Lactation is a critical time in mammalian development, where maternal factors shape offspring outcomes. In this scoping review, we discuss current literature concerning maternal factors that ...influence lactation biology and highlight important associations between changes in milk composition and offspring outcomes. Specifically, we explore maternal nutritional, psychosocial, and environmental exposures that influence non-nutritive bioactive components in milk and their links to offspring growth, development, metabolic, and behavioral outcomes. A comprehensive literature search was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) guidelines. Predetermined eligibility criteria were used to analyze 3,275 papers, and the final review included 40 primary research articles. Outcomes of this review identify maternal obesity to be a leading maternal factor influencing the non-nutritive bioactive composition of milk with notable links to offspring outcomes. Offspring growth and development are the most common modes of programming associated with changes in non-nutritive milk composition due to maternal factors in early life. In addition to discussing studies investigating these key associations, we also identify knowledge gaps in the current literature and suggest opportunities and considerations for future studies.
Extremely low birth weight (ELBW) (<1000 g) survivors are exposed to elevated levels of physiologic stress during their lives and may be susceptible to accelerated aging. Using the oldest known ...longitudinally followed cohort of ELBW survivors, we compared biological aging in this group using an epigenetic clock to a sample of matched normal birth weight (NBW) (>2500 g) control participants.
Buccal cells were collected from 45 ELBW survivors and 49 NBW control participants at 30 to 35 years of age. Epigenetic age was calculated from the weighted average of DNA methylation at 353 cytosine-phosphate-guanine sequence within DNA sites, by using the Illumina Infinium Human Methylation EPIC 850k BeadChip array.
Before and after statistically adjusting for neurosensory impairment and the presence of chronic health conditions, a significant sex by birth weight group interaction was observed in the 353-site epigenetic-clock assay (
= .03), whereby ELBW men had a significantly older epigenetic age than NBW men (4.6 years;
= .01). Women born at ELBW were not found to be epigenetically older than their NBW peers.
The results of this study suggest that prenatal exposures may play an important role in aging, and that men born preterm may experience accelerated aging relative to their peers. We further highlight the need to monitor and promote the health of preterm survivors, with a particular focus on healthy aging across the life span.
Gulf War illness (GWI) is an archetypal, medically unexplained, chronic condition characterised by persistent sickness behaviour and neuroimmune and neuroinflammatory components. An estimated 25-32% ...of the over 900,000 veterans of the 1991 Gulf War fulfil the requirements of a GWI diagnosis. It has been hypothesised that the high physical and psychological stress of combat may have increased vulnerability to irreversible acetylcholinesterase (AChE) inhibitors leading to a priming of the neuroimmune system. A number of studies have linked high levels of psychophysiological stress and toxicant exposures to epigenetic modifications that regulate gene expression. Recent research in a mouse model of GWI has shown that pre-exposure with the stress hormone corticosterone (CORT) causes an increase in expression of specific chemokines and cytokines in response to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor.
C57BL/6J mice were exposed to CORT for 4 days, and exposed to DFP on day 5, before sacrifice 6 h later. The transcriptome was examined using RNA-seq, and the epigenome was examined using reduced representation bisulfite sequencing and H3K27ac ChIP-seq.
We show transcriptional, histone modification (H3K27ac) and DNA methylation changes in genes related to the immune and neuronal system, potentially relevant to neuroinflammatory and cognitive symptoms of GWI. Further evidence suggests altered proportions of myelinating oligodendrocytes in the frontal cortex, perhaps connected to white matter deficits seen in GWI sufferers.
Our findings may reflect the early changes which occurred in GWI veterans, and we observe alterations in several pathways altered in GWI sufferers. These close links to changes seen in veterans with GWI indicates that this model reflects the environmental exposures related to GWI and may provide a model for biomarker development and testing future treatments.
Rat dams show natural variations in maternal care, licking and grooming (LG), that are associated with distinct behavioral and neural phenotypes in offspring. However, there has been limited research ...on the effects of differences in LG received by female pups and of variations in maternal care within the litter. Here, we investigated LG received by measuring active maternal care after pup retrieval of female offspring. We then examined locomotor activity, open field exploration, and restraint stress reactivity in adult female offspring. We also investigated the expression of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) and DNA methylation of the GR17 promoter in the hippocampus. High compared with low LG siblings and female offspring from high compared with low LG dams showed increased locomotor activity. High compared with low LG siblings also showed reduced anxiety behavior regardless of the overall level of LG received in the litter. Unexpectedly, both the lowest licked offspring from low LG litters and the highest licked offspring from high LG litters showed suppressed corticosterone (CORT) responses to stress. However, high LG offspring within litters also showed increased expression of the GR gene, which was negatively correlated with the CORT response to restraint. DNA methylation at 2 CpG sites within GR17 promoter was significantly higher in high LG offspring. These differences in the response to maternal care both within- and between-litters were distinct in part from previous reports of between litter effects, potentially a result of the sex studied or the methods used to observe maternal care.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating idiopathic disease characterized by unexplained fatigue that fails to resolve with sufficient rest. Diagnosis is based on ...a list of symptoms and exclusion of other fatigue-related health conditions. Despite a heterogeneous patient population, immune and hypothalamic-pituitary-adrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined.
