Showing papers in "Environmental Epigenetics in 2018"

Environmentally induced epigenetic transgenerational inheritance of disease.

Abstract: Ancestral environmental exposures such as toxicants, abnormal nutrition or stress can promote the epigenetic transgenerational inheritance of disease and phenotypic variation. These environmental factors induce the epigenetic reprogramming of the germline (sperm and egg). The germline epimutations can in turn increase disease susceptibility of subsequent generations of the exposed ancestors. A variety of environmental factors, species and exposure specificity of this induced epigenetic transgenerational inheritance of disease is discussed with a consideration of generational toxicology. The molecular mechanisms and processes involved in the ability of these inherited epimutations to increase disease susceptibility are discussed. In addition to altered disease susceptibility, the potential impact of the epigenetic inheritance on phenotypic variation and evolution is considered. Observations suggest environmentally induced epigenetic transgenerational inheritance of disease is a critical aspect of disease etiology, toxicology and evolution that needs to be considered.

Alterations in sperm DNA methylation, non-coding RNA expression, and histone retention mediate vinclozolin-induced epigenetic transgenerational inheritance of disease.

Abstract: Epigenetic transgenerational inheritance of disease and phenotypic variation can be induced by several toxicants, such as vinclozolin. This phenomenon can involve DNA methylation, non-coding RNA (ncRNA) and histone retention, and/or modification in the germline (e.g. sperm). These different epigenetic marks are called epimutations and can transmit in part the transgenerational phenotypes. This study was designed to investigate the vinclozolin-induced concurrent alterations of a number of different epigenetic factors, including DNA methylation, ncRNA, and histone retention in rat sperm. Gestating females (F0 generation) were exposed transiently to vinclozolin during fetal gonadal development. The directly exposed F1 generation fetus, the directly exposed germline within the fetus that will generate the F2 generation, and the transgenerational F3 generation sperm were studied. DNA methylation and ncRNA were altered in each generation rat sperm with the direct exposure F1 and F2 generations being distinct from the F3 generation epimutations. Interestingly, an increased number of differential histone retention sites were found in the F3 generation vinclozolin sperm, but not in the F1 or F2 generations. All three different epimutation types were affected in the vinclozolin lineage transgenerational sperm (F3 generation). The direct exposure generations (F1 and F2) epigenetic alterations were distinct from the transgenerational sperm epimutations. The genomic features and gene pathways associated with the epimutations were investigated to help elucidate the integration of these different epigenetic processes. Our results show that the three different types of epimutations are involved and integrated in the mediation of the epigenetic transgenerational inheritance phenomenon.

POHaD: why we should study future fathers.

Abstract: The growing field of 'Developmental Origin of Health and Disease' (DOHaD) generally reflects environmental influences from mother to child. The importance of maternal lifestyle, diet and other environmental exposures before and during gestation period is well recognized. However, few epidemiological designs explore potential influences from the paternal environment on offspring health. This is surprising given that numerous animal models have provided evidence that the paternal environment plays a role in a non-genetic inheritance of pre-conceptional exposures through the male germ line. Recent findings in humans suggest that the epigenome of sperm cells can indeed be affected by paternal exposures. Defects in epigenetic sperm mechanisms may result in persistent modifications, affecting male fertility or offspring health status. We addressed this issue at the LATSIS Symposium 'Transgenerational Epigenetic Inheritance: Impact for Biology and Society', in Zurich, 28-30 August 2017, and here provide important arguments why environmental and lifestyle-related exposures in young men should be studied. The Paternal Origins of Health and Disease (POHaD) paradigm was introduced to stress the need for more research on the role of the father in the transmission of acquired environmental messages from his environment to his offspring. A better understanding of pre-conceptional origins of disease through the paternal exposome will be informative to the field of transgenerational epigenetics and will ultimately help instruct and guide public health policies in the future.

Transgenerational inheritance of behavioral and metabolic effects of paternal exposure to traumatic stress in early postnatal life: evidence in the 4th generation.

