André Krumel Portella

Developmental origins of health and disease (DOHaD)

OBJECTIVE To present a new branch of scientific knowledge, known as the developmental origins of health and disease (DOHaD), covering its concepts, study methods and ethical considerations in addition to the prospects for this area of knowledge. SOURCES A non-systematic review of the biomedical literature intended to identify historical and current references related to the subject under discussion. SUMMARY OF THE FINDINGS Recent studies demonstrate associations between aggressions suffered during the initial phases of somatic development and amplified risk of chronic diseases throughout life, such as obesity, diabetes and cardiovascular diseases. A variety of models have been proposed in attempts to better explain these associations, such as the thrifty phenotype, programming and predictive adaptive response theories and the concept of match or mismatch. Some of the mechanisms possibly involved in these processes are: effects of the environment on gene expression, through epigenetic mechanisms; effects of hormonal signals transmitted to the fetus via the placenta or the newborn via lactation. CONCLUSIONS DOHaD draws together information originating from many different areas of knowledge, proposing new investigative methodologies to elucidate the influence of adverse events that occur during early phases of human development on the pattern of health and disease throughout life. This new scientific field proposes new models of causality and of the mechanisms involved in the emergence and development of chronic diseases. The results of these investigations may result in a significant impact on the prevention of chronic diseases, and also on health promotion in different phases of life.

Severe intrauterine growth restriction is associated with higher spontaneous carbohydrate intake in young women.

Intrauterine growth restriction (IUGR) is associated with metabolic disorders in adulthood. In rats, an early adverse environment alters food preferences in adult life. We investigated whether IUGR is associated with spontaneous macronutrient preferences in humans. Two thousand sixty-three participants from a Brazilian birth cohort were evaluated at 24 y of age using a food frequency questionnaire, physical examination, anthropometric measurements, and biochemical assays (glucose, insulin, cholesterol, and triglycerides). IUGR was defined by the birth weight ratio (BWR = birth weight/mean weight for gestational age). Individuals were classified as non growth restricted (BWR ≥0.85), moderately growth restricted (0.85 > BWR ≥ 0.75), and severely growth restricted (BWR <0.75). Severe IUGR women consumed a greater carbohydrate to protein ratio, even after controlling for social variables. There was a continuous association between growth restriction and later carbohydrate to protein ratio consumption in women. Women from both IUGR groups had a larger waist to hip ratio (WHR). The prevalence of metabolic syndrome was comparable between the groups. IUGR women preferred carbohydrates to protein in their regular diet, suggesting that spontaneous food choices may precede the appearance and contribute to the risk for metabolic diseases in this group.

Intrauterine Growth Restriction and the Fetal Programming of the Hedonic Response to Sweet Taste in Newborn Infants

Intrauterine growth restriction is associated with increased risk for adult metabolic syndrome and cardiovascular disease, which seems to be related to altered food preferences in these individuals later in life. In this study, we sought to understand whether intrauterine growth leads to fetal programming of the hedonic responses to sweet. Sixteen 1-day-old preterm infants received 24% sucrose solution or water and the taste reactivity was filmed and analyzed. Spearman correlation demonstrated a positive correlation between fetal growth and the hedonic response to the sweet solution in the first 15 seconds after the offer (r = 0.864, P = 0.001), without correlation when the solution given is water (r = 0.314, P = 0.455). In fact, the more intense the intrauterine growth restriction, the lower the frequency of the hedonic response observed. IUGR is strongly correlated with the hedonic response to a sweet solution in the first day of life in preterm infants. This is the first evidence in humans to demonstrate that the hedonic response to sweet taste is programmed very early during the fetal life by the degree of intrauterine growth. The altered hedonic response at birth and subsequent differential food preference may contribute to the increased risk of obesity and related disorders in adulthood in intrauterine growth-restricted individuals.

Preliminary evidence for an impulsivity-based thrifty eating phenotype.

Introduction:Low birth weight is associated with obesity and an increased risk for metabolic/cardiovascular diseases in later life.Results:The results of the snack delay test, which encompassed four distinct trials, indicated that the gender × intrauterine growth restriction (IUGR) × trial interaction was a predictor of the ability to delay the food reward (P = 0.002). Among children with normal birth weights, girls showed a greater ability to delay food rewards than did boys (P = 0.014).In contrast, among children with IUGR, there was no such differential ability between girls and boys. Furthermore, in girls, impulsive responding predicted both increased consumption of palatable fat (P = 0.007) and higher BMIs (P = 0.020) at 48 mo of age, although there was no such association with BMI at 36 mo.Discussion:In girls, the quality of fetal growth may contribute to impulsive eating, which may promote an increased intake of fats and consequently higher BMIs. As with the original thrifty phenotype, such a mechanism would be adaptive when food supplies are sparse, but would be problematic in societies with ample access to calorically rich foods.Methods:We examined whether the quality of intrauterine growth programs obesogenic eating behaviors, by investigating (i) the relationship between birth weight and impulsive eating in 3-year-old children (using the snack delay test), and (ii) whether impulsive eating predicts fat intake and/or BMI at 4 years of age (using a laboratory-based test meal).