We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone. We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results.
We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci.
Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population.
The role of breastfeeding in modulating epigenetic factors has been suggested as a possible mechanism conferring its benefits on child development but it lacks evidence. Using extensive DNA ...methylation data from the ALSPAC child cohort, we characterized the genome-wide landscape of DNA methylation variations associated with the duration of exclusive breastfeeding and assessed whether these variations mediate the association between exclusive breastfeeding and BMI over different epochs of child growth.
Exclusive breastfeeding elicits more substantial DNA methylation variations during infancy than at other periods of child growth. At the genome-wide level, 13 CpG sites in girls (miR-21, SNAPC3, ATP6V0A1, DHX15/PPARGC1A, LINC00398/ALOX5AP, FAM238C, NATP/NAT2, CUX1, TRAPPC9, OSBPL1A, ZNF185, FAM84A, PDPK1) and 2 CpG sites in boys (IL16 and NREP), mediate the association between exclusive breastfeeding and longitudinal BMI. We found enrichment of CpG sites located within miRNAs and key pathways (AMPK signaling pathway, insulin signaling pathway, endocytosis). Overall DNA methylation variation corresponding to 3 to 5 months of exclusive breastfeeding was associated with slower BMI growth the first 6 years of life compared to no breastfeeding and in a dose-response manner with exclusive breastfeeding duration.
Our study confirmed the early postnatal period as a critical developmental period associated with substantial DNA methylation variations, which in turn could mitigate the development of overweight and obesity from infancy to early childhood. Since an accelerated growth during these developmental periods has been linked to the development of sustained obesity later in life, exclusive breastfeeding could have a major role in preventing the risks of overweight/obesity and children and adults through DNA methylation mechanisms occurring early in life.
The population dynamics of snowshoe hares (Lepus americanus) are fundamental to the ecosystem dynamics of Canada’s boreal forest. During the 8- to 11-year population cycle, hare densities can ...fluctuate up to 40-fold. Predators in this system (lynx, coyotes, great-horned owls) affect population numbers not only through direct mortality but also through sublethal effects. The chronic stress hypothesis posits that high predation risk during the decline severely stresses hares, leading to greater stress responses, heightened ability to mobilize cortisol and energy, and a poorer body condition. These effects may result in, or be mediated by, differential gene expression. We used an oligonucleotide microarray designed for a closely-related species, the European rabbit (Oryctolagus cuniculus), to characterize differences in genome-wide hippocampal RNA transcript abundance in wild hares from the Yukon during peak and decline phases of a single cycle. A total of 106 genes were differentially regulated between phases. Array results were validated with quantitative real-time PCR, and mammalian protein sequence similarity was used to infer gene function. In comparison to hares from the peak, decline phase hares showed increased expression of genes involved in metabolic processes and hormone response, and decreased expression of immune response and blood cell formation genes. We found evidence for predation risk effects on the expression of genes whose putative functions correspond with physiological impacts known to be induced by predation risk in snowshoe hares. This study shows, for the first time, a link between changes in demography and alterations in neural RNA transcript abundance in a natural population.
That the fear and stress of life-threatening experiences can leave an indelible trace on the brain is most clearly exemplified by post-traumatic stress disorder (PTSD). Many researchers studying the ...animal model of PTSD have adopted utilizing exposure to a predator as a life-threatening psychological stressor, to emulate the experience in humans, and the resulting body of literature has demonstrated numerous long-lasting neurological effects paralleling those in PTSD patients. Even though much more extreme, predator-induced fear and stress in animals in the wild was, until the 1990s, not thought to have any lasting effects, whereas recent experiments have demonstrated that the effects on free-living animals are sufficiently long-lasting to even affect reproduction, though the lasting neurological effects remain unexplored. We suggest neuroscientists and ecologists both have much to gain from collaborating in studying the neurological effects of predator-induced fear and stress in animals in the wild. We outline the approaches taken in the lab that appear most readily translatable to the field, and detail the advantages that studying animals in the wild can offer researchers investigating the "predator model of PTSD."
Effects of stresses associated with extremely preterm birth may be biologically "recorded" in the genomes of individuals born preterm via changes in DNA methylation (DNAm) patterns. Genome-wide DNAm ...profiles were examined in buccal epithelial cells from 45 adults born at extremely low birth weight (ELBW; ≤1000 g) in the oldest known cohort of prospectively followed ELBW survivors (Mage = 32.35 years, 17 male), and 47 normal birth weight (NBW; ≥2500 g) control adults (Mage = 32.43 years, 20 male). Sex differences in DNAm profiles were found in both birth weight groups, but they were greatly enhanced in the ELBW group (77,895 loci) versus the NBW group (3,424 loci), suggesting synergistic effects of extreme prenatal adversity and sex on adult DNAm profiles. In men, DNAm profiles differed by birth weight group at 1,354 loci on 694 unique genes. Only two loci on two genes distinguished between ELBW and NBW women. Gene ontology (GO) and network analyses indicated that loci differentiating between ELBW and NBW men were abundant in genes within biological pathways related to neuronal development, synaptic transportation, metabolic regulation, and cellular regulation. Findings suggest increased sensitivity of males to long-term epigenetic effects of extremely preterm birth. Group differences are discussed in relation to particular gene functions.
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