Abstract: In the past decades, evidence supporting the transmission of acquired traits across generations has reshaped the field of genetics and the understanding of disease susceptibility. In humans, pioneer studies showed that exposure to famine, endocrine disruptors or trauma can affect descendants, and has led to a paradigm shift in thinking about heredity. Studies in humans have however been limited by the low number of successive generations, the different conditions that can be examined, and the lack of mechanistic insight they can provide. Animal models have been instrumental to circumvent these limitations and allowed studies on the mechanisms of inheritance of environmentally induced traits across generations in controlled and reproducible settings. However, most models available today are only intergenerational and do not demonstrate transmission beyond the direct offspring of exposed individuals. Here, we report transgenerational transmission of behavioral and metabolic phenotypes up to the 4th generation in a mouse model of paternal postnatal trauma (MSUS). Based on large animal numbers (up to 124 per group) from several independent breedings conducted 10 years apart by different experimenters, we show that depressive-like behaviors are transmitted to the offspring until the third generation, and risk-taking and glucose dysregulation until the fourth generation via males. The symptoms are consistent and reproducible, and persist with similar severity across generations. These results provide strong evidence that adverse conditions in early postnatal life can have transgenerational effects, and highlight the validity of MSUS as a solid model of transgenerational epigenetic inheritance.

Impacts of bisphenol A (BPA) and phthalate exposures on epigenetic outcomes in the human placenta.

Abstract: The placenta guides fetal growth and development. Bisphenol A (BPA) and phthalates are widespread environmental contaminants and endocrine disruptors, and the placental epigenetic response to these chemicals is an area of growing research interest. Therefore, our objective was to summarize research linking BPA or phthalate exposure to placental outcomes in human pregnancies, with a particular focus on epigenetic endpoints. In PubMed, studies were selected for review (without limiting start date and ending on 1 May 2018) if they reported any direct effects of BPA or phthalates on the placenta in humans. Collectively, available studies suggest that BPA and phthalate exposures are associated with changes to placental micro-RNA expression, DNA methylation, and genomic imprinting. Furthermore, several studies suggest that fetal sex may be an important modifier of placental outcomes in response to these chemicals. Studies in humans demonstrate associations of BPA and phthalate exposure with adverse placental outcomes. Moving forward, more studies should consider sex differences (termed "placental sex") in the measured outcomes, and should utilize appropriate statistical approaches to assess modification by fetal sex. Furthermore, more consistent sample collection and molecular outcome assessment paradigms will be indispensable for making progress in the field. These advances, together with improved non-invasive tools for measuring placental function and outcomes across pregnancy, will be critical for understanding the mechanisms driving placental epigenetic disruption in response to BPA and phthalates, and how these disruptions translate into placental and fetal health.

Transgenerational epigenetic inheritance in birds.

Abstract: While it has been shown that epigenetics accounts for a portion of the variability of complex traits linked to interactions with the environment, the real contribution of epigenetics to phenotypic variation remains to be assessed. In recent years, a growing number of studies have revealed that epigenetic modifications can be transmitted across generations in several animal species. Numerous studies have demonstrated inter- or multi-generational effects of changing environment in birds, but very few studies have been published showing epigenetic transgenerational inheritance in these species. In this review, we mention work conducted in parent-to-offspring transmission analyses in bird species, with a focus on the impact of early stressors on behaviour. We then present recent advances in transgenerational epigenetics in birds, which involve germline linked non-Mendelian inheritance, underline the advantages and drawbacks of working on birds in this field and comment on future directions of transgenerational studies in bird species.

Transgenerational epigenetic inheritance and social responsibility: perspectives from the social sciences

Abstract: Research in environmental epigenetics explores how environmental exposures and life experiences such as food, toxins, stress or trauma can shape trajectories of human health and well-being in complex ways. This perspective resonates with social science expertise on the significant health impacts of unequal living conditions and the profound influence of social life on bodies in general. Environmental epigenetics could thus provide an important opportunity for moving beyond long-standing debates about nature versus nurture between the disciplines and think instead in 'biosocial' terms across the disciplines. Yet, beyond enthusiasm for such novel interdisciplinary opportunities, it is crucial to also reflect on the scientific, social and political challenges that a biosocial model of body, health and illness might entail. In this paper, we contribute historical and social science perspectives on the political opportunities and challenges afforded by a biosocial conception of the body. We will specifically focus on what it means if biosocial plasticity is not only perceived to characterize the life of individuals but also as possibly giving rise to semi-stable traits that can be passed on to future generations. That is, we will consider the historical, social and political valences of the scientific proposition of transgenerational epigenetic inheritance. The key question that animates this article is if and how the notion of transgenerational epigenetic inheritance creates new forms of responsibilities both in science and in society. We propose that, ultimately, interdisciplinary conversation and collaboration is essential for responsible approaches to transgenerational epigenetic inheritance in science and society.

