Thrifty Phenotype Research Articles

The maladaptive significance of maternal effects for plants in anthropogenically modified environments

Maternal effects directly and indirectly modify an offspring’s phenotype during development, preparing the offspring for an environment similar to an environment experienced by the mother. Evolutionarily, this could be adaptive if organisms did not experience a large amount of environmental variation across generations. We argue increased anthropogenic changes have led maternal effects to be maladaptive in plants. Similar problems in humans have been proposed, where metabolic diseases may be increased by a mismatch between the in utero environment and the adult environment; often referred to as the Barker Hypothesis. Plants may experience similar metabolic and functional disorders, caused by maternal effects generated from unreliable environmental cues. In the last 200 years, human activities have increased habitat fragmentation, changed patterns of nutrient deposition, and increased climatic variation within and among years. In this manuscript, we suggest that ecologists should consider the increased negative influence of maternal effects on plant growth and reproduction in spatially fragmented and temporally stochastic landscapes. Several implications for conservation and research arise from this discussion: (1) researchers should focus on evolutionarily relevant measures of spatial and temporal heterogeneity, (2) the maternal history of seeds used for population restoration should be considered, and (3) contiguous habitats should be constructed to reduce the impact of evolutionary traps.

Is chromium from stainless steel utensils responsible for epidemic of type 2 diabetes?

Type 2 diabetes prevalence is rising rapidly in developing world especially in India in last few decades. ‘Thrifty phenotype’ and ‘westernization of lifestyle’ is used to explain this epidemic. Chromium is an important modulator in insulin and glucose metabolism. Preconceptional chromium exposure has been demonstrated to raise the corticosterone and glucose levels in offspring of rodent model. Chromium is chelated when acidic food is stored in the stainless steel utensils. Chromium levels are shown to be high in Asian Indians. The hyperinsulinemia and insulin resistance is demonstrated in Indians from the newborn stage. We hypothesize that increased exposure to chromium in preconceptional and/or fetal stage leads to altered epigenetic control and altered endocrine and metabolic functioning. Increasing urbanization has led to increasing use of stainless steel and resultant exposure to chromium is at the least partly responsible for rising prevalence of type 2 diabetes. If proven avoiding or modifying the use of stainless steel utensils will halt the present epidemic of type 2 diabetes.

Highlights in this issue

The incidence of psychiatric diseases was investigated by a register study based on about 1.5 million persons born 1974–1996. The odds rate of major psychiatric disorders was 1.88 among individuals born below 27 weeks compared to those who were born full-term. Similar ratios were found for minor psychiatric disorders or use of psychotropic drugs. The risk increased in proportion to the degree of prematurity. However, the incidence of psychiatric disorders was relatively small compared to cerebral palsy or cognitive deficits. This is reported by René Mathiasen et al., pp. 691–699. See also article by Phyllis Zelkowitz et al., showing that early intervention programmes targeting anxious mothers promote optimal developmental outcome, pp. 700–704. Prone sleeping has been found to increase oxygen saturation both in preterm infants and also adults in intensive care. However, prone sleeping should be avoided among infants, and parents can be confused if they must change the position of the baby when the preterm baby is discharged. Dawn Elder et al. have now reinvestigated oxygenation in prone and supine position. They found no disadvantage for preterm infants sleeping in supine position before discharge. See pp. 661–665. Playing music for babies in the NICU may be pleasant but is it also good for the health? This has been investigated by Monica Olischar et al. in Melbourne. They analyzed the impact of music on the quality of sleep-wake cycles and quiet sleep in term and near-term infants. Although they did not find any statistical significance, they found a trend of easier discernibility of sleep-wake cycling among those infants who were exposed for music. Although this is a small study with a limited number of infants, it indicates that music can be good for the baby (pp. 670–675). Malignant solid tumours constitute about 40% of all cancer among children. The overall annual incidence was found to be 65/million children. The survival rate has increased from 76% to 82% during the two last decades. The incidence is stable. See article by Gustaf Ljungman et al., pp. 750–757. Malnutrition during early life alters gene expression and programmes the body structure function for life. This so called Barker hypothesis is now well established. Nicola Winder, David Barker et al. now show that the size and shape of the placental surface predict childhood blood pressure. Factors like implantation, expansion of the chorionic surface, and compensatory mechanisms may explain this (pp. 653–660).

