, we found some long-lasting positive effects of early-life exercise, but minimal effects of early-life fructose, regardless of the mouse line.

It is now accepted that the way our health evolves with aging is intimately linked to the quality of our early life. The present review highlights the emerging data of Developmental Origins of Health and Disease field on developmental disruption by toxicants and their subsequent effect on type 2 diabetes. We report adverse neonatal effects of several food contaminants during pregnancy and lactation, among them bisphenol A, chlorpyrifos, perfluorinated chemicals on pancreas integrity and functionality in later life. The described alterations, in conjunction with disruption of β cell mass in early life, can lead to dysregulation of glucose metabolism, insulin synthesis, which facilitates the development of insulin resistance and progression of diabetes in the adult. Despite limited and often inconclusive epidemiologic and experimental data, more recent data clearly show that infants appear to be at increased risk of type 2 diabetes in later life. This may be a result of continued exposure to chemical food contaminants during the critical window of pancreas development. In societies already burdened with increased incidence of non-communicable chronic diseases, there is a clear need for information regarding the potential harmful effects of chemical food contaminants on adult health diseases. [ABSTRACT FROM PUBLISHER]

Prenatal development is highly plastic and readily influenced by the environment. Adverse conditions have been shown to alter organ development and predispose offspring to chronic diseases, including diabetes and hypertension. Notably, it appears that the changes in glucocorticoid hormones or glucocorticoid receptor (GR) levels in peripheral tissues could play a role in the development of chronic diseases. We have previously demonstrated that in vitro fertilization (IVF) and preimplantation embryo culture is associated with growth alterations and glucose intolerance in mice. However, it is unknown if GR signaling is affected in adult IVF offspring. Here we show that GR expression is increased in inbred (C57Bl6/J) and outbred (CF-1× B6D2F1/J) blastocysts following in vitro culture and elevated levels are also present in the adipose tissue of adult male mice. Importantly, genes involved in lipolysis and triglyceride synthesis and responsive to GR were also increased in adipose tissue, indicating that increased GR activates downstream gene pathways. The promoter region of GR, previously reported to be epigenetically modified by perinatal manipulation, showed no changes in DNA methylation status. Our findings demonstrate that IVF results in a long-term change in GR gene expression in a sex- and tissue-specific manner. These changes in adipose tissues may well contribute to the metabolic phenotype in mice conceived by IVF. [ABSTRACT FROM PUBLISHER]

The rise in the occurrence of obesity to epidemic proportions has made it a global concern. Great difficulty has been experienced in efforts to control this growing problem with lifestyle interventions. Thus, attention has been directed to understanding the events of one of the most critical periods of development, perinatal life. Early life adversity driven by maternal obesity has been associated with an increased risk of metabolic disease and obesity in the offspring later in life. Although a mechanistic link explaining the relationship between maternal and offspring obesity is still under investigation, the gut microbiota has come forth as a new factor that may play a role modulating metabolic function of both the mother and the offspring. Emerging evidence suggests that the gut microbiota plays a much larger role in mediating the risk of developing non-communicable disease, including obesity and metabolic dysfunction in adulthood. With the observation that the early life colonization of the neonatal and postnatal gut is mediated by the perinatal environment, the number of studies investigating early life gut microbial establishment continues to grow. This paper will review early life gut colonization in experimental animal models, concentrating on the role of the early life environment in offspring gut colonization and the ability of the gut microbiota to dictate risk of disease later in life. [ABSTRACT FROM PUBLISHER]

In today's world, there is an unprecedented rise in the prevalence of chronic metabolic diseases, including obesity, insulin resistance and type 2 diabetes (T2D). The pathogenesis of T2D includes both genetic and environmental factors, such as excessive energy intake and physical inactivity. It has recently been suggested that environmental factors experienced during early stages of development, including the intrauterine and neonatal periods, might play a major role in predisposing individuals to T2D. Furthermore, several studies have shown that such early environmental conditions might even contribute to disease risk in further generations. In this review, we summarise recent data describing how parental nutrition during development increases the risk of diabetes in the offspring. We also discuss the potential mechanisms underlying transgenerational inheritance of metabolic disease, with particular emphasis on epigenetic mechanisms. [ABSTRACT FROM PUBLISHER]