Simulated climate warming and mitochondrial haplogroup modulate testicular small non-coding RNA expression in the neotropical pseudoscorpion, Cordylochernes scorpioides

Abstract: Recent theory suggests that tropical terrestrial arthropods are at significant risk from climate warming. Metabolic rate in such ectothermic species increases exponentially with environmental temperature, and a small temperature increase in a hot environment can therefore have a greater physiological impact than a large temperature increase in a cool environment. In two recent studies of the neotropical pseudoscorpion, Cordylochernes scorpioides, simulated climate warming significantly decreased survival, body size and level of sexual dimorphism. However, these effects were minor compared with catastrophic consequences for male fertility and female fecundity, identifying reproduction as the life stage most vulnerable to climate warming. Here, we examine the effects of chronic high-temperature exposure on epigenetic regulation in C. scorpioides in the context of naturally occurring variation in mitochondrial DNA. Epigenetic mechanisms, including DNA methylation, histone modifications and small non-coding RNA (sncRNA) expression, are particularly sensitive to environmental factors such as temperature, which can induce changes in epigenetic states and phenotypes that may be heritable across generations. Our results indicate that exposure of male pseudoscorpions to elevated temperature significantly altered the expression of >60 sncRNAs in testicular tissue, specifically microRNAs and piwi-interacting RNAs. Mitochondrial haplogroup was also a significant factor influencing both sncRNAs and mitochondrial gene expression. These findings demonstrate that chronic heat stress causes changes in epigenetic profiles that may account for reproductive dysfunction in C. scorpioides males. Moreover, through its effects on epigenetic regulation, mitochondrial DNA polymorphism may provide the potential for an adaptive evolutionary response to climate warming.

Diesel exhaust and house dust mite allergen lead to common changes in the airway methylome and hydroxymethylome.

Abstract: Exposures to diesel exhaust particles (DEP) from traffic and house dust mite (HDM) allergens significantly increase risks of airway diseases, including asthma. This negative impact of DEP and HDM may in part be mediated by epigenetic mechanisms. Beyond functioning as a mechanical barrier, airway epithelial cells provide the first line of immune defense towards DEP and HDM exposures. To understand the epigenetic responses of airway epithelial cells to these exposures, we exposed human bronchial epithelial cells to DEP and HDM and studied genome-wide 5-methyl-cytosine (5mC) and 5-hydroxy-methylcytosine (5hmC) at base resolution. We found that exposures to DEP and HDM result in elevated TET1 and DNMT1 expression, associated with 5mC and 5hmC changes. Interestingly, over 20% of CpG sites are responsive to both exposures and changes in 5mC at these sites negatively correlated with gene expression differences. These 5mC and 5hmC changes are located in genes and pathways related to oxidative stress responses, epithelial function and immune cell responses and are enriched for binding sites of transcription factors (TFs) involved in these pathways. Histone marks associated with promoters, enhancers and actively transcribed gene bodies were associated with exposure-induced DNA methylation changes. Collectively, our data suggest that exposures to DEP and HDM alter 5mC and 5hmC levels at regulatory regions bound by TFs, which coordinate with histone marks to regulate gene networks of oxidative stress responses, epithelial function and immune cell responses. These observations provide novel insights into the epigenetic mechanisms that mediate the epithelial responses to DEP and HDM in airways.

The public reception of putative epigenetic mechanisms in the transgenerational effects of trauma.