Elevated insulin sensitivity and β-cell function during pregnancy in mothers of growth-restricted newborns

The "Barker hypothesis" suggests that low birth weight might predict future risk of developing obesity, cardiovascular disease, and type 2 diabetes. Identification of the causes of fetal growth restriction (FGR) is critical for preventive and management strategies. Some studies indicate that maternal carbohydrate metabolism might be involved in FGR development. We aimed to evaluate, in a large number of normotensive pregnant women with normal glucose tolerance, the effect of insulin sensitivity and β-cell function on unexplained fetal growth. A total of 1,814 Caucasian pregnant women with normal prepregnancy body mass index were tested with a 75-g, 2-h glucose load (24-28 gestation wk). Insulin sensitivity was evaluated with fasting (QUICKI) and dynamic index (OGIS) and β-cell function with a modified insulinogenic index as ΔAUC(insulin)/ΔAUC(glucose) and disposition index. FGR was a birth weight below the 5th percentile for gestational age. FGR developed in 99 (5.5%) pregnant women that showed significantly higher QUICKI, OGIS, insulinogenic, and disposition index with respect to women with normal-weight babies (P < 0.0001). By using multiple regression analysis in the FRG group, QUICKI and OGIS appeared as significant independent variables (P < 0.0001 and P < 0.0366, respectively). We conclude that elevated insulin sensitivity seems to be one of the factors involved in determining unexplained fetal growth retardation; its assessment, even only in the fasting state, could be useful to guide any possible monitoring and therapeutic strategies to reduce fetal complications.

Retard de croissance intra-utérin et devenir à l’âge adulte

The epidemiologist David Barker was among the first to develop the concept that some adult diseases might have their origins during fetal life, based notably on a strong association between low birth weight and the risk of chronic diseases in adulthood (coronary artery disease, hypertension and stroke, type 2 diabetes, and osteoporosis). Several other groups replicated these results in other populations, thus confirming that birth weight is a determining factor of adult health. Intra-uterine growth retardation (IUGR) has been widely used as a marker of poor fetal nutrition and health, but some antenatal nutritional disturbances can increase the risk of diseases later in life without affecting fetal growth. The risk of diseases in adulthood appears to be further increased when IUGR is associated with rapid postnatal catch-up growth. This suggests that fetal malnutrition induces adaptations necessary for fetal survival and health, but that it also undermines future health if the postnatal environment is unfavorable. The fetal origins of adult diseases has major public health implications and calls for reinforced pre- and post-natal prevention strategies.

Fetal origin of vascular aging

Aging is increasingly regarded as an independent risk factor for development of cardiovascular diseases such as atherosclerosis and hypertension and their complications (e.g. MI and Stroke). It is well known that vascular disease evolve over decades with progressive accumulation of cellular and extracellular materials and many inflammatory processes. Metabolic syndrome, obesity and diabetes are conventionally recognized as risk factors for development of coronary vascular disease (CVD). These conditions are known to accelerate ageing process in general and vascular ageing in particular. Adverse events during intrauterine life may programme organ growth and favour disease later in life, popularly known as, ‘Barker's Hypothesis’. The notion of fetal programming implies that during critical periods of prenatal growth, changes in the hormonal and nutritional milieu of the conceptus may alter the full expression of the fetal genome, leading to permanent effects on a range of physiological.

Perinatal Exposure to Environmental Chemicals Induces Epigenomic Changes in Offspring

Many researchers propose that invisible internal alterations that occur through exposure to environmental factors during fetal or neonatal stages affect the risk of cancer, hypertension, and diabetes after maturation. Barker's hypothesis, which states that reduced fetal growth is strongly associated with metabolic syndromes including cardiovascular disease and diabetes, has now been widely accepted and expanded into the Developmental Origins of Health and Disease (DOHaD). Potential molecular mechanisms underlying this phenomenon include the alteration and persistence of epigenomic programming. Clear biochemical evidence has not yet been obtained in human studies; however, in laboratory animals, the fetal environment including physical and chemical factors altered epigenomic states such as DNA methylation and histone modification, and persistent changes affected specific gene expression regulation, resulting in disease susceptibility. Furthermore, in recent studies, environmental chemical exposure during pregnancy altered sperm DNA methylation patterns of male offspring, and the altered status and resulting phenotypes were inherited in the next generation. Challenging and eccentric studies focusing on epigenetic transgenerational effects are currently being conducted to demonstrate the existence of Lamarckian inheritance.