We examined developmental programming studies that reported sex-specific effects published between 2012 and 2014, and examined whether the authors reported a statistical approach to explicitly test whether the effect of treatment differed between the sexes, for example, a sex by treatment interaction term. Less than half of the studies that reported sex-specific effects described explicitly testing whether effects were indeed sex-specific; in most cases, an effect was considered ‘sex-specific’ if it was significant in one sex but not the other. This is not a robust approach, since significance in one sex and lack of significance in the other sex does not imply a significant difference between the sexes. However, sample size often limits statistical power to detect interactions. We suggest that if the effect is significant in only one sex, but the interaction term is not significant, alternative solutions would be to present the confidence intervals for the effect size for each sex, or using Bayesian approaches to calculate the probability that the effect sizes differ between the sexes. We present a simple example of a Bayesian analysis to illustrate that this approach is reasonably easy to implement and interpret. [ABSTRACT FROM PUBLISHER]

Predisposition to offspring metabolic dysfunction due to poor maternal nutrition differs with the developmental stage at exposure. Post-weaning nutrition also influences offspring phenotype in either adverse or beneficial ways. We studied a well-established rat maternal protein-restriction model to determine whether post-weaning dietary intervention improves adverse outcomes produced by a deficient maternal nutritional environment in pregnancy. Pregnant rats were fed a controlled diet (C, 20% casein) during pregnancy and lactation (CC) or were fed a restricted diet (R, 10% casein isocaloric diet) during pregnancy and C diet during lactation (RC). After weaning, the offspring were fed the C diet. At postnatal day (PND) 70 (young adulthood), female offspring either continued with the C diet (CCC and RCC) or were fed commercial Chow Purina 5001 (I) to further divide the animals into dietary intervention groups CCI and RCI. Another group of mothers and offspring were fed I throughout (III). Offspring food intake was averaged between PND 95–110 and 235–250 and carcass and liver compositions were measured at PND 25 and 250. Leptin (PND 110 and 250) and serum glucose, triglycerides and cholesterol (PND 250) levels were measured. Statistical analysis was carried out using ANOVA. At PND 25, body and liver weights were similar between groups; however, CCC and RCC carcass protein:fat ratios were lower compared with III diet. At PND 110 and 250, offspring CCC and RCC had higher body weight, food intake and serum leptin compared with CCI and RCI. CCI had lower carcass fat and increased protein compared with CCC and improved fasting glucose and triglycerides. Adult dietary intervention partially overcomes adverse effects of programming. Further studies are needed to determine the mechanisms involved. [ABSTRACT FROM PUBLISHER]

The development and life performance of 404 high-producing Holstein dairy cows was studied from birth onwards and during two lactations. The management, environment and parental genetics of the cows were known in detail. Cluster analysis identified four performance ‘types’: high-yielding (HY) cows and persistently high-yielding (PHY) cows, which accounted for 33% of the animals; medium-yielding (MY) cows, 41%; and low-yielding (LY) cows, 26%. Prenatal determinants of the life performance of the progeny were analyzed. Developmental and environmental factors were excluded as determinants of performance (including birth weight, level of passive immunity transfer, growth rate, age at first parturition and reproductive efficiency). Life performance did show minor seasonal effects, with more HY cows but less PHY being born during the cold season (90.1% in HY; 58.3% in PHY v. 81.5%). Instead, the single most important factor influencing life performance of daughters was maternal age. HY cows were born from the youngest mothers (1.89±1.14 parturitions, 3.12±1.42-year old), whereas LY cows were born from the oldest (2.72±1.80 parturitions, 3.97±2.01-year old; P<0.001). Life performance of the dams did not differ among clusters. In addition, metabolic parameters (fat and protein yield) were found to correlate significantly with yields between the first and second lactations (milk yield: r=0.357; fat yield: r=0.211; protein yield: r=0.277; P<0.0001), suggesting the influence of the individual. These results suggest that under optimal health, nutritional and environmental conditions, maternal aging is an important determinant of the life performance of progeny and argue for the need to identify conditions that contribute to health and disease in progeny according to the Developmental Origin of Health and Disease or DOHaD concept. Our findings may help the development of novel management guidelines for dairy farms. [ABSTRACT FROM PUBLISHER]