Abstract: There has been great interest in the possibility that effects of trauma might be passed from parent to offspring through epigenetic mechanisms. This topic has stimulated discussion and controversy in the scientific literature, the popular press, and culture at large. This article describes the initial observations that have led to recent examinations of epigenetic mechanisms in association with effects of parental trauma exposure on offspring. Epigenetic research in animals has provided models for how such effects might be transmitted. However, the attribution of any specific epigenetic mechanisms in human studies of offspring of trauma survivors is premature at this time. The article describes some of the ways in which initial epigenetic findings in the offspring of trauma survivors have been represented in the popular media. Reports have ranged from overly simplistic and sensationalistic claims to global dismissals. The authors discuss the importance of clarity in language when describing epigenetic findings for lay audiences, the need to emphasize the limitations as well as the promise of research on intergenerational transmission of trauma effects, and the importance of countering popular interpretations that imply a reductionist biological determinism. Scientists have an obligation to assist in translating important research findings and nascent avenues of research to the public. It is important to recognize the ways in which this research may unintentionally be received as supporting a narrative of permanent and significant damage in offspring, rather than contributing to discussions of potential resilience, adaptability, and mutability in biological systems affected by stress.

Role of DNA methylation in altered gene expression patterns in adult zebrafish ( Danio rerio) exposed to 3, 3', 4, 4', 5-pentachlorobiphenyl (PCB 126)

Abstract: There is growing evidence that environmental toxicants can affect various physiological processes by altering DNA methylation patterns. However, very little is known about the impact of toxicant-induced DNA methylation changes on gene expression patterns. The objective of this study was to determine the genome-wide changes in DNA methylation concomitant with altered gene expression patterns in response to 3, 3', 4, 4', 5-pentachlorobiphenyl (PCB126) exposure. We used PCB126 as a model environmental chemical because the mechanism of action is well-characterized, involving activation of aryl hydrocarbon receptor, a ligand-activated transcription factor. Adult zebrafish were exposed to 10 nM PCB126 for 24 h (water-borne exposure) and brain and liver tissues were sampled at 7 days post-exposure in order to capture both primary and secondary changes in DNA methylation and gene expression. We used enhanced Reduced Representation Bisulfite Sequencing and RNAseq to quantify DNA methylation and gene expression, respectively. Enhanced reduced representation bisulfite sequencing analysis revealed 573 and 481 differentially methylated regions in the liver and brain, respectively. Most of the differentially methylated regions are located more than 10 kilobases upstream of transcriptional start sites of the nearest neighboring genes. Gene Ontology analysis of these genes showed that they belong to diverse physiological pathways including development, metabolic processes and regeneration. RNAseq results revealed differential expression of genes related to xenobiotic metabolism, oxidative stress and energy metabolism in response to polychlorinated biphenyl exposure. There was very little correlation between differentially methylated regions and differentially expressed genes suggesting that the relationship between methylation and gene expression is dynamic and complex, involving multiple layers of regulation.

Persistent 6-OH-BDE-47 exposure impairs functional neuronal maturation and alters expression of neurodevelopmentally-relevant chromatin remodelers.

Abstract: Polybrominated diphenyl ethers (PBDEs) are a pervasive class of brominated flame retardants that are present in the environment at particularly high levels, especially in the United States. Their environmental stability, propensity for bioaccumulation, and known potential for neurotoxicity has evoked interest regarding their effects on the developing nervous system. Exposure to PBDEs has been strongly associated with neurodevelopmental disorders. However, the details of their mechanistic roles in such disorders are incompletely understood. Here, we report the effects of one of the most prevalent congeners, BDE-47, and its hydroxylated metabolites on the maturation and function of embryonic rat cortical neurons. Prolonged exposure to 6OH-BDE-47 produces the strongest effects amongst the parent BDE-47 congener and its tested hydroxylated metabolites. These effects include: i) disruption of transcriptional responses to neuronal activity, ii) dysregulation of multiple genes associated with neurodevelopmental disorders, and intriguingly, iii) altered expression of several subunits of the developmentally-relevant BAF (Brg1-associated factors) chromatin remodeling complex, including the key subunit BAF170. Taken together, our data indicate that persistent exposure to 6OH-BDE-47 may interfere with neurodevelopmental chromatin remodeling mechanisms and gene transcription programs, which in turn are likely to interfere with downstream processes such as synapse development and overall functional maturity of neurons. Results from this study have identified a novel aspect of 6OH-BDE-47 toxicity and open new avenues to explore the effects of a ubiquitous environmental toxin on epigenetic regulation of neuronal maturation and function.

Diet changes alter paternally inherited epigenetic pattern in male Wild guinea pigs.

