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Locomotion is a defining characteristic of animal life and plays a crucial role in most behaviors. Locomotion involves physical activity, which can have far-reaching effects on physiology and neurobiology, both acutely and chronically. In human populations and in laboratory rodents, higher levels of physical activity are generally associated with positive health outcomes, although excessive exercise can have adverse consequences. Whether and how such relationships occur in wild animals is unknown. Behavioral variation among individuals arises from genetic and environmental factors and their interactions as well as from developmental programming (persistent effects of early-life environment). Although tremendous progress has been made in identifying genetic and environmental influences on individual differences in behavior, early-life effects are not well understood. Early-life effects can in some cases persist across multiple generations following a single exposure and, in principle, may constrain or facilitate the rate of evolution at multiple levels of biological organization. Understanding the mechanisms of such transgenerational effects (e.g., exposure to stress hormones in utero, inherited epigenetic alterations) may prove crucial to explaining unexpected and/or sex-specific responses to selection as well as limits to adaptation. One area receiving increased attention is early-life effects on adult physical activity. Correlational data from epidemiological studies suggest that early-life nutritional stress can (adversely) affect adult human activity levels and associated physiological traits (e.g., body composition, metabolic health). The few existing studies of laboratory rodents demonstrate that both maternal and early-life exercise can affect adult levels of physical activity and related phenotypes. Going forward, rodents offer many opportunities for experimental studies of (multigenerational) early-life effects, including studies that use maternal exposures and cross-fostering designs.

The double burden of under- and overnutrition profoundly affects human health globally. According to the World Health Organization, obesity and diabetes rates have almost doubled worldwide since 1980, and, in 2011, more than 40 million children under 5 years of age were overweight. Ecologic factors, parental genetics and fitness, and the intrauterine environment significantly influence the likelihood of offspring developing the dysmetabolic diathesis of obesity. This report examines the effects of these factors, including preconception, intrauterine and postnatal energy balance affecting programming of transgenerational transmission, and development of chronic diseases later in life-in particular, diabesity and its comorbidities.

Background: Early childhood (0–3 years) is a critical period for obesity prevention, when tendencies in eating behaviors and physical activity are established. Yet, little is understood about how the environment shapes children's genetic predisposition for these behaviors during this time. The Baylor Infant Twin Study (BITS) is a two phase study, initiated to study obesity risk factors from infancy. Data collection has been completed for Phase 1 in which three sub‐studies pilot central measures for Phase 2. A novel infant temperament assessment, based on observations made by trained researchers was piloted in Behavior Observation Pilot Protocol (BOPP) study, a new device for measuring infant feeding parameters (the "orometer") in the Baylor Infant Orometer (BIO), and methods for analyzing DNA methylation in twins of unknown chorionicity in EpiTwin. Methods: EpiTwin was a cross‐sectional study of neonatal twins, while up to three study visits occurred for the other studies, at 4‐ (BOPP, BIO), 6‐ (BOPP), and 12‐ (BOPP, BIO) of age. Measurements for BOPP and BIO included temperament observations, feeding observations, and body composition assessments while EpiTwin focused on collecting samples of hair, urine, nails, and blood for quantifying methylation levels at 10 metastable epialleles. Additional data collected include demographic information, zygosity, chorionicity, and questionnaire‐based measures of infant behaviors. Results: Recruitment for all three studies was completed in early 2020. EpiTwin recruited 80 twin pairs (50% monochorionic), 31 twin pairs completed the BOPP protocol, and 68 singleton infants participated in BIO. Conclusions: The psychometric properties of the data from all three studies are being analyzed currently. The resulting findings will inform the development of the full BITS protocol, with the goal of completing assessments at 4‐, 6‐, 12‐, and 14‐month of age for 400 twin pairs. [ABSTRACT FROM AUTHOR]

