Governing dual objectives within single policy mixes : an empirical analysis of large carnivore policies in six European countries

Policy mixes (i.e. the total structure of policy processes, strategies, and instruments) are complex constructs that can quickly become incoherent, inconsistent, and incomprehensive. This is amplified when the policy mix strives to meet multiple objectives simultaneously, such as in the case of large carnivore policy mixes. Building on Rogge and Reichardt's analytical framework for the analysis of policy mixes, we compare the policy mixes of Norway, Sweden, Finland, the Netherlands, Germany (specifically Saxony and Bavaria), and Spain (specifically Castilla y Leon). The study shows that the large carnivore policy mixes in the case countries show signs of lacking vertical and horizontal coherence in the design of policy processes, weak consistency between objectives and designated policy instruments, and, as a consequence, lacking comprehensiveness. We conclude that creating consistent, coherent, and comprehensive policy mixes that build on multiple objectives requires stepping away from sectorized policy development, toward a holistic, systemic approach, strong collaborative structures across policy boundaries and regions, the inclusion of diverse stakeholders, and constant care and attention to address all objectives simultaneously rather than in isolation.Peer reviewe

Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life

The epidemic increase of type 2 diabetes and obesity in developed countries cannot be explained by overnutrition, physical inactivity and/or genetic factors alone. Epidemiologic evidence suggests that an adverse intrauterine environment, in particular a shortage or excess of nutrients is associated with increased risks for many complex diseases later in life. An impressive example for the ‘fetal origins of adult disease’ is gestational diabetes mellitus which usually presents in 1% to >10% of third trimester pregnancies. Intrauterine hyperglycemia is not only associated with increased perinatal morbidity and mortality, but also with increased lifelong risks of the exposed offspring for obesity, metabolic, cardiovascular and malignant diseases. Accumulating evidence suggests that fetal overnutrition (and similarly undernutrition) lead to persistent epigenetic changes in developmentally important genes, influencing neuroendocrine functions, energy homeostasis and metabolism. The concept of fetal programming has important implications for reproductive medicine. Because during early development the epigenome is much more vulnerable to environmental cues than later in life, avoiding adverse environmental factors in the periconceptional and intrauterine period may be much more important for the prevention of adult disease than any (i.e. dietetic) measures in infants and adults. A successful pregnancy should not primarily be defined by the outcome at birth but also by the health status in later life

Epigenetic signatures of gestational diabetes mellitus on cord blood methylation

Background: Intrauterine exposure to gestational diabetes mellitus (GDM) confers a lifelong increased risk for metabolic and other complex disorders to the offspring. GDM-induced epigenetic modifications modulating gene regulation and persisting into later life are generally assumed to mediate these elevated disease susceptibilities. To identify candidate genes for fetal programming, we compared genome-wide methylation patterns of fetal cord bloods (FCBs) from GDM and control pregnancies. Methods and results: Using Illumina’s 450K methylation arrays and following correction for multiple testing, 65 CpG sites (52 associated with genes) displayed significant methylation differences between GDM and control samples. Four candidate genes, ATP5A1, MFAP4, PRKCH, and SLC17A4, from our methylation screen and one, HIF3A, from the literature were validated by bisulfite pyrosequencing. The effects remained significant after adjustment for the confounding factors maternal BMI, gestational week, and fetal sex in a multivariate regression model. In general, GDM effects on FCB methylation were more pronounced in women with insulin-dependent GDM who had a more severe metabolic phenotype than women with dietetically treated GDM. Conclusions: Our study supports an association between maternal GDM and the epigenetic status of the exposed offspring. Consistent with a multifactorial disease model, the observed FCB methylation changes are of small effect size but affect multiple genes/loci. The identified genes are primary candidates for transmitting GDM effects to the next generation. They also may provide useful biomarkers for the diagnosis, prognosis, and treatment of adverse prenatal exposures

Additional file 2: Figure S1. of Epigenetic signatures of gestational diabetes mellitus on cord blood methylation

Estimation of blood cell composition based on 450K methylation array profiles. Blue box plots show the distribution of cell types in GDM cord blood and red box plots in control samples. The median is represented by a horizontal line. The bottom of the box indicates the 25th percentile and the top the 75th percentile. Outliers are shown as circles. (DOC 146 kb

Additional file 4: Table S3. of Epigenetic signatures of gestational diabetes mellitus on cord blood methylation

Multivariate analyses (adjusting for maternal BMI, gestational age, and fetal sex): CpG methylation of candidate genes in GDM versus control FCB samples. (DOC 68 kb

Additional file 1: Table S1. of Epigenetic signatures of gestational diabetes mellitus on cord blood methylation

Primers for pyrosequencing. (DOC 52 kb

Hypermethylation of the non-imprinted maternal <i>MEG3</i> and paternal <i>MEST</i> alleles is highly variable among normal individuals

<div><p>Imprinted genes show parent-specific activity (functional haploidy), which makes them particularly vulnerable to epigenetic dysregulation. Here we studied the methylation profiles of oppositely imprinted genes at single DNA molecule resolution by two independent parental allele-specific deep bisulfite sequencing (DBS) techniques. Using Roche (GSJunior) next generation sequencing technology, we analyzed the maternally imprinted <i>MEST</i> promoter and the paternally imprinted <i>MEG3</i> intergenic (IG) differentially methylated region (DMR) in fetal cord blood, adult blood, and visceral adipose tissue. Epimutations were defined as paternal or maternal alleles with >50% aberrantly (de)methylated CpG sites, showing the wrong methylation imprint. The epimutation rates (range 2–66%) of the paternal <i>MEST</i> and the maternal <i>MEG3</i> IG DMR allele, which should be completely unmethylated, were significantly higher than those (0–15%) of the maternal <i>MEST</i> and paternal <i>MEG3</i> alleles, which are expected to be fully methylated. This hypermethylation of the non-imprinted allele (HNA) was independent of parental origin. Very low epimutation rates in sperm suggest that HNA occurred after fertilization. DBS with Illumina (MiSeq) technology confirmed HNA for the <i>MEST</i> promoter and the <i>MEG3</i> IG DMR, and to a lesser extent, for the paternally imprinted secondary <i>MEG3</i> promoter and the maternally imprinted <i>PEG3</i> promoter. HNA leads to biallelic methylation of imprinted genes in a considerable proportion of normal body cells (somatic mosaicism) and is highly variable between individuals. We propose that during development and differentiation maintenance of differential methylation at most imprinting control regions may become to some extent redundant. The accumulation of stochastic and environmentally-induced methylation errors on the non-imprinted allele may increase epigenetic diversity between cells and individuals.</p></div