142 - Sociology and the Barker Hypothesis: Transdisciplinary approaches to obesity

142 - Sociology and the Barker Hypothesis: Transdisciplinary approaches to obesity

Growth Patterns of Premature Infants Up to 40th Term Week of Corrected Age

Study purpose were to describe growth patterns of premature infants in weight, length and head circumference from birth to 40th week of corrected ages (CA) and to explore factors affecting patterns. A longitudinal descriptive study was conducted with 267 premature infants. They were categorized into 2 groups; GA group with measurements at birth and the CA group with measurements at CA, which was categorized into 3 groups (group 1-3) by WHO guideline for gestational age (GA) at birth. GA group presented greater measures in all than CA group at same week of life. Among CA groups, group 3 showed the highest measurements, up to 37 weeks of life, though this disappeared at 38-40 weeks. Reversely, group 1 revealed the highest growth rates in all measures, followed by group 2 and group 3. Significant interaction was observed in all measures between week of life and any type of groups. Higher measures in GA group, as well group 3 among CA groups, supported the superiority of intra-uterine environment overriding quality of regimen from NICU. Regardless of growth acceleration, smaller infants remain smaller, indicating that intra-uterine thrifty phenotype may continue at least up to the 40th week of CA.

An evolutionary review of human telomere biology: The thrifty telomere hypothesis and notes on potential adaptive paternal effects

Telomeres, repetitive DNA sequences found at the ends of linear chromosomes, play a role in regulating cellular proliferation, and shorten with increasing age in proliferating human tissues. The rate of age-related shortening of telomeres is highest early in life and decreases with age. Shortened telomeres are thought to limit the proliferation of cells and are associated with increased morbidity and mortality. Although natural selection is widely assumed to operate against long telomeres because they entail increased cancer risk, the evidence for this is mixed. Instead, here it is proposed that telomere length is primarily limited by energetic constraints. Cell proliferation is energetically expensive, so shorter telomeres should lead to a thrifty phenotype. Shorter telomeres are proposed to restrain adaptive immunity as an energy saving mechanism. Such a limited immune system, however, might also result in chronic infections, inflammatory stress, premature aging, and death--a more "disposable soma." With an increased reproductive lifespan, the fitness costs of premature aging are higher and longer telomeres will be favored by selection. Telomeres exhibit a paternal effect whereby the offspring of older fathers have longer telomeres due to increased telomere lengths of sperm with age. This paternal effect is proposed to be an adaptive signal of the expected age of male reproduction in the environment offspring are born into. The offspring of lineages of older fathers will tend to have longer, and thereby less thrifty, telomeres, better preparing them for an environment with higher expected ages at reproduction.

The gap junction as a “Biological Rosetta Stone”: implications of evolution, stem cells to homeostatic regulation of health and disease in the Barker hypothesis

The discovery of the gap junction structure, its functions and the family of the "connexin" genes, has been basically ignored by the major biological disciplines. These connexin genes code for proteins that organize to form membrane-associated hemi-channels, "connexons", co-join with the connexons of neighboring cells to form gap junctions. Gap junctions appeared in the early evolution of the metazoan. Their fundamental functions, (e.g., to synchronize electrotonic and metabolic functions of societies of cells, and to regulate cell proliferation, cell differentiation, and apoptosis), were accomplished via integrating the extra-cellular triggering of intra-cellular signaling, and therefore, regulating gene expression. These functions have been documented by genetic mutations of the connexin genes and by chemical modulation of gap junctions. Via genetic alteration of connexins in knock-out and transgenic mice, as well as inherited connexin mutations in various human syndromes, the gap junction has been shown to be directly linked to many normal cell functions and multiple diseases, such as birth defects, reproductive, neurological disorders, immune dysfunction and cancer. Specifically, the modulation of gap junctional intercellular communication (GJIC), either by increasing or decreasing its functions by non-mutagenic chemicals or by oncogenes or tumor suppressor genes in normal or "initiated" stem cells and their progenitor cells, can have a major impact on tumor promotion or cancer chemoprevention and chemotherapy. The overview of the roles of the gap junction in the evolution of the metazoan and its potential in understanding a "systems" view of human health and aging and the diseases of aging will be attempted.