Abstract: Epigenetic modifications, of which DNA methylation is the most stable, are a mechanism conveying environmental information to subsequent generations via parental germ lines. The paternal contribution to adaptive processes in the offspring might be crucial, but has been widely neglected in comparison to the maternal one. To address the paternal impact on the offspring's adaptability to changes in diet composition, we investigated if low protein diet (LPD) in F0 males caused epigenetic alterations in their subsequently sired sons. We therefore fed F0 male Wild guinea pigs with a diet lowered in protein content (LPD) and investigated DNA methylation in sons sired before and after their father's LPD treatment in both, liver and testis tissues. Our results point to a 'heritable epigenetic response' of the sons to the fathers' dietary change. Because we detected methylation changes also in the testis tissue, they are likely to be transmitted to the F2 generation. Gene-network analyses of differentially methylated genes in liver identified main metabolic pathways indicating a metabolic reprogramming ('metabolic shift'). Epigenetic mechanisms, allowing an immediate and inherited adaptation may thus be important for the survival of species in the context of a persistently changing environment, such as climate change.

Transgenerational epigenetic inheritance: from biology to society-Summary Latsis Symposium Aug 28-30, 2017, Zürich, Switzerland.

Abstract: In biology, inheritance is a process that ensures the transfer of features and traits from parent to offspring. The most classic view of parental inheritance is that it is genetic and is embedded in genes contained in the genome in germ cells. However, genetic inheritance is now known to contribute to only a part of what an individual can transmit to its progeny. Thus, further to innate traits that each individual receives from its parents, acquired traits, which are traits acquired upon exposure to environmental factors or personal experiences, can also be inherited. This form of inheritance is not encoded in the sequence of genes but is mediated by mechanisms and processes elicited by the environment that modify the activity of the genome persistently across generations. Because it is not encoded in DNA sequences, it is called epigenetic or non-genetic. These mechanisms establish a link between the genome and the environment. They relate to the extremely important question of nature versus nurture namely, how much our own make-up is genetically or epigenetically determined, a question that remains unresolved. In August 2017, an international symposium was organized in Zurich, Switzerland to address the question of epigenetic inheritance. The Latsis symposium 2017 on “Transgenerational epigenetic inheritance: from biology to society” held at the ETH Zurich gathered international leaders in the field and focused on major questions and current challenges raised by the concept of epigenetic inheritance. The symposium was one of the first fully dedicated to the theme of epigenetic inheritance and covered scientific aspects from invertebrates to humans, and from behavior to metabolism in humans and animal models, mental health and epidemiology, bioinformatics and ethics. The symposium lasted 2.5 days and was attended by about 150 people from different countries. The program was structured in sessions of 3–3 h 30 min each (total of five sessions) including invited talks and short oral presentations. This summary provides an overview of the speakers’ presentations and focuses on four major topics: (i) evidence and challenges for epigenetic inheritance in humans, (ii) new insight and major questions raised by work in animal models, (iii) methodologies in epigenetics and (iv) evolution, societal impact and broader considerations.

Longitudinal effects of developmental bisphenol A, variable diet, and physical activity on age-related methylation in blood.

Abstract: Research indicates that environmental factors can alter DNA methylation, but the specific effects of environmental exposures on epigenetic aging remain unclear Here, using a mouse model of human-relevant exposures, we tested the hypothesis that early-life exposure to bisphenol A (BPA), variable diet, and/or changes in physical activity would modify rates of age-related methylation at several target regions, as measured from longitudinal blood samples (2, 4, and 10 months old) DNA methylation was quantified at two repetitive elements (LINE-1, IAP), two imprinted genes (Igf2, H19), and one non-imprinted gene (Esr1) in isogenic mice developmentally exposed to Control, Control + BPA (50 µg/kg diet), Western high-fat diet (WHFD), or Western + BPA diets In blood samples, Esr1 DNA methylation increased significantly with age, but no other investigated loci showed significant age-related methylation LINE-1 and IAP both showed significant negative environmental deflection by WHFD exposure (P < 005) Esr1also showed significant negative environmental deflection by WHFD exposure in female mice (P = 002), but not male mice Physical activity had a non-significant positive effect on age-related Esr1 methylation in female blood, suggesting that it may partially abrogate the effects of WHFD on the aging epigenome These results suggest that developmental nutritional exposures can modify age-related DNA methylation patterns at a gene related to growth and development As such, environmental deflection of the aging epigenome may help to explain the growing prevalence of chronic diseases in human populations

Frequency of heavy vehicle traffic and association with DNA methylation at age 18 years in a subset of the Isle of Wight birth cohort.