The main role of early nutritional programming in the current rise of obesity and associated diseases is well known. However, translational studies are mostly based in postnatal food excess and, thus, there is a paucity of information on the phenotype of individuals with prenatal deficiencies but adequate postnatal conditions. Thus, we assessed the effects of prenatal programming (comparing descendants from females fed with a diet fulfilling 100 or only 50% of their nutritional requirements for pregnancy) on gene expression, patterns of growth and fattening, metabolic status and puberty attainment of a swine model of obesity/leptin resistance with controlled postnatal nutrition and opportunity of exercise. Maternal restriction was related to changes in the relationships among gene expression of positive (insulin-like growth factors 1 and 2) and negative (myostatin) regulators of muscle growth, with negative correlations in gilts from restricted pregnancies and positive relationships in the control group. In spite of these differences, the patterns of growth and fattening and the metabolic features during juvenile growth were similar in control gilts and gilts from restricted pregnancies. Concomitantly, there was a lack of differences in the timing of puberty attainment. However, after reaching puberty and adulthood, females from restricted pregnancies were heavier and more corpulent than control gilts, though such increases in weight and size were not accompanied by increases in adiposity. In conclusion, in spite of changes in gene expression induced by developmental programming, the propensity for higher weight and adiposity of individuals exposed to prenatal malnutrition may be modulated by controlled food intake and opportunity of physical exercise during infant and juvenile development. [ABSTRACT FROM PUBLISHER]

Epidemiological studies, including those in identical twins, and in individuals in utero during periods of famine have provided robust evidence of strong correlations between low birth-weight and subsequent risk of disease in later life, including type 2 diabetes (T2D), CVD, and metabolic syndrome. These and studies in animal models have suggested that the early environment, especially early nutrition, plays an important role in mediating these associations. The concept of early life programming is therefore widely accepted; however the molecular mechanisms by which early environmental insults can have long-term effects on a cell and consequently the metabolism of an organism in later life, are relatively unclear. So far, these mechanisms include permanent structural changes to the organ caused by suboptimal levels of an important factor during a critical developmental period, changes in gene expression caused by epigenetic modifications (including DNA methylation, histone modification and microRNA) and permanent changes in cellular ageing. Many of the conditions associated with early-life nutrition are also those which have an age-associated aetiology. Recently, a common molecular mechanism in animal models of developmental programming and epidemiological studies has been development of oxidative stress and macromolecule damage, specifically DNA damage and telomere shortening. These are phenotypes common to accelerated cellular ageing. Thus, this review will encompass epidemiological and animal models of developmental programming with specific emphasis on cellular ageing and how these could lead to potential therapeutic interventions and strategies which could combat the burden of common age-associated disease, such as T2D and CVD. [ABSTRACT FROM PUBLISHER]

The intake of marine n-3 PUFA has been shown to decrease the risk of CVD in a number of studies. Since the development of CVD is often a lifelong process, marine n-3 PUFA intake early in life may also affect the development of later CVD. The aim of the present study was to investigate the association between maternal intake of marine n-3 PUFA during the second trimester of pregnancy and factors associated with cardiometabolic risk in the 20-year-old offspring. The study was based on the follow-up of the offspring of a Danish pregnancy cohort who participated in a study conducted from 1988 to 1989. A total of 965 pregnant women were originally included in the cohort and detailed information about the intake of marine n-3 PUFA during the second trimester was collected. In 2008–9, the offspring were invited to participate in a clinical examination including anthropometric, blood pressure (BP) and short-term heart rate variability measurements. Also, a fasting venous blood sample was drawn from them. Multiple linear regression modelling, using the lowest quintile of marine n-3 PUFA intake as the reference, was used to estimate the association with all outcomes. A total of 443 offspring participated in the clinical examination. No association between the intake of marine n-3 PUFA during the second trimester of pregnancy and offspring adiposity, glucose metabolism, BP or lipid profile was found. In conclusion, no association between the intake of marine n-3 PUFA during the second trimester of pregnancy and the factors associated with cardiometabolic risk in the 20-year-old offspring could be detected. [ABSTRACT FROM PUBLISHER]