The thrifty phenotype: An adaptation in growth or metabolism?

The thrifty phenotype hypothesis is widely used to interpret associations between early nutritional experience and degenerative disease risks. However, it remains unclear what is adaptive about early life thrift, and biomedical approaches struggle to explain why associations between early growth and later disease hold across the entire range of birth size. This issue can be addressed using a simple model, attributing disease to a high metabolic load (large tissue masses, rich diet, and sedentary lifestyle) relative to metabolic capacity (physiological traits contingent on fetal/infant development). In this context, different hypotheses regarding the long-term functions of thrift can be examined. The "predictive adaptive response" hypothesis considers thrift to involve metabolic adaptations (insulin resistance and central adiposity) that emerge in anticipation of a poor quality adult breeding environment. The competing "maternal capital" hypothesis considers thrift to involve reductions in lean mass and organ phenotype arising through constraints on maternal phenotype, reflecting both maternal developmental experience and current ecological conditions. This hypothesis assumes offspring developmental responses to stresses such as temperature, altitude, and nutritional ecology occur under the influence of maternal capital indices, including size, physiology, reproductive history and social status. I argue that insulin resistance only emerges after infancy, and far from being anticipatory of a low nutritional plane, indicates perturbations of metabolism. Following exposure of early thrifty growth to the obesogenic niche. Thrift as early growth variability represents a plausible profile of developmental plasticity for human evolutionary history, aiding understand how the modern obesogenic environment interacts with physiological variability to induce disease.

Environmental induction of the fetal epigenome

The healthy adult is the result of successful interaction between the maternal environment and the developing fetal epigenome. The Barker hypothesis first suggested that in utero exposure to the maternal environment impacts adult health and disease. Since the origin of this theory, numerous studies have lent further support. Epigenomic alteration involves DNA methylation and histone modifications. Pregnancy, when the epigenome is typically actively programmed, is a vulnerable time, when exposures may have the most profound epigenetic effect. Recent advances have allowed an understanding of the extent and mechanism by which environmental exposures alter the epigenome of the fetus. Healthcare providers who treat and counsel reproductive-age women are in a unique position to protect against these epigenetic alterations and therefore prevent adverse impact on the developing fetus that may manifest throughout life.

The Dutch Hunger Winter and the developmental origins of health and disease

In the early 1980s, David Barker and others noted a paradox: although overall rates of cardiovascular disease increase with rising national prosperity, the least prosperous residents of a wealthy nation suffer the highest rates. He and others proposed over a series of studies that an adverse fetal environment followed by plentiful food in adulthood may be a recipe for adult chronic disease, a claim referred to as the Barker Hypothesis. These studies generally correlated birth weight and other infant parameters to the incidence of adult disease. Detractors, including an editorial in BMJ in 1995, complained that “[e]arly nutrition is inferred indirectly from fetal and infant growth, and fetal growth especially is a doubtful surrogate measure” (1). Most of the epidemiological studies were also vulnerable to confounding factors, particularly social class, that influence both intrauterine and adult environment, which delayed acceptance of the hypothesis. In PNAS, Rooij et al. (2) present another chapter in the ongoing study of the children of the Dutch Hunger Winter, a key test of the hypothesis (2). They show that, in addition to the previously shown effects of food restriction in utero on metabolism and cardiovascular health, there are effects on age-associated decline of cognitive functions. In the winter and spring of 1944 after a railway strike, the German occupation limited rations such that people, including pregnant women, in the western region of The Netherlands, including Amsterdam, received as little as 400–800 calories/d. The famine affected people of all social classes and was followed by growing prosperity in the postwar period. Thus, the Dutch Hunger Winter study, from which results were first published in 1976, provides an almost perfectly designed, although tragic, human experiment in the effects of intrauterine deprivation on subsequent adult health. This study has provided crucial support and fundamental insights for the growing field of the developmental origins of health and disease (DOHaD).