Extensive human and animal model data show that environmental influences during critical periods of prenatal and early postnatal development can cause persistent alterations in energy balance regulation. Although a potentially important factor in the worldwide obesity epidemic, the fundamental mechanisms underlying such developmental programming of energy balance are poorly understood, limiting our ability to intervene. Most studies of developmental programming of energy balance have focused on persistent alterations in the regulation of energy intake; energy expenditure has been relatively underemphasised. In particular, very few studies have evaluated developmental programming of physical activity. The aim of this review is to summarise recent evidence that early environment may have a profound impact on establishment of individual propensity for physical activity. Recently, we characterised two different mouse models of developmental programming of obesity; one models fetal growth restriction followed by catch-up growth, and the other models early postnatal overnutrition. In both studies, we observed alterations in body-weight regulation that persisted to adulthood, but no group differences in food intake. Rather, in both cases, programming of energy balance appeared to be due to persistent alterations in energy expenditure and spontaneous physical activity (SPA). These effects were stronger in female offspring. We are currently exploring the hypothesis that developmental programming of SPA occurs via induced sex-specific alterations in epigenetic regulation in the hypothalamus and other regions of the central nervous system. We will summarise the current progress towards testing this hypothesis. Early environmental influences on establishment of physical activity are likely an important factor in developmental programming of energy balance. Understanding the fundamental underlying mechanisms in appropriate animal models will help determine whether early life interventions may be a practical approach to promote physical activity in man. [ABSTRACT FROM PUBLISHER]

Cancer has long been viewed as a genetic disease; however, epigenetic silencing as the result of aberrant promoter DNA methylation is frequently associated with cancer development, suggesting an epigenetic component to the disease. Nonetheless, it has remained unclear whether an epimutation (an aberrant change in epigenetic regulation) can induce tumorigenesis. Here, we exploited a functionally validated cis-acting regulatory element and devised a strategy to induce developmentally regulated genomic targeting of DNA methylation. We used this system to target DNA methylation within the p16Ink4a promoter in mice in vivo. Engineered p16Ink4a promoter hypermethylation led to transcriptional suppression in somatic tissues during aging and increased the incidence of spontaneous cancers in these mice. Further, mice carrying a germline p16Ink4a mutation in one allele and a somatic epimutation in the other had accelerated tumor onset and substantially shortened tumor-free survival. Taken together, these results provide direct functional evidence that p16Ink4a epimutation drives tumor formation and malignant progression and validate a targeted methylation approach to epigenetic engineering. [ABSTRACT FROM AUTHOR]

Background: Epigenetic mechanisms provide one potential explanation for how environmental influences in early life cause long-term changes in chronic disease susceptibility. Whereas epigenetic dysregulation is increasingly implicated in various rare developmental syndromes and cancer, the role of epigenetics in complex chronic diseases, such as cardiovascular disease, type 2 diabetes and obesity, remains largely uncharacterized. Extensive work in animal models is required to develop specific hypotheses that can be practicably tested in humans. Animal Models: We have developed a mouse model showing that methyl donor supplementation prevents transgenerational amplification of obesity, suggesting a role for DNA methylation in the developmental establishment of body weight regulation. Conclusions: Coupling such models with recently developed epigenomic technologies should ultimately enable us to determine if epigenetics is an important link between early life events and adult disease. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Human epidemiologic data indicate that nutrition during prenatal and early postnatal development can affect susceptibility to various chronic diseases in adulthood (the developmental origins hypothesis). Controlled studies in animal models corroborate that nutritional exposures during critical periods of development wield lasting influences on gene expression and metabolism, but our understanding of the fundamental biological mechanisms underlying such phenomena remains rudimentary. Nutritional influences on the developmental establishment of epigenetic gene regulatory mechanisms could link early nutrition to adult chronic disease susceptibility. Just as genetic variation contributes to individual susceptibility to chronic disease, it is increasingly evident that so too does epigenetic variation. Very little is known about the factors that contribute to interindividual variation in epigenotype. It is critically important to determine whether nutrition and other environmental influences during development affect the establishment of human epigenotype. Most previous studies of nutritional influences on epigenetic regulation have focused on nutrients known to affect one-carbon metabolism. For example, supplementation during development with methyl donors including folic acid and vitamin B12 appears to induce DNA hypermethylation at specific loci by increasing the flux through the DNA methylation pathway. This article will consider the mechanisms by which fatty acid nutrition during prenatal and early postnatal nutrition might affect the establishment of epigenetic gene regulatory mechanisms. Choline, a component of the phospholipid phosphatidylcholine, stands at the intersection of lipid and one-carbon metabolism; upon conversion to betaine, its three methyl groups are available to one-carbon metabolism. Potentially much more important than providing methyl groups for DNA methylation, dietary fatty acids could affect the establishment of epigenetic mechanisms by stimulating transcription of specific genes during critical developmental windows. For example, the peroxisome proliferator activated receptor-α (PPAR-α) transcription factor is activated by a variety of fatty acids to transactivate specific genes. PPAR-α-mediated transcriptional activation during critical ontogenic periods could impede epigenetic silencing of genes involved in fatty acid metabolism. Lastly, recent data indicate that lipids and lipoprotein components interact directly with chromatin structure to influence gene expression. Hence, intake of specific dietary fatty acids during development could induce persistent changes in gene expression by altering the establishment of epigenetic mechanisms. [ABSTRACT FROM AUTHOR]