Both Food Restriction and High-Fat Diet during Gestation Induce Low Birth Weight and Altered Physical Activity in Adult Rat Offspring: The “Similarities in the Inequalities” Model

We have previously described a theoretical model in humans, called “Similarities in the Inequalities”, in which extremely unequal social backgrounds coexist in a complex scenario promoting similar health outcomes in adulthood. Based on the potential applicability of and to further explore the “similarities in the inequalities” phenomenon, this study used a rat model to investigate the effect of different nutritional backgrounds during gestation on the willingness of offspring to engage in physical activity in adulthood. Sprague-Dawley rats were time mated and randomly allocated to one of three dietary groups: Control (Adlib), receiving standard laboratory chow ad libitum; 50% food restricted (FR), receiving 50% of the ad libitum-fed dam’s habitual intake; or high-fat diet (HF), receiving a diet containing 23% fat. The diets were provided from day 10 of pregnancy until weaning. Within 24 hours of birth, pups were cross-fostered to other dams, forming the following groups: Adlib_Adlib, FR_Adlib, and HF_Adlib. Maternal chow consumption and weight gain, and offspring birth weight, growth, physical activity (one week of free exercise in running wheels), abdominal adiposity and biochemical data were evaluated. Western blot was performed to assess D2 receptors in the dorsal striatum. The “similarities in the inequalities” effect was observed on birth weight (both FR and HF groups were smaller than the Adlib group at birth) and physical activity (both FR_Adlib and HF_Adlib groups were different from the Adlib_Adlib group, with less active males and more active females). Our findings contribute to the view that health inequalities in fetal life may program the health outcomes manifested in offspring adult life (such as altered physical activity and metabolic parameters), probably through different biological mechanisms.

Neurobehavioral determinants of nutritional security in fetal growth–restricted individuals

Fetal growth restriction results from a failure to achieve a higher growth potential and has been associated with many maternal conditions, such as chronic diseases (infections, hypertension, and some cases of diabetes and obesity), exposures (tobacco smoke, drugs), and malnutrition. This early adversity induces a series of adaptive physiological responses aimed at improving survival, but imposing increased risk for developing chronic nontransmittable diseases (obesity, type II diabetes, cardiovascular disease) in the long term. Recently, mounting evidence has shown that fetal growth impairment is related to altered feeding behavior and preferences through the life course. When living in countries undergoing nutritional transition, in which individuals experience the coexistence of underweight and overweight problems (the “double burden of malnutrition”), fetal growth–restricted children can be simultaneously growth restricted and overweight—a double burden of malnutrition at the individual level. Considering food preferences as an important aspect of nutrition security, we will summarize the putative neurobiological mechanisms at the core of the relationship between fetal growth and nutrition security over the life course and the evidence linking early life adversity to later food preferences.

Could preference for palatable foods in neonatally handled rats alter metabolic patterns in adult life

Previous studies indicate that, in adulthood, neonatally handled rats consume more sweet food than nonhandled rats. The aim of the present study was to assess the effects of the chronic exposure to a palatable diet (chocolate) in adult neonatally handled rats. We measured the consumption of foods (standard lab chow and chocolate), body weight gain, abdominal fat deposition, and levels of plasma lipids, glucose, insulin, and corticosterone in adult neonatally handled (10 min/d, first 10 d of life) and nonhandled rats. We found an increased intake of chocolate in handled rats, but this consumption decreased over time. Handled male animals exhibited higher body weight, higher caloric efficiency, and lower triglyceride levels. Nonhandled females that were exposed long-term to the highly caloric diet had increased abdominal fat deposition compared with handled females. Overall female rats had increased abdominal fat deposition, higher total cholesterol and glucose levels, and lower insulin in comparison with males. Interestingly, chocolate consumption diminished the weight of the adrenal glands in both handled and nonhandled animals. These findings suggest that neonatal handling induces a particular metabolic pattern that is sex specific.

Litter size reduction alters insulin signaling in the ventral tegmental area and influences dopamine-related behaviors in adult rats.

Postnatal overfeeding is a well-known model of early-life induced obesity and glucose intolerance in rats. However, little is known about its impact on insulin signaling in specific brain regions such as the mesocorticolimbic system, and its putative effects on dopamine-related hedonic food intake in adulthood. For this study, rat litters were standardized to 4 (small litter - SL) or 8 pups (control - NL) at postnatal day 1. Weaning was at day 21, and all tests were conducted after day 60 of life in male rats. In Experiment 1, we demonstrated that the SL animals were heavier than the NL at all time points and had decreased AKT/pAKT ratio in the Ventral Tegmental Area (VTA), without differences in the skeletal muscle insulin signaling in response to insulin injection. In Experiment 2, the standard rat chow intake was addressed using an automated system (BioDAQ, Research Diets(®)), and showed no differences between the groups. On the other hand, the SL animals ingested more sweet food in response to the 1 min tail-pinch challenge and did not develop conditioned place preference to sweet food. In Experiment 3 we showed that the SL rats had increased VTA TH content but had no difference in this protein in response to a sweet food challenge, as the NL had. The SL rats also showed decreased levels of dopamine D2 receptors in the nucleus accumbens. Here we showed that early postnatal overfeeding was linked to an altered functioning of the mesolimbic dopamine pathway, which was associated with altered insulin signaling in the VTA, suggesting increased sensitivity, and expression of important proteins of the dopaminergic system.

