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    Paternal age at childbearing and offspring psychiatric and academic morbidity. D'Onofrio Brian M,Rickert Martin E,Frans Emma,Kuja-Halkola Ralf,Almqvist Catarina,Sjölander Arvid,Larsson Henrik,Lichtenstein Paul JAMA psychiatry IMPORTANCE:Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors. OBJECTIVE:To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity. DESIGN, SETTING, AND PARTICIPANTS:We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2,615,081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins. EXPOSURE:Paternal age at childbearing. MAIN OUTCOMES AND MEASURES:Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity. RESULTS:In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings. CONCLUSIONS AND RELEVANCE:Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity. 10.1001/jamapsychiatry.2013.4525
    Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Lambrot R,Xu C,Saint-Phar S,Chountalos G,Cohen T,Paquet M,Suderman M,Hallett M,Kimmins S Nature communications Epidemiological studies suggest that a father's diet can influence offspring health. A proposed mechanism for paternal transmission of environmental information is via the sperm epigenome. The epigenome includes heritable information such as DNA methylation. We hypothesize that the dietary supply of methyl donors will alter epigenetic reprogramming in sperm. Here we feed male mice either a folate-deficient or folate-sufficient diet throughout life. Paternal folate deficiency is associated with increased birth defects in the offspring, which include craniofacial and musculoskeletal malformations. Genome-wide DNA methylation analysis and the subsequent functional analysis identify differential methylation in sperm of genes implicated in development, chronic diseases such as cancer, diabetes, autism and schizophrenia. While >300 genes are differentially expressed in offspring placenta, only two correspond to genes with differential methylation in sperm. This model suggests epigenetic transmission may involve sperm histone H3 methylation or DNA methylation and that adequate paternal dietary folate is essential for offspring health. 10.1038/ncomms3889
    Paternal low protein diet programs preimplantation embryo gene expression, fetal growth and skeletal development in mice. Watkins Adam J,Sirovica Slobodan,Stokes Ben,Isaacs Mark,Addison Owen,Martin Richard A Biochimica et biophysica acta. Molecular basis of disease Defining the mechanisms underlying the programming of early life growth is fundamental for improving adult health and wellbeing. While the association between maternal diet, offspring growth and adult disease risk is well-established, the effect of father's diet on offspring development is largely unknown. Therefore, we fed male mice an imbalanced low protein diet (LPD) to determine the impact on post-fertilisation development and fetal growth. We observed that in preimplantation embryos derived from LPD fed males, expression of multiple genes within the central metabolic AMPK pathway was reduced. In late gestation, paternal LPD programmed increased fetal weight, however, placental weight was reduced, resulting in an elevated fetal:placental weight ratio. Analysis of gene expression patterns revealed increased levels of transporters for calcium, amino acids and glucose within LPD placentas. Furthermore, placental expression of the epigenetic regulators Dnmt1 and Dnmt3L were increased also, coinciding with altered patterns of maternal and paternal imprinted genes. More strikingly, we observed fetal skeletal development was perturbed in response to paternal LPD. Here, while offspring of LPD fed males possessed larger skeletons, their bones comprised lower volumes of high mineral density in combination with reduced maturity of bone apatite. These data offer new insight in the underlying programming mechanisms linking poor paternal diet at the time of conception with the development and growth of his offspring. 10.1016/j.bbadis.2017.02.009