Genistein, the major phytoestrogen in soy, is linked to diminished female reproductive performance and to cancer chemoprevention and decreased adipose deposition. Dietary genistein may also play a role in the decreased incidence of cancer in Asians compared with Westerners, as well as increased cancer incidence in Asians immigrating to the United States. Here, we report that maternal dietary genistein supplementation of mice during gestation, at levels comparable with humans consuming high-soy diets, shifted the coat color of heterozygous viable yellow agouti (Avy/a) offspring toward pseudoagouti. This marked phenotypic change was significantly associated with increased methylation of six cytosine-guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. The extent of this DNA methylation was similar in endodermal, mesodermal, and ectodermal tissues, indicating that genistein acts during early embryonic development. Moreover, this genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from obesity. Thus, we provide the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome. [ABSTRACT FROM AUTHOR]

Pancreatic islets of type 2 diabetes patients have altered DNA methylation, contributing to islet dysfunction and the onset of type 2 diabetes. The cause of these epigenetic alterations is largely unknown. We set out to test whether (i) islet DNA methylation would change with aging and (ii) early postnatal overnutrition would persistently alter DNA methylation. We performed genome-scale DNA methylation profiling in islets from postnatally over-nourished (suckled in a small litter) and control male mice at both postnatal day 21 and postnatal day 180. DNA methylation differences were validated using quantitative bisulfite pyrosequencing, and associations with expression were assessed by RT-PCR. We discovered that genomic regions that are hypermethylated in exocrine relative to endocrine pancreas tend to gain methylation in islets during aging (R 2 = 0.33, P  < 0.0001). These methylation differences were inversely correlated with mRNA expression of genes relevant to β cell function [including Rab3b (Ras-related protein Rab-3B), Cacnb3 (voltage-dependent L-type calcium channel subunit 3), Atp2a3 (sarcoplasmic/endoplasmic reticulum calcium ATPase 3) and Ins2 (insulin 2)]. Relative to control, small litter islets showed DNA methylation differences directly after weaning and in adulthood, but few of these were present at both ages. Surprisingly, we found substantial overlap of methylated loci caused by aging and small litter feeding, suggesting that the age-associated gain of DNA methylation happened much earlier in small litter islets than control islets. Our results provide the novel insights that aging-associated DNA methylation increases reflect an epigenetic drift toward the exocrine pancreas epigenome, and that early postnatal overnutrition may accelerate this process. [ABSTRACT FROM AUTHOR]