Abstract: Assessment of changes in DNA methylation (DNA-m) has the potential to identify adverse environmental exposures. To examine DNA-m among a subset of participants (n = 369) in the Isle of Wight birth cohort who reported variable near resident traffic frequencies. We used self-reported frequencies of heavy vehicles passing by the homes of study subjects as a proxy measure for TRAP, which were: never, seldom, 10 per day, 1-9 per hour and >10 per hour. Methylation of cytosine-phosphate-guanine (CpG) dinucleotide sequences in the DNA was assessed from blood samples collected at age 18 years (n = 369) in the F1 generation. We conducted an epigenome wide association study to examine CpGs related to the frequency of heavy vehicles passing by subjects' homes, and employed multiple linear regression models to assess potential associations. We repeated some of these analysis in the F2 generation (n = 140). Thirty-five CpG sites were associated with heavy vehicular traffic. After adjusting for confounders, we found 23 CpGs that were more methylated, and 11 CpGs that were less methylated with increasing heavy vehicular traffic frequency among all subjects. In the F2 generation, 2 of 31 CpGs were associated with traffic frequencies and the direction of the effect was the same as in the F1 subset while differential methylation of 7 of 31 CpG sites correlated with gene expression. Our findings reveal differences in DNA-m in participants who reported higher heavy vehicular traffic frequencies when compared to participants who reported lower frequencies.

Pre-reproductive stress and fluoxetine treatment in rats affect offspring A-to-I RNA editing, gene expression and social behavior.

Abstract: Adenosine to inosine RNA editing is an epigenetic process that entails site-specific modifications in double-stranded RNA molecules, catalyzed by adenosine deaminases acting on RNA (ADARs). Using the multiplex microfluidic PCR and deep sequencing technique, we recently showed that exposing adolescent female rats to chronic unpredictable stress before reproduction affects editing in the prefrontal cortex and amygdala of their newborn offspring, particularly at the serotonin receptor 5-HT2c (encoded by Htr2c). Here, we used the same technique to determine whether post-stress, pre-reproductive maternal treatment with fluoxetine (5 mg/kg, 7 days) reverses the effects of stress on editing. We also examined the mRNA expression of ADAR enzymes in these regions, and asked whether social behavior in adult offspring would be altered by maternal exposure to stress and/or fluoxetine. Maternal treatment with fluoxetine altered Htr2c editing in offspring amygdala at birth, enhanced the expression of Htr2c mRNA and RNA editing enzymes in the prefrontal cortex, and reversed the effects of pre-reproductive stress on Htr2c editing in this region. Furthermore, maternal fluoxetine treatment enhanced differences in editing of glutamate receptors between offspring of control and stress-exposed rats, and led to enhanced social preference in adult offspring. Our findings indicate that pre-gestational fluoxetine treatment affects patterns of RNA editing and editing enzyme expression in neonatal offspring brain in a region-specific manner, in interaction with pre-reproductive stress. Overall, these findings imply that fluoxetine treatment affects serotonergic signaling in offspring brain even when treatment is discontinued before gestation, and its effects may depend upon prior exposure to stress.

Dairy cows - an opportunity in the research field of non-genetic inheritance?

Abstract: More than 1 billion cattle are raised annually for meat and milk production. Dairy cows are repeatedly impregnated and separated from their calves, usually within the first 24 h after birth. Here, I suggest that dairy cows undergo a procedure comparable to the 'Maternal separation combined with unpredictable maternal stress' paradigm (MSUS), which is used to study the non-genetic inheritance (NGI) of phenotypes in rodents. I discuss what research on dairy cows may bring to the research field of NGI. The resulting research findings are likely to have benefits to our understanding of MSUS, NGI and consumer safety.