    Early life of fathers affects offspring fitness in a wild rodent. Van Cann Joannes,Koskela Esa,Mappes Tapio,Mikkonen Anne-Mari,Mokkonen Mikael,Watts Phillip C Journal of evolutionary biology Intergenerational fitness effects on offspring due to the early life of the parent are well studied from the standpoint of the maternal environment, but intergenerational effects owing to the paternal early life environment are often overlooked. Nonetheless, recent laboratory studies in mammals and ecologically relevant studies in invertebrates predict that paternal effects can have a major impact on the offspring's phenotype. These nongenetic, environment-dependent paternal effects provide a mechanism for fathers to transmit environmental information to their offspring and could allow rapid adaptation. We used the bank vole Myodes glareolus, a wild rodent species with no paternal care, to test the hypothesis that a high population density environment in the early life of fathers can affect traits associated with offspring fitness. We show that the protein content in the diet and/or social environment experienced during the father's early life (prenatal and weaning) influence the phenotype and survival of his offspring and may indicate adaptation to density-dependent costs. Furthermore, we show that experiencing multiple environmental factors during the paternal early life can lead to a different outcome on the offspring phenotype than stimulated by experience of a single environmental factor, highlighting the need to study developmental experiences in tandem rather than independent of each other. 10.1111/jeb.13516
    Obese father's metabolic state, adiposity, and reproductive capacity indicate son's reproductive health. McPherson Nicole O,Fullston Tod,Bakos Hassan W,Setchell Brian P,Lane Michelle Fertility and sterility OBJECTIVE:To determine whether dietary and exercise regimes in obese males can provide a novel intervention window for improving the reproductive health of the next generation. DESIGN:Experimental animal study. SETTING:University research facilities. ANIMAL(S):C57BL6 male and female mice. INTERVENTION(S):Mice were fed a control diet (6% fat) or high-fat diet (21% fat) for 9 weeks. After the initial feeding, high-fat-diet males were allocated to diet and/or exercise interventions for a further 9 weeks. After intervention males were mated with females fed standard chow (4% fat) before and during pregnancy. MAIN OUTCOME MEASURE(S):F1 sperm motility, count, morphology, capacitation, mitochondrial function, and sperm binding and weight of reproductive organs. RESULT(S):Our primary finding was that diet intervention alone in founders improved offspring sperm motility and mitochondrial markers of sperm health (decreased reactive oxygen species and mitochondrial membrane potential), ultimately improving sperm binding. Sperm binding and capacitation was also improved in F1 males born to a combined diet and exercise intervention in founders. Founder sperm parameters and metabolic measures as a response to diet and/or exercise (i.e., lipid/glucose homeostasis, sperm count and morphology) correlated with offspring's sperm function, independent of founder treatment. This implicates paternal metabolic and reproductive status in predicting male offspring's reproductive function. CONCLUSION(S):This is the first study to show that improvements to both metabolic (lipids, glucose and insulin sensitivity) and reproductive function (sperm motility and morphology) in obese fathers via diet and exercise interventions can improve subsequent reproductive health in offspring. 10.1016/j.fertnstert.2013.12.007
    Paternal methyl donor deficient diets during development affect male offspring behavior and memory-related gene expression in mice. Sahara Yuji,Matsuzawa Daisuke,Ishii Daisuke,Fuchida Takahiro,Goto Takashi,Sutoh Chihiro,Shimizu Eiji Developmental psychobiology It has become increasingly evident that the methylation of DNA, known as an epigenetic marker, affects behavior in animals. In our previous study, a methyl-donors (folate, methionine, and choline)-deficient (FMCD) diet during the juvenile period could be shown to affect anxiety-like behavior and fear memory, accompanied by alteration in some gene expression and their methylations in the hippocampus. One question is whether the fear memory of a parent affects the fear responses of offspring. To explore this question in the present study, C57BL/6 J male (F0) mice were given a FMCD diet from 3 to 12 weeks of age. After confirming the effect of the FMCD diet on the behavior and gene expression of F0 mice, their male offspring (F1-FMCD mice) were examined using the same behavioral batteries and genetic analysis. F0 diet-based differences in F1 behavior were observed, accompanied by the differences in the expression of memory-related genes (Camk2α and PP1) and promoter methylation of the PP1 gene in the hippocampus. Our results add evidence that behavior and gene expression of the F1 generation could be altered due to differences in the father's intake of methyl-donor nutrients. 10.1002/dev.21801
    Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice. Morgan Hannah L,Paganopoulou Panaigota,Akhtar Sofia,Urquhart Natalie,Philomin Ranmini,Dickinson Yasmin,Watkins Adam J The Journal of physiology KEY POINTS:A low protein diet had minimal effects on paternal cardiovascular function or renin-angiotensin system activity. Paternal low protein diet modified F1 neonatal and adult offspring renin-angiotensin system activity and cardiovascular function in a sperm and/or seminal plasma specific manner. Paternal low protein diet modified F1 male offspring testicular expression of central epigenetic regulators. Significant changes in F2 neonatal offspring growth and tissue angiotensin-converting enzyme activity were programmed by paternal low protein diet in a sperm and/or seminal plasma specific manner. ABSTRACT:Although the impact of maternal diet on adult offspring health is well characterized, the role that a father's diet has on his offspring's health remains poorly defined. We establish the significance of a sup-optimal paternal low protein diet for offspring vascular homeostasis and define the sperm and seminal plasma specific programming effects on cardiovascular health. Male C57BL6 mice were fed either a control normal protein diet (NPD; 18% protein) or an isocaloric low protein diet (LPD; 9% protein) for a minimum of 7 weeks. Using artificial insemination, in combination with vasectomized male mating, we generated offspring derived from either NPD or LPD sperm (devoid of seminal plasma) but in the presence of NPD or LPD seminal plasma (devoid of sperm). We observed that either LPD sperm or seminal fluid at conception impaired adult offspring vascular function in response to both vasoconstrictors and dilators. Underlying these changes in vascular function were significant changes in serum, lung and kidney angiotensin-converting enzyme (ACE) activity, established in F1 offspring from 3 weeks of age, maintained into adulthood and present also within juvenile F2 offspring. Furthermore, we observed differential expression of multiple central renin-angiotensin system regulators in adult offspring kidneys. Finally, paternal diet modified the expression profiles of central epigenetic regulators of DNA methylation, histone modifications and RNA methylation in adult F1 male testes. These novel data reveal the impact of sub-optimal paternal nutrition on offspring cardiovascular well-being, programming offspring cardiovascular function through both sperm and seminal plasma specific mechanisms over successive generations. 10.1113/JP278270
    The remarkable legacy of a father's diet on the health of his offspring. Fleming Tom P Proceedings of the National Academy of Sciences of the United States of America 10.1073/pnas.1813731115
    Father's obesity programs the adipose tissue in the offspring via the local renin-angiotensin system and MAPKs pathways, especially in adult male mice. Ornellas Fernanda,Bringhenti Isabele,Mattos Brenda Akemi N F,Mandarim-de-Lacerda Carlos Alberto,Aguila Marcia Barbosa European journal of nutrition PURPOSE:Studies demonstrated the influence of mother's obesity on offspring. However, the father is also related to programming the future generation. The study aimed to evaluate the effects of father's obesity upon white adipose tissue (WAT) remodeling, resulting in activation of signaling pathways and inflammation in male and female offspring. METHODS:Male C57BL/6 mice received control diet (lean father group; 17% energy from lipids) or high-fat diet (obese father group; 49% energy from lipids) for 8 weeks before mating. The mothers received control diet throughout the experiment. Mice were mated: lean mother and lean father, and lean mother and obese father. Offspring received control diet from weaning until 3 months of age when they were studied. RESULTS:In the offspring, father's obesity led to decreased QUICKI with impairment of the insulin signaling pathway in both sexes. In line with these findings, in white adipose tissue, male offspring demonstrated hypertrophied adipocytes, enhanced proinflammatory cytokines, overactivation of components of the local renin-angiotensin system (RAS) and extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of peroxisome proliferator-activated receptors (alpha and gamma). CONCLUSIONS:We observed that father's obesity influences the offspring in adult life, with an impairment in insulin homeostasis, adipocyte remodeling, and adipose tissue overexpression of IL-6 and TNF-alpha in male offspring. The activation of local RAS and ERK1/2, a concomitant PPAR diminishing, and impairment in phosphorylation of AKT and IRS-1 could explain at least in part the findings regardless of the increase in body mass in the offspring. 10.1007/s00394-017-1473-4