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Micronutrient status of parents can affect long term health of their progeny. Around 2 billion humans are affected by chronic micronutrient deficiency. In this study we use zebrafish as a model system to examine morphological, molecular and epigenetic changes in mature offspring of parents that experienced a one-carbon (1-C) micronutrient deficiency. Zebrafish were fed a diet sufficient, or marginally deficient in 1-C nutrients (folate, vitamin B12, vitamin B6, methionine, choline), and then mated. Offspring livers underwent histological examination, RNA sequencing and genome-wide DNA methylation analysis. Parental 1-C micronutrient deficiency resulted in increased lipid inclusion and we identified 686 differentially expressed genes in offspring liver, the majority of which were downregulated. Downregulated genes were enriched for functional categories related to sterol, steroid and lipid biosynthesis, as well as mitochondrial protein synthesis. Differential DNA methylation was found at 2869 CpG sites, enriched in promoter regions and permutation analyses confirmed the association with parental feed. Our data indicate that parental 1-C nutrient status can persist as locus specific DNA methylation marks in descendants and suggest an effect on lipid utilization and mitochondrial protein translation in F1 livers. This points toward parental micronutrients status as an important factor for offspring health and welfare.

Diet has been shown to influence epigenetic key players, such as DNA methylation, which can regulate the gene expression potential in both parents and offspring. Diets enriched in omega-6 and deficient in omega-3 PUFAs (low dietary omega-3/omega-6 PUFA ratio), have been associated with the promotion of pathogenesis of diseases in humans and other mammals. In this study, we investigated the impact of increased dietary intake of arachidonic acid (ARA), a physiologically important omega-6 PUFA, on 2 generations of zebrafish. Parental fish were fed either a low or a high ARA diet, while the progeny of both groups were fed the low ARA diet. We screened for DNA methylation on single base-pair resolution using reduced representation bisulfite sequencing (RRBS). The DNA methylation profiling revealed significant differences between the dietary groups in both parents and offspring. The majority of differentially methylated loci associated with high dietary ARA were found in introns and intergenic regions for both generations. Common loci between the identified differentially methylated loci in F0 and F1 livers were reported. We described overlapping gene annotations of identified methylation changes with differential expression, but based on a small number of overlaps. The present study describes the diet-associated methylation profiles across genomic regions, and it demonstrates that parental high dietary ARA modulates DNA methylation patterns in zebrafish liver.

DNA methylation has an important role in intergenerational inheritance. An increasing number of studies have reported evidence of germline inheritance of DNA methylation induced by nutritional signals in mammals. Vitamins and minerals as micronutrients contribute to growth performance in vertebrates, including Atlantic salmon (Salmo salar), and also have a role in epigenetics as environmental factors that alter DNA methylation status. It is important to understand whether micronutrients in the paternal diet can influence the offspring through alterations of DNA methylation signatures in male germ cells.

Disproportionate high intake of n-6 polyunsaturated fatty acids (PUFAs) in the diet is considered as a major human health concern. The present study examines changes in the hepatic gene expression pattern of adult male zebrafish progeny associated with high levels of the n-6 PUFA arachidonic acid (ARA) in the parental diet. The parental generation (F0) was fed a diet which was either low (control) or high in ARA (high ARA). Progenies of both groups (F1) were given the control diet. No differences in body weight were found between the diet groups within adult stages of either F0 or F1 generation. Few differentially expressed genes were observed between the two dietary groups in the F0 in contrast to the F1 generation. Several links were found between the previous metabolic analysis of the parental fish and the gene expression analysis in their adult progeny. Main gene expression differences in the progeny were observed related to lipid and retinoid metabolism by PPARα/RXRα playing a central role in mediating changes to lipid and long-chain fatty acid metabolism. The enrichment of genes involved in β-oxidation observed in the progeny, corresponded to the increase in peroxisomal β-oxidative degradation of long-chain fatty acids in the parental fish metabolomics data. Similar links between the F0 and F1 generation were identified for the methionine cycle and transsulfuration pathway in the high ARA group. In addition, estrogen signalling was found to be affected by parental high dietary ARA levels, where gene expression was opposite directed in F1 compared to F0. This study shows that the dietary n-3/n-6 PUFA ratio can alter gene expression patterns in the adult progeny. Whether the effect is mediated by permanent epigenetic mechanisms regulating gene expression in developing gametes needs to be further investigated.

