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.
Rat mothers exhibit natural variations in care and can shape offspring adult behaviour and their maternal care by affecting the dopaminergic system. We explored whether genotype and ...gene × environment interactions are involved in these processes in nulliparous female offspring. We assessed maternal licking/grooming toward individual female pups during the first week postpartum and dopamine‐related behaviour of the offspring in adulthood. Behaviours explored included strategy shifting, impulsive action and sucrose preference. Single nucleotide polymorphisms in the dopamine receptor 2, dopamine transporter and catechol‐O‐methyltransferase genes were examined in relation to offspring behaviour and baseline dopamine turnover in select brain regions. Dopamine receptor 2 (RS107017253) variation moderated, or interacted with, the relationship between early‐life licking received and behaviour. Specifically, offspring with the A/A genotype showed a significant correlation between early‐life licking received and behaviour. Offspring with the A/G and G/G genotypes did not show this relationship. Dopamine transporter gene variation affected offspring behaviour regardless of early‐life licking received. Our findings suggest that genotype can directly affect dopamine‐related behaviours and alter the sensitivity of offspring to the maternal environment. This could be informative on how maternal care is transmitted between generations of female offspring.
A cardinal feature of the reaction to stress is the promotion of energy mobilization, enabling appropriate behavioural responses. Predator odours are naturalistic and ecologically relevant stressors ...present over evolutionary timescales. In this study, we asked whether maternal predator odour exposure could program long-term energy mobilization in C57BL/6 mice offspring. To test this hypothesis, we measured rates of oxygen consumption in prenatally predator odour exposed mice in adulthood while controlling for levels of locomotor activity at baseline and under stress. Circulating thyroid hormone levels and the transcript abundance of key regulators of the hypothalamic-pituitary-thyroid axis within the periventricular nucleus (PVN) of the hypothalamus and in the liver, including carriers and receptors and thyrotropin-releasing hormone, were measured as endocrine mediators facilitating energy availability. Prenatally predator odour exposed mice of both sexes mobilized more energy during lower energy demand periods of the day and under stressful conditions. Further, prenatally predator odour exposed mice displayed modifications of their hypothalamic-pituitary-thyroid axis through increased circulating thyroxine and thyroid hormone receptor α within the PVN and decreased transthyretin in the liver. Overall, these results suggest that maternal exposure to predator odour is sufficient to increase long-term energy mobilization in adult offspring.
Introduction
Rat mothers exhibit natural variations in care that propagate between generations of female offspring. However, there is limited information on genetic variation that could influence ...this propagation.
Methods
We assessed early‐life maternal care received by individual female rat offspring, later‐life maternal care provisioning, and dopaminergic activity in the maternal brain in relation to naturally occurring genetic polymorphisms linked to the dopaminergic system. We also conducted a systematic analysis of other genetic variants potentially related to maternal behavior in our Long‐Evans rat population.
Results
While we did not find a direct relationship between early‐life licking received and later‐life licking provisioning, this relationship was indirectly affected by dopamine levels in the nucleus accumbens and dependent on variation in the dopamine receptor 2 gene (rs107017253). More specifically, female rat offspring with the A/G genotype showed a positive relationship between average licking received and dopamine levels in the nucleus accumbens of the maternal brain; there was no relationship with female rat offspring with the A/A genotype. The higher dopamine levels in the nucleus accumbens corresponded with higher maternal licking provisioning from postnatal days 2–9. We also discovered and validated several new variants that were predicted by our systematic analysis.
Conclusion
Our findings suggest that genetic variation influences the relationship between early‐life maternal care received and the dopaminergic system of the maternal brain, which can indirectly influence later‐life maternal care provisioning.
Rat mothers exhibit natural variations in care that propagate between generations of female offspring, but there is limited information on genetic variation that influences this propagation. We assessed early‐life maternal care received by individual female rat offspring in relation to genetic polymorphisms linked to dopaminergic activity, maternal care provisioning, and dopaminergic activity in the maternal brain. We found that dopamine receptor 2 (rs107017253) variation interacted with the relationship between early‐life maternal care received and dopamine levels in the nucleus accumbens which, in turn, were associated with later‐life maternal care provisioning.
•Cocaine prior to pregnancy enhanced psychomotor sensitivity to cocaine in adult male offspring.•This enhanced sensitivity to cocaine in the offspring was associated with increased gene expression of ...DRD1 in mPFC.•Cocaine prior to pregnancy had no effect on maternal behavior during lactation.•Cocaine prior to pregnancy had no effect on CORT, GR or CRF gene expression in offspring.
There is evidence that maternal experience prior to pregnancy can play an important role in behavioral, physiological, and genetic programming of offspring. Likewise, exposure to cocaine in utero can result in marked changes in central nervous system function of offspring. In this study, we examined whether exposure of rat dams to cocaine prior to pregnancy subsequently alters indices of behavior, physiology, and gene expression in offspring. Multiple outcome measures were examined in adult male offspring: (1) behavioral expression of cocaine-induced psychomotor activation; (2) levels of corticosterone in response to immobilization stress; and (3) expression of multiple genes, including dopamine receptor D1 (DRD1) and D2 (DRD2), glucocorticoid receptor (GR), and corticotropin-releasing factor (CRF), in functionally relevant brain regions. Adult Sprague-Dawley females were exposed to cocaine (15–30mg/kg, i.p.) or saline for 10 days, and were then mated to drug naïve males of the same strain. Separate groups of adult male offspring were tested for their acute psychomotor response to cocaine (0, 15, 30mg/kg, i.p.), corticosterone responsivity to 20min of immobilization stress, and expression of multiple genes using quantitative PCR. Offspring of dams exposed to cocaine prior to conception exhibited increased psychomotor sensitivity to cocaine, and upregulated gene expression of DRD1 in the medial prefrontal cortex (mPFC). Neither stress-induced corticosterone levels nor gene expression of GR or CRF genes were altered. These data suggest that cocaine exposure before pregnancy can serve to enhance psychomotor sensitivity to cocaine in offspring, possibly via alterations in dopamine function that include upregulation of the DRD1.