Background: Bronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important mechanism by which environmental factors might interact with genes involved in allergy and asthma development. Objective: This study was designed to test whether epigenetic mechanisms might contribute to asthma protection conferred by early microbial exposure. Methods: Pregnant maternal mice were exposed to the farm-derived gram-negative bacterium Acinetobacter lwoffii F78. Epigenetic modifications in the offspring were analyzed in TH1- and TH2-relevant genes of CD4+ T cells. Results: Prenatal administration of A lwoffii F78 prevented the development of an asthmatic phenotype in the progeny, and this effect was IFN-γ dependent. Furthermore, the IFNG promoter of CD4+ T cells in the offspring revealed a significant protection against loss of histone 4 (H4) acetylation, which was closely associated with IFN-γ expression. Pharmacologic inhibition of H4 acetylation in the offspring abolished the asthma-protective phenotype. Regarding TH2-relevant genes only at the IL4 promoter, a decrease could be detected for H4 acetylation but not at the IL5 promoter or the intergenic TH2 regulatory region conserved noncoding sequence 1 (CNS1). Conclusion: These data support the hygiene concept and indicate that microbes operate by means of epigenetic mechanisms. This provides a new mechanism in the understanding of gene-environment interactions in the context of allergy protection. [ABSTRACT FROM AUTHOR]

The article reports that sex-specific epigenetic mechanisms regulate neurodevelopment and demonstrates how human genomic regions are associated with body mass index in humans. It discusses the limited ontogenic windows, and sex differences in sensitivity to developmental programming of obesity and provides a resource for epigenetic analyses of developmental programming of energy balance.

Abstract: Fundulus heteroclitus (Atlantic killifish or mummichog) inhabiting a creosote-contaminated Superfund site on the Elizabeth River (VA, USA), exhibit a lack of induction of cytochrome P4501A (CYP1A) mRNA, immunodetectable protein, and catalytic activity after exposure to typical inducers. This “refractory CYP1A phenotype” is not explained by alterations in mRNA expression of known CYP1A transcription factors. Furthermore, the refractory phenotype is lost progressively during development in laboratory-reared F1 generation fish. Thus, while heritable, the refractory CYP1A phenotype does not appear to be genetically based. To test the hypothesis that cytosine methylation at CpG sites in the promoter region of CYP1A underlies the refractory CYP1A phenotype, we employed bisulfite sequencing to compare the methylation status of CpG sites in the CYP1A promoter region of DNA from killifish from the Elizabeth River and a reference site. We examined genomic DNA both from livers of wild-caught adult killifish and from pools of F1 generation embryos raised in the laboratory. In fish from both the contaminated and the reference site, cytosine methylation was not detectable at any of the 34 CpG sites examined, including 3 that are part of putative xenobiotic response elements. [Copyright &y& Elsevier]

Objective: To evaluate the effect of infertility and intracytoplasmic sperm injection (ICSI) on DNA methylation of offspring.Design: Microarray analysis of DNA methylation in archived neonatal bloodspots of in vitro fertilization (IVF)/ICSI-conceived children compared with controls born to fertile and infertile parents.Setting: Academic research laboratory.Patient(s): Neonatal blood spots of 137 newborns conceived spontaneously, through intrauterine insemination (IUI), or through ICSI using fresh or cryopreserved (frozen) embryo transfer.Intervention(s): None.Main Outcome Measure(s): The Illumina Infinium HumanMethylation450k BeadChip assay determined genome-wide DNA methylation. Methylation differences between conception groups were detected using a Bioconductor package, ChAMP, in conjunction with Adjacent Site Clustering (A-clustering).Result(s): The methylation profiles of assisted reproductive technology and IUI newborns were dramatically different from those of naturally (in vivo) conceived newborns. Interestingly, the profiles of ICSI-frozen (FET) and IUI infants were strikingly similar, suggesting that cryopreservation may temper some of the epigenetic aberrations induced by IVF or ICSI. The DNA methylation changes associated with IVF/ICSI culture conditions and/or parental infertility were detected at metastable epialleles, suggesting a lasting impact on a child's epigenome.Conclusion(s): Both infertility and ICSI alter DNA methylation at specific genomic loci, an effect that is mitigated to some extent by FET. The impact of assisted reproductive technology and/or fertility status on metastable epialleles in humans was uncovered. This study provides an expanded set of loci for future investigations on IVF populations. [ABSTRACT FROM AUTHOR]