A moderate surplus of the one carbon (1C) nutrients methionine, folic acid, vitamin B6 and B12 above dietary recommendations for Atlantic salmon has shown to improve growth and reduce hepatosomatic index in the on-growing saltwater period when fed throughout smoltification. Metabolic properties and molecular mechanisms determining the improved growth are unexplored. Here, we investigate metabolic and transcriptional signatures in skeletal muscle taken before and after smoltification to acquire deeper insight into pathways and possible nutrient–gene interactions. A control feed (Ctrl) or 1C nutrient surplus feed (1C+) were fed to Atlantic salmon 6 weeks prior to smoltification until 3 months after saltwater transfer. Both metabolic and gene expression signatures revealed significant 1C nutrient-dependent changes already at pre-smolt, but differences intensified when analysing post-smolt muscle. Transcriptional differences revealed lower expression of genes related to translation, growth and amino acid metabolisation in post-smolt muscle when fed additional 1C nutrients. The 1C+ group showed less free amino acid and putrescine levels, and higher methionine and glutathione amounts in muscle. For Ctrl muscle, the overall metabolic profile suggests a lower amino acid utilisation for protein synthesis, and increased methionine metabolisation in polyamine and redox homoeostasis, whereas transcription changes are indicative of compensatory growth regulation at local tissue level. These findings point to fine-tuned nutrient–gene interactions fundamental for improved growth capacity through better amino acid utilisation for protein accretion when salmon was fed additional 1C nutrients throughout smoltification. It also highlights potential nutritional programming strategies on improved post-smolt growth through 1C+ supplementation before and throughout smoltification.

This study explores the effect of high dietary arachidonic acid (ARA) levels (high ARA) compared with low dietary ARA levels (control) on the general metabolism using zebrafish as the model organism. The fatty acid composition of today’s ‘modern diet’ tends towards higher n-6 PUFA levels in relation to n-3 PUFA. Low dietary n-3:n-6 PUFA ratio is a health concern, as n-6 PUFA give rise to eicosanoids and PG, which are traditionally considered pro-inflammatory, especially when derived from ARA. Juvenile zebrafish fed a high-ARA diet for 17 d had a lower whole-body n-3:n-6 PUFA ratio compared with zebrafish fed a low-ARA (control) diet (0·6 in the control group v. 0·2 in the high-ARA group). Metabolic profiling revealed altered levels of eicosanoids, PUFA, dicarboxylic acids and complex lipids such as glycerophospholipids and lysophospholipids as the most significant differences compared with the control group. ARA-derived hydroxylated eicosanoids, such as hydroxy-eicosatetraenoic acids, were elevated in response to high-ARA feed. In addition, increased levels of oxidised lipids and amino acids indicated an oxidised environment due to n-6 PUFA excess in the fish. To conclude, our results indicate that an ARA-enriched diet induces changes in complex lipids and immune-related eicosanoids and increases levels of oxidised lipids and amino acids, suggesting oxidative stress and lipid peroxidation.

A moderate surplus of the one carbon (1C) nutrients methionine, folic acid, vitamin B 6 and B 12 above dietary recommendations for Atlantic salmon has shown to improve growth and reduce hepatosomatic index in the on-growing saltwater period when fed throughout smoltification. Metabolic properties and molecular mechanisms determining the improved growth are unexplored. Here, we investigate metabolic and transcriptional signatures in skeletal muscle taken before and after smoltification to acquire deeper insight into pathways and possible nutrient–gene interactions. A control feed (Ctrl) or 1C nutrient surplus feed (1C+) were fed to Atlantic salmon 6 weeks prior to smoltification until 3 months after saltwater transfer. Both metabolic and gene expression signatures revealed significant 1C nutrient-dependent changes already at pre-smolt, but differences intensified when analysing post-smolt muscle. Transcriptional differences revealed lower expression of genes related to translation, growth and amino acid metabolisation in post-smolt muscle when fed additional 1C nutrients. The 1C+ group showed less free amino acid and putrescine levels, and higher methionine and glutathione amounts in muscle. For Ctrl muscle, the overall metabolic profile suggests a lower amino acid utilisation for protein synthesis, and increased methionine metabolisation in polyamine and redox homoeostasis, whereas transcription changes are indicative of compensatory growth regulation at local tissue level. These findings point to fine-tuned nutrient–gene interactions fundamental for improved growth capacity through better amino acid utilisation for protein accretion when salmon was fed additional 1C nutrients throughout smoltification. It also highlights potential nutritional programming strategies on improved post-smolt growth through 1C+ supplementation before and throughout smoltification.