We are what we eat

Born Large for Gestational Age: Bigger Is Not Always Better

Epidemic of Childhood Obesity: Implications for Kidney Disease

Andrea Cupp made a serendipitous discovery when she was a postdoctoral fellow at Washington State University: While investigating how chemicals affect sex determination in embryonic animals, she bred the offspring of pregnant rats that had been dosed with an insecticide called methoxyclor. When the males from that litter grew into adults, they had decreased sperm counts and higher rates of infertility. Cupp had seen these same abnormalities in the animals’ fathers, which had been exposed to methoxyclor in the womb. But this latest generation hadn’t been exposed that way, which suggested that methoxyclor’s toxic effects had carried over generations. “At first I couldn’t believe it,” says Cupp’s advisor, Michael Skinner, a biochemist and Washington State professor. “But then we repeated the breeding experiments and found that the results held up.” Skinner and Cupp, who is now a professor at the University of Nebraska–Lincoln, published their findings in 2005.1 Since that paper—which showed that reproductive effects not just from methoxyclor but also from the fungicide vinclozolin persisted for at least four generations—the number of published articles reporting similar transgenerational findings has increased steadily. “In the last year and half there’s been an explosion in studies showing transgenerational effects from exposure to a wide array of environmental stressors,” says Lisa Chadwick, a program administrator at the National Institute of Environmental Health Sciences (NIEHS). “This is a field that’s really starting to take off.” According to Chadwick, the new findings compel a reevaluation of how scientists perceive environmental health threats. “We have to think more long-term about the effects of chemicals that we’re exposed to every day,” she says. “This new research suggests they could have consequences not just for our own health and for that of our children, but also for the health of generations to come.” Figure 1 Glossary The NIEHS recently issued requests for applications totaling $3 million for research on transgenerational effects in mammals.2 Chadwick says funded studies will address two fundamental data needs, one pertaining to potential transgenerational mechanisms and another to the number of chemicals thought to exert these effects. These studies will extend to what’s known as the F3 generation—the great-grandchildren of the originally exposed animal. That’s because chemicals given to pregnant females (the F0 generation) interact not only with the fetal offspring (the F1 generation) but also the germ cells developing within those offspring, which mature into the sperm and eggs that give rise to the F2 generation. Thus, the F3 animals are the first generation to be totally unexposed to the original agent. Effects that extend to the F2 generation are known as “multigenerational,” whereas those that extend to the F3 generation are known as “transgenerational.”3 Transgenerational effects have now been reported for chemicals including permethrin, DEET, bisphenol A, certain phthalates, dioxin, jet fuel mixtures, nicotine, and tributyltin, among others. Most of these findings come from rodent studies.4,5,6,7 But preliminary evidence that chemical effects can carry over generations in humans is also emerging, although no F3 data have been published yet. Given the challenges of tracking effects over multiple human lifespans, the evidence is more difficult to interpret, particularly with respect to potential mechanisms, says Tessa Roseboom, a professor of early development and health at the Academic Medical Center in Amsterdam, the Netherlands. Still, some reports have linked nutritional deficiencies from famine and exposure to diethylstilbestrol (DES)—a nonsteroidal estrogen used to protect against miscarriage from the 1940s to the 1970s—to effects that persist among the grandchildren of exposed women.8,9,10,11,12,13

Epigenetic modifiers enhance the synergistic cytotoxicity of combined nucleoside analog-DNA alkylating agents in lymphoma cell lines

Bronchial asthma in children is a common chronic disease. Obesity can affect the risk of bronchial asthma, its phenotype, and prognosis. Objective of the review. To present and summarize information on the causal relationship of the non-eosinophilic endotype of bronchial asthma associated with obesity in children and on possible mechanisms of targeting the pathogenesis of these conditions to improve the effectiveness of controller therapy. Material and methods. A search of local and foreign literature was conducted on the relationship between various links in the pathogenesis of bronchial asthma and obesity and on possible ways to increase the effectiveness of therapy. We used Scopus, Web of Science, PubMed, Google Scholar, eLibrary, and Cyberleninka databases. Results. Many clinical studies and observations showed an association between obesity and bronchial asthma in children. Several mechanisms may be involved in developing obesity-associated bronchial asthma in children, including decreased physical activity, abnormal lung ventilation, chronic systemic inflammation, hormone effects, genetic factors, and comorbidities. Obesity can contribute to asthma pathogenesis due to mechanical, inflammatory, genetic, metabolic, and immune factors. Physical inactivity and systemic corticosteroid therapy seem to increase the risk of obesity in children with asthma. Conclusion. Identification of obesity-associated asthma phenotype is important for treatment. In addition to the controller therapy of bronchial asthma, lifestyle should be adjusted, healthy nutrition and physical activity of the patient should be encouraged, and comorbidities should be treated. Future studies should clarify the relationship between bronchial asthma and obesity and the mechanisms underlying the pathogenesis of these two conditions, with a view to personalizing therapy.