Decreased exercise in adults with birth weights

The Barker hypothesis, also referred to as the Developmental Origins of Adult Diseases Hypothesis, relates adverse outcomes in adults to low birth weight. A category of low birth weight individuals are those born preterm, which has been linked to abnormalities in glucose metabolism and blood pressure in childhood. Adult degenerative diseases are adversely affected by a lack of exercise. Kajantie et al from Helsinki, Finland, report that young adults (mean age 22 years) who had birth weights <1500 g exercise less than a comparison group of young adults born with normal birth weights at term. This is a useful observation because exercise is a modifiable variable that may decrease the already increased risks of diseases, such as diabetes, stroke, and heart disease, in this high risk group. Article page 610 ▸ Adults Born at Very Low Birth Weight Exercise Less than Their Peers Born at TermThe Journal of PediatricsVol. 157Issue 4PreviewTo study the effects of very low birth weight (VLBW, <1500 g) birth on physical activity, an important protective and modifiable factor. Full-Text PDF

Big mother or small baby: which predicts hypertension?

According to the Barker hypothesis, intrauterine growth restriction and premature delivery adversely affect cardiovascular health in adult life. The association of childhood hypertension as a cardiovascular risk factor and birth weight has been understudied. In a prospective cohort study, the authors evaluated the effect of birth weight, gestational age, maternal prepregnancy body mass index (BMI), and child BMI z score at the time of enrollment on the systolic and diastolic blood pressure (BP) z score in 3024 (1373 women) consecutive outpatient clinic patients aged 2.05 to 18.58 years. The latest National Health and Nutrition Examination Survey (NHANES III) was used to calculate the age-dependent z scores. The median z scores of BMI (+0.48, range -6.96-6.64), systolic BP (+0.41, range -4.50-6.73), and diastolic BP (+0.34, range -3.15-+6.73) were all significantly greater than the NHANES III reference population. Systolic BP z score did not correlate with birth weight or gestational age, but did correlate with maternal prepregnancy BMI (r=.090, P<.0001) and BMI z score (r=.209, P<.0001). Diastolic BP z score positively correlated with birth weight (0.037, P=.044), gestational age (r=.052, P=.005), BMI z score(r=.106, P<.0001), and maternal prepregnancy BMI (r=.062, P=.0007). In contrast to what would be expected from the Barker hypothesis, the authors found no negative correlation between BP z score and birth weight or gestational age. This study suggests that a high BMI, a big mom, and a high birth weight are more important risk factors for hypertension during childhood than low birth weight or gestational age.

Fetal and life course origins of serum lipids in mid-adulthood: results from a prospective cohort study

BackgroundDuring the past two decades, the hypothesis of fetal origins of adult disease has received considerable attention. However, critique has also been raised regarding the failure to take the explanatory role of accumulation of other exposures into consideration, despite the wealth of evidence that social circumstances during the life course impact on health in adulthood. The aim of the present prospective cohort study was to examine the contributions of birth weight and life course exposures (cumulative socioeconomic disadvantage and adversity) to dyslipidemia and serum lipids in mid-adulthood.MethodsA cohort (effective n = 824, 77%) was prospectively examined with respect to self-reported socioeconomic status as well as stressors (e.g., financial strain, low decision latitude, separation, death or illness of a close one, unemployment) at the ages of 16, 21, 30 and 43 years; summarized in cumulative socioeconomic disadvantage and cumulative adversity. Information on birth weight was collected from birth records. Participants were assessed for serum lipids (total cholesterol, low- and high-density lipoprotein cholesterol and triglycerides), apolipoproteins (A1 and B) and height and weight (for the calculation of body mass index, BMI) at age 43. Current health behavior (alcohol consumption, smoking and snuff use) was reported at age 43.ResultsCumulative life course exposures were related to several outcomes; mainly explained by cumulative socioeconomic disadvantage in the total sample (independently of current health behaviors but attenuated by current BMI) and also by cumulative adversity in women (partly explained by current health behavior but not by BMI). Birth weight was related only to triglycerides in women, independently of life course exposures, health behaviors and BMI. No significant association of either exposure was observed in men.ConclusionsSocial circumstances during the life course seem to be of greater importance than birth weight for dyslipidemia and serum lipid levels in adulthood.