An infant's early developmental environment plays a pivotal role in the programming of its physiological phenotype. The identification of the factors in the maternal environment that mediate the effects of maternal obesity and diet is essential to the development of clinical intervention strategies. Maternal hyperglycaemia, hyperinsulinaemia, hypertriglyceridaemia, hyperleptinaemia and altered inflammatory cytokines concentrations are potentially important predictive factors of her future offspring's susceptibility to metabolic disease. Using a diet-induced obese mouse model, we have investigated which of these maternal factors could induce adverse metabolic programming in the offspring. Female C57Bl/6 mice were fed either laboratory chow (10% fat) or high fat diet (42% fat) for 10 weeks before mating and throughout gestation. At day 18 of pregnancy, maternal body weight, body composition and glucose tolerance were measured, as well as plasma insulin, adiponectin, RBP4, leptin, resistin and the inflammatory cytokines (IL6, IL10, IL12, IL1β, IFNγ, KC, TNF-α). At day 18 of pregnancy, high fat-fed dams were significantly heavier than the chow dams and had increased fat mass. High fat-fed dams had higher 5 h fasting blood glucose than chow dams and elevated plasma insulin. Although the obese dams had both reduced plasma adiponectin and resistin levels compared with lean dams, their plasma IL6, IL10 and IFNγ levels were all increased. High fat feeding in pregnancy leads to altered plasma concentrations of both adipokines and adipocytokines in the dam that may directly pass to the fetus and affect their development. [ABSTRACT FROM PUBLISHER]

It is widely recognized that environmental insults during adulthood including smoking, lack of exercise and a poor diet increases an individual's risk of cardiovascular disease (CVD). However, research initiated over the last two decades has highlighted that our risk of CVD can be programmed following adverse exposures during early development. Such adverse exposures may include, undernutrition, placental insufficiency, hypoxia, overnutrition and obesity. This review aims to address the current Western obesity crisis by addressing the long-term impact of maternal overnutrition and obesity on the offspring's future risk of CVD. Although current human studies have observed the presence of adverse CVD markers in children born to obese mothers, animal models have proved vital in understanding the underlying mechanisms involved. Mechanisms suggested to be involved in the programming of CVD in the offspring include increased oxidative stress, inflammation, lipotoxicity and epigenetics. CVD remains the greatest cause of death worldwide, therefore further understanding of the mechanisms mediating these effects is important in the development of intervention strategies. [ABSTRACT FROM PUBLISHER]

Maternal undernutrition during pregnancy increases offspring obesity and metabolic disease risk. We hypothesized that periconceptional undernutrition in sheep from 60 days before conception through to day 30 of gestation (UN) would decrease voluntary locomotor activity in adult offspring. Distance travelled was measured at 18 months of age for ∼48 h in the paddock. Data were analysed using multiple regression analysis, with explanatory variables including sex, nutrition group, birth weight, average time between GPS measurements and percentage of time during the measurement period spent in daylight. Mean (±s.e.) distance walked (m/h) was greater for control (CON) than UN animals, and greater for females than males [110.2 (6.5), CON females; 110.7 (6.3), CON males; 105.1 (5.3), UN females and 95.5 (5.8), UN males; P = 0.02 for nutrition group effect and for sex effect]. Periconceptional undernutrition may lead to a significant decrease in voluntary physical activity in adult offspring. [ABSTRACT FROM PUBLISHER]

A growing body of evidence highlights the importance of the nutritional or other environmental stimuli during critical periods of development in the long-term programming of organ systems and homeostatic pathways of the organism. The adverse influences early in development and particularly during intrauterine life have been shown to programme the risks for adverse health outcomes in adult life. The mechanisms underlying developmental programming remain still unclear. However, increasing evidence has been accumulated indicating the important role of epigenetic regulation including DNA methylation, histone modifications and non-coding RNAs in the developmental programming of late-onset pathologies, including cancer, neurodegenerative diseases, and type 2 diabetes. The maternal substance abuse during pregnancy, including smoking, drinking and psychoactive drug intake, is one of the important factors determining the process of developmental programming in modern human beings. The impact of prenatal drug/substance exposure on infant and early childhood development is currently in the main focus. The long-term programming effects of such exposures on aging and associated pathologies, however, have been reported only rarely. The purpose of this review is to provide a summary of recent research findings which indicate that maternal substance abuse during pregnancy and/or neonatal period can programme not only a child's health status, but also can cause long-term or even life-long health outcomes via mechanisms of epigenetic memory. [ABSTRACT FROM PUBLISHER]

Adaptations of post-hatching animals have attracted far more study than have embryonic responses to environmental challenges, but recent research suggests that we have underestimated the complexity and flexibility of embryos. We advocate a dynamic view of embryos as organisms capable of responding - on both ecological and evolutionary timescales - to their developmental environments. By viewing embryos in this way, rather than assuming an inability of pre-hatching stages to adapt and respond, we can broaden the ontogenetic breadth of evolutionary and ecological research. Both biotic and abiotic factors affect embryogenesis, and embryos exhibit a broad range of behavioural and physiological responses that enable them to deal with changes in their developmental environments in the course of interactions with their parents, with other embryos, with predators, and with the physical environment. Such plasticity may profoundly affect offspring phenotypes and fitness, and in turn influence the temporal and spatial dynamics of populations and communities. Future research in this field could benefit from an integrated framework that combines multiple approaches (field investigations, manipulative experiments, ecological modelling) to clarify the mechanisms and consequences of embryonic adaptations and plasticity., (© 2022 Cambridge Philosophical Society.)