BackgroundWe investigated the individual and additive effects of three modifiable maternal metabolic factors, including pre-pregnancy overweight/obesity, gestational weight gain (GWG), and gestational diabetes mellitus (GDM), on early childhood growth trajectories and obesity risk.MethodsA total of 1 425 mother-offspring dyads (953 black and 472 white) from a longitudinal birth cohort were included in this study. Latent class growth modeling was performed to identify the trajectories of body mass index (BMI) from birth to four years in children. Poisson regression models were used to examine the associations between the maternal metabolic risk factors and child BMI trajectories and obesity risk at four years.ResultsWe identified three discrete BMI trajectory groups, characterized as rising-high-BMI (12.6%), moderate-BMI (61.0%), or low-BMI (26.4%) growth. Both maternal pre-pregnancy obesity (adjusted relative risk [adjRR] = 1.96; 95% CI: 1.36–2.83) and excessive GWG (adjRR = 1.71, 95% CI: 1.13–2.58) were significantly associated with the rising-high-BMI trajectory, as manifested by rapid weight gain during infancy and a stable but high BMI until four years. All three maternal metabolic indices were significantly associated with childhood obesity at age four years (adjRR for pre-pregnancy obesity = 2.24, 95% CI: 1.62–3.10; adjRR for excessive GWG = 1.46, 95% CI: 1.01–2.09; and adjRR for GDM = 2.14, 95% = 1.47–3.12). In addition, risk of rising-high BMI trajectory or obesity at age four was stronger among mothers with more than one metabolic risk factor. We did not observe any difference in these associations by race.ConclusionMaternal pre-pregnancy obesity, excessive GWG, and GDM individually and jointly predict rapid growth and obesity at age four in offspring, regardless of race. Interventions targeting maternal obesity and metabolism may prevent or slow the rate of development of childhood obesity.

Recognizing Pregnancy-Associated Cardiovascular Risk Factors

Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics

Nonalcoholic Fatty Liver Disease in Children: Where Are We?

PML-RARα/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia

A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins

BackgroundGestational diabetes mellitus (GDM), characterized by hyperglycemia that develops during pregnancy, increases the risk of fetal macrosomia, childhood obesity and cardiometabolic disorders later in life. This process has been attributed partly to DNA methylation modifications in growth and stress-related pathways. Nutrients involved with one-carbon metabolism (OCM), such as folate, choline, betaine, and vitamin B12, provide methyl groups for DNA methylation of these pathways. Therefore, this study aimed to determine whether maternal OCM nutrient intakes and levels modified fetal DNA methylation and in turn altered fetal growth patterns in pregnancies with and without GDM.ResultsIn this prospective study at a single academic institution from September 2016 to June 2019, we recruited 76 pregnant women with and without GDM at 25–33 weeks gestational age and assessed their OCM nutrient intake by diet recalls and measured maternal blood OCM nutrient levels. We also collected placenta and cord blood samples at delivery to examine fetal tissue DNA methylation of the genes that modify fetal growth and stress response such as insulin-like growth factor 2 (IGF2) and corticotropin-releasing hormone (CRH). We analyzed the association between maternal OCM nutrients and fetal DNA methylation using a generalized linear mixed model. Our results demonstrated that maternal choline intake was positively correlated with cord blood CRH methylation levels in both GDM and non-GDM pregnancies (r = 0.13, p = 0.007). Further, the downstream stress hormone cortisol regulated by CRH was inversely associated with maternal choline intake (r = − 0.36, p = 0.021). Higher maternal betaine intake and serum folate levels were associated with lower cord blood and placental IGF2 DNA methylation (r = − 0.13, p = 0.049 and r = − 0.065, p = 0.034, respectively) in both GDM and non-GDM pregnancies. Further, there was an inverse association between maternal betaine intake and birthweight of infants (r = − 0.28, p = 0.015).ConclusionsIn conclusion, we observed a complex interrelationship between maternal OCM nutrients and fetal DNA methylation levels regardless of GDM status, which may, epigenetically, program molecular pathways related to fetal growth and stress response.

Nuclear events such as chromatin condensation, DNA cleavage at internucleosomal sites, and histone release from chromatin are recognized as hallmarks of apoptosis. However, there is no complete understanding of the molecular events underlying these changes. It is likely that epigenetic changes such as DNA methylation and histone modifications that are involved in chromatin dynamics and structure are also involved in the nuclear events described. In this report we have shown that apoptosis is associated with global DNA hypomethylation and histone deacetylation events in leukemia cells. Most importantly, we have observed a particular epigenetic signature for early apoptosis defined by a release of hypoacetylated and trimethylated histone H4 and internucleosomal fragmented DNA that is hypermethylated and originates from perinuclear heterochromatin. These findings provide one of the first links between apoptotic nuclear events and epigenetic markers.

COVID-19 Special Collection

Childhood obesity is a global health concern that has its origins before birth. Although genetics plays a crucial role, increasing evidence suggests that epigenetic modifications during fetal life could also influence its incidence. In this model, during the fetal period, interactions between genetic makeup, intrauterine factors, and environmental conditions, increase the risk of childhood obesity. This is in accordance with the Developmental Origins of Health and Disease (DOHaD) hypothesis, in which specific intrauterine environments can have long-lasting effects on the immune system’s essential functions during crucial stages of fetal growth, resulting in permanent changes to the immune function of the offspring. Consequently, dysfunction can consequently make the offspring more prone to inflammatory and immune-related disorders later in life. In this review, we examine how maternal inflammation could influence the risk of childhood obesity. We propose that during pregnancy, modification of the expression of critical genes in metabolic and signaling pathways, such as the kynurenine (Kyn) pathway, occurs due to increased levels of maternal inflammation. We also propose that such expression differences are mediated by epigenetic changes. Furthermore, we also hypothesize that the Kyn pathway produces metabolites that have immunoregulatory effects and may play a crucial role in regulating inflammation during pregnancy. As a result, interventions aimed at improving maternal inflammation may be able to help alleviate the risk of childhood obesity.