Transgenerational effects of maternal care interact with fetal growth and influence attention skills at 18 months of age.

BACKGROUND Evidence suggests that there is an association between being born small for gestational age (SGA) and an increased risk of internalizing and externalizing problems, such as ADHD. Additionally, individuals who report having received a lower quality of maternal care show an increased prevalence of depression and anxiety, and they are generally worse caregivers of their offspring. Therefore, an interaction between the birth weight status and the quality of maternal care perceived by the mother could affect behavioral outcomes of the children. AIMS Evaluate the influence of being born SGA and parental bonding, as perceived by the mother during her infancy, on the childrens behavior at 18 months of age. STUDY DESIGN Nested cross-sectional study within a Canadian prenatal cohort (MAVAN, Maternal Adversity, Vulnerability and Neurodevelopment) recruited from 2003 to 2010. SUBJECTS Data from 305 children who were evaluated at 18 months of age. OUTCOME MEASURES Early Childhood Behavior Questionnaire--ECBQ and Infant-Toddler Social and Emotional Assessment--ITSEA) were included. RESULTS Children born SGA whose mothers reported low maternal care during her infancy (using the Parental Bonding Instrument--PBI) showed lower scores in the attentional set shifting trait (ECBQ, p=0.002) and attention construct (ITSEA, p=0.05) at 18 months of age. We also found that SGA increases decreases cuddliness (p=0.011) and poor perceived maternal care decreases low intensity pleasure (p=0.016) on the ECBQ. CONCLUSIONS These findings suggest a complex transgenerational transmission whereby mothers own care interacts with the fetal growth of her offspring to predict its attentional skills at 18 months of age.

Facial Expressions in Small for Gestational Age Newborns

In a recent article published in the Journal of Child Neurology, Rotstein et al suggest that there is no difference in the facial recognition patterns for taste between small for gestational age and control newborns, except for the perception of distilled water. Nonetheless, when analyzing their Figure 1A, it seems to us that this result regarding water versus sucrose facial expressions resembles very much the one we described previously. We evaluated 1-day-old preterm infants that received 24% sucrose solution or water on the taste reactivity test, and we found a highly positive correlation between fetal growth and the hedonic response in the group exposed to the sweet solution but not in the group exposed to water. In other words, the more intense the intrauterine growth restriction, the lower the frequency of the hedonic response observed, suggesting that intrauterine growth restriction is linked to a decreased sensitivity to the enjoyment elicited by the sweet taste. However, because our results derived from a clinical trial, we were not able to compare the same child’s response across different trials, as Rotstein et al could. Water is tasteless and odorless and therefore to us the pattern of response to water should be considered as a baseline or simple motor response. If Rotstein et al had studied the response using a sucrose to water ratio in each group, the expected pattern of reactivity in control children becomes clear, which almost double the hedonic response when tasting the sucrose solution in relation to water. On the other hand, the same ratio in small for gestational age children would be near to one, suggesting that they were unable to recognize the pleasurable sensation associated with sugar. The authors interpreted the finding as if the control group had a decreased perception for water and attributed this odd finding to ‘‘an artifact due to multiple comparisons.’’ To us, this is a simple misinterpretation of the data. The main question then becomes why is there such a discrete response to the other solutions tested (quinine, citrate). A possible explanation is that the ‘‘dislike’’ side of the scale has a worse discerning ability. Another question is why small for gestational age children have an increased baseline response to water when compared to controls; however, this is easily explained by a peculiar motor development in small for gestational age infants, which has been extensively described, and likely to be present already at birth. Besides using the response to distilled water as a baseline in the Rotstein et al study, it would have been interesting to see if there is a continuous correlation between birth weight and the response scale values; for that, they could have used the birth weight ratio (observed birth weight divided by the mean population birth weight specific for sex and gestational age) as we did in our study. Rotstein and colleagues’ findings reassure us about the idea that small for gestational age infants have indeed a difficulty in discriminating plain water from the sucrose flavor, as seen in our study. We propose that this inability to detect the pleasurable sensation associated with sugar predisposes them to develop an increased consumption of palatable foods later in life, as we and others have described. The increased preference for palatable foods could be an important factor contributing to the development of obesity and its metabolic consequences in the small for gestational age population. As intrauterine growth restriction is often seen in a context of social vulnerability and poor food security, the fetal programming of food preferences is an essential topic in preventive research.