A Paradigm Shift is Required for the Risk Assessment of Potential Human Health After Exposure to Low Level Chemical Exposures

Chemicals are known to be associated with birth defects, cancer, cardiovascular diseases, immunological, reproductive, and neurological disorders. In response to recent reviews of limitations of current concepts and techniques for toxicity testing, this commentary challenges the paradigm that chemicals are directly responsible for DNA damage in the genomic-nuclear DNA in relevant cells of the human body. This challenge is not that mutations do not play roles in human-inherited or somatic diseases but that chemical exposures bring about disease end points by epigenetic mechanisms or by alterations in adult stem cell numbers in utero (ie, the Barker hypothesis) or postnatally, by selecting preexisting mutated cells. Classic concepts, that is, multistage, multimechanism process of carcinogenesis, stem cell theory of cancer, and newer and ignored concepts, such as cancer stem cells and cell-cell communication, will be used to support the view that the toxic effect of chemicals is mediated by nonmutagenic mechanisms at human relevant exposures.

Is body size at birth related to circadian salivary cortisol levels in adulthood? Results from a longitudinal cohort study

BackgroundThe hypothesis of fetal origins of adult disease has during the last decades received interest as an explanation of chronic, e.g. cardiovascular, disease in adulthood stemming from fetal environmental conditions. Early programming and enduring dysregulations of the hypothalamic-pituitary-adrenal (HPA axis), with cortisol as its end product, has been proposed as a possible mechanism by which birth weight influence later health status. However, the fetal origin of the adult cortisol regulation has been insufficiently studied. The present study aims to examine if body size at birth is related to circadian cortisol levels at 43 years.MethodsParticipants were drawn from a prospective cohort study (n = 752, 74.5%). Salivary cortisol samples were collected at four times during one day at 43 years, and information on birth size was collected retrospectively from delivery records. Information on body mass during adolescence and adulthood and on health behavior, medication and medical conditions at 43 years was collected prospectively by questionnaire and examined as potential confounders. Participants born preterm or < 2500 g were excluded from the main analyses.ResultsAcross the normal spectrum, size at birth (birth weight and ponderal index) was positively related to total (area under the curve, AUC) and bedtime cortisol levels in the total sample. Results were more consistent in men than in women. Descriptively, participants born preterm or < 2500 g also seemed to display elevated evening and total cortisol levels. No associations were found for birth length or for the cortisol awakening response (CAR).ConclusionsThese results are contradictory to previously reported negative associations between birth weight and adult cortisol levels, and thus tentatively question the assumption that only low birth weight predicts future physiological dysregulations.

Reply

We read with great interest the comments by Dr. Maitra regarding our article1 published in HEPATOLOGY. We thank the author for his kind interest in our work and welcome the opportunity to clarify the points raised by him. First, there is a difference between a field study and a clinic-based study. Despite its fallacies, the measurement of alanine aminotransferase remains the most cost-effective screening tool for significant underlying liver disease, even nonalcoholic fatty liver (NAFL) disease.2 Moreover, an elevated alanine aminotransferase level is one of the components of the various noninvasive scoring systems used for identifying NAFL subjects with advanced liver disease.3 Unfortunately, despite attempts to develop multiple noninvasive (but not necessarily cheap) scoring systems or tests for identifying subjects with nonalcoholic steatohepatitis, liver biopsy remains the ultimate gold standard for diagnosing nonalcoholic steatohepatitis.3 Second, despite the concerns regarding the unconventional forms of ethanol consumption by tribals in India, there were only 35 tribals (1.8%) among the 1911 subjects, and we rigorously excluded alcohol consumption in our study population (see the supporting information for our article1). Finally, we also speculated about the role of malnutrition in the genesis of NAFL in our population.1 However, in a case-control substudy of subsets of subjects with a body mass index < 18.5 kg/m2, we found that those with NAFL had higher indices of adiposity and a higher prevalence of markers of metabolic syndrome versus those without NAFL (see the supporting tables for our article1). We agree with Maitra that the thrifty phenotype hypothesis,4 introduced approximately 20 years ago to explain the associations between poor fetal and infant growth and the increased risk of developing impaired glucose tolerance and metabolic syndrome in adult life, can play a pathophysiological role in the development of the third-world NAFL phenotype, as highlighted by us.1 Kshaunish Das*, Abhijit Chowdhury , * Divisions of Gastroenterology, Institute of Postgraduate Medical Education and Research, Kolkata, India, Hepatology, School of Digestive and Liver Diseases, Institute of Postgraduate Medical Education and Research, Kolkata, India.