Studies in experimental animals and human subjects have suggested that intake of n-3 fatty acids in early life can affect cardiovascular risk factors in adult life. Therefore, the aim of the present study was to investigate the effect of fish oil (FO) supplementation during the third trimester of pregnancy on blood pressure (BP), heart rate (HR) and HR variability (HRV) in the 19-year-old offspring. The study was based on follow-up of a randomised, controlled trial from 1990, in which 533 pregnant women were randomised to FO, olive oil (OO) or no oil (NO) during the last trimester of pregnancy. The offspring was invited to a physical examination including BP, HR and HRV measurements. A subgroup consisting of the offspring of mothers with a low baseline fish intake also had 24 h HRV determined. The OO group was used as reference and multiple linear regression modelling was used to compare the FO and OO groups. A total of 180 of the offspring from the FO and OO groups agreed to participate in the study (45 %). The adjusted difference between the FO and OO groups was 2 (95 % CI − 1, 4) mmHg in systolic and 1 (95 % CI 0, 3) mmHg in diastolic BP. The difference in HR was 1 (95 % CI − 2, 4). Also, HRV indices did not differ significantly between groups. Hence, FO supplementation during late pregnancy was not associated with offspring BP, HR and HRV during adolescence. [ABSTRACT FROM PUBLISHER]

Maternal exposure to environmental agents throughout pregnancy may change certain metabolic processes during the offspring's mammary gland development and alter the epigenome. This may predispose the offspring to breast cancer later in life. The purpose of the present study was to examine the effect of maternal protein restriction on the regulation of cyclin-dependent kinase inhibitor 1 (p21) gene expression in the mammary gland of rat offspring. Timed-mated Sprague–Dawley rats were fed one of the two isoenergetic diets, control (C, 18 % casein) or low protein (LP, 9 % casein), during gestation. Compared with the C group, LP offspring showed a decrease of p21 in the mammary gland at both the mRNA and protein levels. Chromatin immunoprecipitation assay demonstrated that the down-regulation of p21 transcription in LP offspring was associated with reduced acetylation of histone H3 and dimethylation of H3K4 within the p21 promoter region, but was not associated with acetylation of histone H4 or histone methylation. DNA methylation analysis using bisulphite sequencing did not detect differences in methylation at the p21 promoter between the offspring of the C and LP groups. We conclude that maternal protein restriction inhibits p21 gene expression in the mammary gland of offspring through histone modifications at the promoter region of the p21 gene. [ABSTRACT FROM PUBLISHER]

It is well established that altered maternal nutrition may induce long-term metabolic consequences in offspring. However, the effects of maternal undernutrition during different developmental windows on sex-specific growth and metabolism in offspring are not well defined. We investigated the effect of moderate maternal undernutrition during pregnancy and/or lactation on postnatal growth and metabolic outcomes in offspring. Wistar rats were randomly assigned to one of four groups: (1) control (CONT) dams fed a standard diet throughout pregnancy and lactation; (2) dams undernourished to 50 % of CONT during pregnancy (UNP); (3) dams fed at 50 % of CONT throughout lactation (UNL); (4) dams fed at 50 % of CONT throughout pregnancy and lactation (UNPL). UNP and UNPL offspring were lighter at birth compared to CONT and UNL. UNL and UNPL offspring were growth restricted at weaning and remained smaller into adulthood. UNP males and females developed increased adiposity and hyperleptinaemia in adulthood compared to all other groups. Adiposity in UNL and UNPL males was similar to CONT offspring. In UNL and UNPL females, adiposity was lower than for CONT females. Markers of bone mass, lipid metabolism and hepatic function were altered in UNP offspring but were similar in UNL and UNPL offspring compared to CONT. Lack of catch-up growth during lactation in offspring of undernourished mothers prevented development of adiposity and related metabolic disorders in later life. These data highlight that the timing and duration of undernutrition during critical windows of development exert differential effects on postnatal outcomes in a sex-specific manner. [ABSTRACT FROM PUBLISHER]