Endocrine-disrupting chemicals, epigenetics, and skeletal system dysfunction: exploration of links using bisphenol A as a model system

Abstract: Early life exposures to endocrine-disrupting chemicals (EDCs) have been associated with physiological changes of endocrine-sensitive tissues throughout postnatal life. Although hormones play a critical role in skeletal growth and maintenance, the effects of prenatal EDC exposure on adult bone health are not well understood. Moreover, studies assessing skeletal changes across multiple generations are limited. In this article, we present previously unpublished data demonstrating dose-, sex-, and generation-specific changes in bone morphology and function in adult mice developmentally exposed to the model estrogenic EDC bisphenol A (BPA) at doses of 10 μg (lower dose) or 10 mg per kg bw/d (upper dose) throughout gestation and lactation. We show that F1 generation adult males, but not females, developmentally exposed to bisphenol A exhibit dose-dependent reductions in outer bone size resulting in compromised bone stiffness and strength. These structural alterations and weaker bone phenotypes in the F1 generation did not persist in the F2 generation. Instead, F2 generation males exhibited greater bone strength. The underlying mechanisms driving the EDC-induced physiological changes remain to be determined. We discuss potential molecular changes that could contribute to the EDC-induced skeletal effects, with an emphasis on epigenetic dysregulation. Furthermore, we assess the necessity of intact sex steroid receptors to mediate these effects. Expanding future assessments of EDC-induced effects to the skeleton may provide much needed insight into one of the many health effects of these chemicals and aid in regulatory decision making regarding exposure of vulnerable populations to these chemicals.

Fatherhood alters gene expression within the MPOA.

Abstract: Female parenting is obligate in mammals, but fathering behavior among mammals is rare. Only 3-5% of mammalian species exhibit biparental care, including humans, and mechanisms of fathering behavior remain sparsely studied. However, in species where it does exist, paternal care is often crucial to the survivorship of offspring. The present study is the first to identify new gene targets linked to the experience of fathering behavior in a biparental species using RNA sequencing. In order to determine the pattern of gene expression within the medial preoptic area that is specifically associated with fathering behavior, we identified genes in male prairie voles (Microtus ochrogaster) that experienced one of three social conditions: virgin males, pair bonded males, and males with fathering experience. A list of genes exhibiting different expression patterns in each comparison (i.e. Virgin vs Paired, Virgin vs Fathers, and Paired vs Fathers) was evaluated using the gene ontology enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes pathways analysis to reveal metabolic pathways associated with specific genes. Using these tools, we generated a filtered list of genes that exhibited altered patterns of expression in voles with different amounts of social experience. Finally, we used NanoString to quantify differences in the expression of these selected genes. These genes are involved in a variety of processes, with enrichment in genes associated with immune function, metabolism, synaptic plasticity, and the remodeling of dendritic spines. The identification of these genes and processes will lead to novel insights into the biological basis of fathering behavior.

Hypersensitivity to sertraline in the absence of hippocampal 5-HT1AR and 5-HTT gene expression changes following paternal corticosterone treatment

Abstract: The male germ line is capable of transmitting a legacy of stress exposure to the next generation of offspring. This transgenerational process manifests by altering offspring affective behaviours, cognition and metabolism. Paternal early life trauma causes hippocampal serotonergic dysregulation in male offspring. We previously showed a transgenerational modification to male offspring anxiety-like behaviours by treatment of adult male breeders with corticosterone (CORT) prior to mating. In the present study, we used offspring from our paternal CORT model and characterised offspring serotonergic function by examining their responses to the 5HT1AR agonist, 8-OH-DPAT, and the selective serotonin reuptake inhibitor, sertraline. We also examined whether post-weaning environmental enrichment, a paradigm well-known to modulate serotonergic signalling in the brain, had the capacity to normalise the anxiety phenotype of male offspring. Finally, we assessed gene expression levels of 5HT1AR and serotonin transporter in the offspring hippocampus to determine whether deficits in gene transcription contributed to the male-only anxiety phenotype. We report that male and female offspring of CORT-treated fathers are hypersensitive to sertraline but have normal hypothermic responses to 8-OH-DPAT. No deficits in htr1a and sert were found in association with paternal CORT treatment, and environmental enrichment did not rescue the anxiety phenotype of male offspring on the elevated-plus maze. These findings indicate that varying forms of paternal stress exert different effects on offspring brain serotonergic function.

Bugs in the program: can pregnancy drugs and smoking disturb molecular reprogramming of the fetal germline, increasing heritable risk for autism and neurodevelopmental disorders?