Long-term sequelae of extremely low birth weight (ELBW; ≤1000 g) may contribute to accelerated biological aging. This hypothesis was examined by analyzing a range of risk factors with a molecular age ...marker in adults born at ELBW or normal birth weight (NBW; ≥2500 g). DNAm age-the weighted average of DNA methylation at 353 cytosine-phosphate-guanine (CpG) sites from across the genome-was derived from a sample of 45 ELBW (M
= 32.35 years) and 47 NBW control (M
= 32.44 years) adults, using the Illumina 850k BeadChip Array. At two assessments undertaken 9 years apart (at 23 and 32 years), cumulative risks were summed from six domains with potential to affect physiological and psychological health: resting respiratory sinus arrhythmia, blood pressure, basal cortisol, grip strength, body mass index, and self-esteem. At age 32 years, cumulative risks were differentially associated with epigenetic age in ELBW survivors (interaction, p < 0.01). For each additional risk factor they possessed, ELBW survivors (B = 1.43) were biologically 2.16 years older than NBW adults (B = -0.73), by the fourth decade of life. Developmental change, epigenetic maintenance, and intervention targets are discussed.
To identify subtypes in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) based on DNA methylation profiles and health scores.
DNA methylome profiles in immune cells were integrated with ...symptomatology from 70 women with ME/CFS using similarity network fusion to identify subtypes.
We discovered four ME/CFS subtypes associated with DNA methylation modifications in 1939 CpG sites, three RAND-36 categories and five DePaul Symptom Questionnaire measures. Methylation patterns of immune response genes and differences in physical functioning and postexertional malaise differentiated the subtypes.
ME/CFS subtypes are associated with specific DNA methylation differences and health symptomatology and provide additional evidence of the potential relevance of metabolic and immune differences in ME/CFS with respect to specific symptoms.
Epigenetics in mood disorders McGowan, Patrick O; Kato, Tadafumi
Environmental health and preventive medicine,
01/2008, Letnik:
13, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Depression develops as an interaction between stress and an individual's vulnerability to stress. The effect of early life stress and a gene-environment interaction may play a role in the development ...of stress vulnerability as a risk factor for depression. The epigenetic regulation of the promoter of the glucocorticoid receptor gene has been suggested as a molecular basis of such stress vulnerability. It has also been suggested that antidepressive treatment, such as antidepressant medication and electroconvulsive therapy, may be mediated by histone modification on the promoter of the brain-derived neurotrophic factor gene. Clinical genetic studies in bipolar disorder suggest the role of genomic imprinting, although no direct molecular evidence of this has been reported. The role of DNA methylation in mood regulation is indicated by the antimanic effect of valproate, a histone deacetylase inhibitor, and the antidepressive effect of S-adenosyl methionine, a methyl donor in DNA methylation. Studies of postmortem brains of patients have implicated altered DNA meA methylation of the promoter region of membrane-bound catechol-O-methyltransferase in bipolar disorder. An altered DNA methylation status of PPIEL (peptidylprolyl isomerase E-like) was found in a pair of monozygotic twins discordant for bipolar disorder. Hypomethylation of PPIEL was also found in patients with bipolar II disorder in a case control analysis. These fragmentary findings suggest the possible role of epigenetics in mood disorders. Further studies of epigenetics in mood disorders are warranted.
Rat dams differ naturally in the level of maternal care they provide to their offspring within the same litter. We explored possible mechanisms of differential maternal care focused on genetic ...variation. We examined single nucleotide polymorphisms in the glucocorticoid receptor, FK506-binding protein, and serotonin transporter genes in two separate cohorts, and the relationship between differential maternal care received, genotype, and offspring phenotype. Allelic variation in all three genes was significantly associated with levels of maternal care received by offspring and behavioral and endocrine stress responses in adulthood. Differences in pup behavior were also associated with allelic variation in these genes. Together, these results indicate that the dam/pup interaction is dynamic and implicate the genotype of the offspring in influencing the level of maternal care received. They further suggest that some genotypes may have a dampening effect on the impact of maternal care on stress-related phenotypes in adulthood.
...unraveling complex phenotypes depends to a large extent upon an ability to discriminate what are likely many distinct conditions. Biological differences observed in myalgic ...encephalomyelitis/chronic fatigue syndrome Studies that have investigated the immune response in ME/CFS patients have reported deficiencies in major cell types of the innate immune system, including natural killer cells exhibiting decreased cytotoxicity, cytotoxic T cells with reduced receptor expression and attenuated B cell response compared with healthy controls (9). DNA methylation modifications in myalgic encephalomyelitis/chronic fatigue syndrome Research by our group using DNA microarrays identified methylation differences >20% in 1192 CpG sites, corresponding to 826 genes, in peripheral blood mononuclear cells of ME/CFS patients (12). An in vitro examination of peripheral blood mononuclear cell GC sensitivity using a T cell mitogen revealed two ME/CFS subtypes: a GC-hypersensitive subtype that included patients with enhanced negative feedback to GCs, and a GC-typical subtype showing sensitivity similar to controls (13).
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