Maternal low-protein (LP) diets programme β-cell secretion, potentially altering the emergence of ageing of offspring pancreatic function. We hypothesised that isolated pancreatic islet β-cell secretory responses are blunted in offspring exposed to LP during development and age-related reduction is influenced by the developmental stage of exposure to decreased nutrition. We studied male offspring of rats fed control (C) or LP protein (R) diets in pregnancy, first letter and/or lactation second letter of CC, RR, CR or RC groups. Serum glucose, insulin and homeostatic model assessment (HOMA) were measured. Pancreatic islets were isolated and in vitro insulin secretion quantified in low (LG – 5 mm) or high glucose (HG – 11 mm). Body weight and serum values between groups were similar at all ages. Insulin and HOMA rose with age and were highest at postnatal day (PND) 450 in all groups. At PND 36, insulin secretion was greatest in RR and RC. Only CC increased insulin secretion to HG. By PND 110, restricted groups responded less to LG but increased secretion to HG. By PND 450, CC offspring alone increased secretion to HG. Despite minimal differences in circulating insulin and glucose, reduced maternal protein intake affected insulin secretion at all ages. In addition, ageing reduced function in all R groups compared with CC by PND 110 and further by PND 450 most markedly in RC. We conclude that maternal LP diet during pregnancy and/or lactation impairs offspring insulin secretory response to a glucose challenge and alters the trajectory of ageing of pancreatic insulin secretion. [ABSTRACT FROM PUBLISHER]

Increasing evidence from the EU Project EARNEST and many other investigators demonstrates that early nutrition and lifestyle have long-term effects on later health and the risk of common non-communicable diseases (known as ‘developmental programming’). Because of the increasing public health importance and the transgenerational nature of the problem, obesity and associated disorders are the focus of the new EU funded project ‘EarlyNutrition’. Currently, three key hypotheses have been defined: the fuel mediated ‘in utero’ hypothesis suggests that intrauterine exposure to an excess of fuels, most notably glucose, causes permanent changes of the fetus that lead to obesity in postnatal life; the accelerated postnatal weight gain hypothesis proposes an association between rapid weight gain in infancy and an increased risk of later obesity and adverse outcomes; and the mismatch hypothesis suggests that experiencing a developmental ‘mismatch’ between a sub-optimal perinatal and an obesogenic childhood environment is related to a particular predisposition to obesity and corresponding co-morbidities. Using existing cohort studies, ongoing and novel intervention studies and a basic science programme to investigate those key hypotheses, project EarlyNutrition will provide the scientific foundations for evidence-based recommendations for optimal nutrition considering long-term health outcomes, with a focus on obesity and related disorders. Scientific and technical expertise in placental biology, epigenetics and metabolomics will provide understanding at the cellular and molecular level of the relationships between early life nutritional status and the risk of later adiposity. This will help refine strategies for intervention in early life to prevent obesity. [ABSTRACT FROM PUBLISHER]

Both in man and in animal models, changes in food intake and body composition in later life have been reported after alterations in perinatal nutrition. Therefore, we hypothesised that early postnatal undernutrition in the rat induces permanent changes in energy balance. Food restriction (FR) during lactation was achieved by enlarging litter size to twenty pups, whereas control animals were raised in litters containing ten pups. Energy intake and resting energy expenditure were determined in adult males. Early postnatal FR resulted in acute growth restriction followed by incomplete catch-up in body weight, body length and BMI. At the age of 12 months, middle-aged FR males had significantly lower absolute resting energy expenditure (200 v. 216??kJ/24??h, P??=??0??009), absolute energy intake (281 v. 310??kJ/24??h, P??=??0??001) and energy intake adjusted for BMI (284 v. 305??kJ/24??h, P??=??0??016) than controls, whereas resting energy expenditure adjusted for BMI did not differ significantly between the groups (204 v. 211??kJ/24??h, P??=??0??156). The amount of energy remaining for other functions was lower in FR males (80 v. 94??kJ/24??h, P??=??0??044). Comparable data were obtained at the age of 6 months. These results indicate that in rats energy balance can be programmed by early nutrition. A low early postnatal food intake appears to programme these animals for a low energy intake and to remain slender in adult life. [ABSTRACT FROM PUBLISHER]