Abstract: In a seeming paradox, the prevalence of autism spectrum disorder (ASD) has surged, while at the same time research has pointed to the strong heritability of this neurodevelopmental pathology. Here an autism research philanthropist suggests a biological phenomenon of exogenously induced 'gamete disruption' that could reconcile these seemingly contradictory observations. Mining information from her own family history and that of her fellow autism parents, while also engaging with the scientific community, she proposes that a subset of the autisms may be rooted in a variety of molecular glitches in parental gametes induced by certain acute exposures during the parents' own fetal or neonatal development. These exposures include but are not limited to synthetic hormone drugs, tobacco, and general anesthesia. Consistent with this hypothesis, animal models have demonstrated adverse neurobehavioral outcomes in grandoffspring of gestating dams exposed to hormone-disrupting compounds, tobacco components, and general anesthesia. A recent epidemiological study showed a link between grandmaternal smoking and risk for ASD in grandoffspring through the maternal line. Given the urgency of the autism crisis, combined with the biological plausibility of this mostly unexplored paradigm, the writer contends that questions of nongenetic inheritance should be a priority in autism research.

Does cross-generational epigenetic inheritance contribute to cultural continuity?

Abstract: Human studies of cross-generational epigenetic inheritance have to consider confounding by social patterning down the generations, often referred to as 'cultural inheritance'. This raises the question to what extent is 'cultural inheritance' itself epigenetically mediated rather than just learnt. Human studies of non-genetic inheritance have demonstrated that, beyond foetal life, experiences occurring in mid-childhood before puberty are the most likely to be associated with cross-generational responses in the next generation(s). It is proposed that cultural continuity is played out along the axis, or 'payoff', between responsiveness and stability. During the formative years of childhood a stable family and/or home permits small children to explore and thereby learn. To counter disruptions to this family home ideal, cultural institutions such as local schools, religious centres and market places emerged to provide ongoing stability, holding the received wisdom of the past in an accessible state. This cultural support allows the growing child to freely indulge their responsiveness. Some of these prepubertal experiences induce epigenetic responses that also transfer molecular signals to the gametes through which they contribute to the conception of future offspring. In parallel co-evolution with growing cultural support for increasing responsiveness, 'runaway' responsiveness is countered by the positive selection of genetic variants that dampen responsiveness. Testing these ideas within longitudinal multigenerational cohorts will need information on ancestors/parents' own communities and experiences (Exposome scans) linked to ongoing Phenome scans on grandchildren; coupled with epigenome analysis, metastable epialleles and DNA methylation age. Interactions with genetic variants affecting responsiveness should help inform the broad hypothesis.

Effect of a locally adapted genome on environmentally induced epigenetic variation.

Abstract: Both genetic variation and environmentally induced epigenetic changes allow organisms to persist through the heterogeneity of their habitats. Selection on genetic variation can promote local adaptation of populations. However, in absence of genetic variation, clonal organisms mostly rely on epigenetics to respond to environmental heterogeneity. We used the potential of unisexual organisms in incorporating their host genome, to empirically assess whether the presence of a locally adapted genome affects environmentally induced epigenetic changes in clonal organisms. We addressed this problematic by using unisexual lineages of the kleptogen vertebrate Ambystoma laterale-jeffersonianum complex that can optionally incorporate genetic material from locally adapted sexual hosts through genomic exchanges. More specifically, we compared environmentally induced epigenetic changes between lineages strictly reproducing clonally vs. those incorporating a locally adapted genome. The results revealed that both lineage and sample site components, as well as their interaction, affected epigenetic variation. When lineages were analysed separately, differences among sample sites were only detected in lineages impervious to genomic exchanges. Sample sites had no significant effect on the epigenetic variation of lineages that performed genomic exchanges. These results suggest that environmentally induced epigenetic variation among sites depends more on the lack of locally adapted alleles than on the level of genetic variation.

Nutrition meets heredity: a case of RNA-mediated transmission of acquired characters

Abstract: RNA-based inheritance provides a reasonable hypothesis to explain multigenerational maintenance of the disease in the progeny of either a male or female parent suffering from the metabolic syndrome (obesity and type 2 diabetes) induced by abnormal diet. Although, it is still difficult to formulate a complete rational mechanism, study of inheritance is a most direct way to learn about the epigenetic control of gene expression and we wished to summarised our current approach along this line.