A paternal environmental legacy: Evidence for epigenetic inheritance through the male germ line

Literature on maternal exposures and the risk of epigenetic changes or diseases in the offspring is growing. Paternal contributions are often not considered. However, some animal and epidemiologic studies on various contaminants, nutrition, and lifestyle‐related conditions suggest a paternal influence on the offspring's future health. The phenotypic outcomes may have been attributed to DNA damage or mutations, but increasing evidence shows that the inheritance of environmentally induced functional changes of the genome, and related disorders, are (also) driven by epigenetic components. In this essay we suggest the existence of epigenetic windows of susceptibility to environmental insults during sperm development. Changes in DNA methylation, histone modification, and non‐coding RNAs are viable mechanistic candidates for a non‐genetic transfer of paternal environmental information, from maturing germ cell to zygote. Inclusion of paternal factors in future research will ultimately improve the understanding of transgenerational epigenetic plasticity and health‐related effects in future generations.     

Focus: The Science of Stress: Potential Societal and Cultural Implications of Transgenerational Epigenetic Methylation of Trauma and PTSD: Pathology or Resilience?

Psychological trauma is unique in that it is an environmental event that could induce biological changes and post-traumatic stress disorder (PTSD), depression, or other mood disorders in some patients. On the other hand, there may be no psychopathology (in most cases), or even sometimes post-traumatic growth and resilience. According to the DSM-5, trauma is a prerequisite for PTSD and traumatic stress disorder, but not for depressive episodes or mood disorders, or other psychiatric conditions. This paper brings attention to the preliminary literature on transgenerational inheritance due to trauma exposure and its societal and cultural implications. There is accumulating evidence that exposure to trauma can be passed transgenerationally through epigenetic inheritance leading to changes in gene expression and possible disorders or resilience. The effects of resilience from transgenerational inheritance have not been studied, but should be, for a full understanding not only of the disease risk across generations, but also of its social and cultural implications. The epigenetic pathologic effects across generations also need further studies, as the current research is preliminary; larger replications are needed for definitive and more complete understanding. I present here a glimpse of where we are, a vision of where we should go in terms of future research direction for disease risk transmission, and recommend studies of resilience and post-traumatic growth across generations, as well as other studies related to the societal implications at the population level.     

Prospects for incorporation of epigenetic biomarkers in human health and environmental risk assessment of chemicals

Epigenetic mechanisms have gained relevance in human health and environmental studies, due to their pivotal role in disease, gene × environment interactions and adaptation to environmental change and/or contamination. Epigenetic mechanisms are highly responsive to external stimuli and a wide range of chemicals has been shown to determine specific epigenetic patterns in several organisms. Furthermore, the mitotic/meiotic inheritance of such epigenetic marks as well as the resulting changes in gene expression and cell/organismal phenotypes has now been demonstrated. Therefore, epigenetic signatures are interesting candidates for linking environmental exposures to disease as well as informing on past exposures to stressors. Accordingly, epigenetic biomarkers could be useful tools in both prospective and retrospective risk assessment but epigenetic endpoints are currently not yet incorporated into risk assessments. Achieving a better understanding on this apparent impasse, as well as identifying routes to promote the application of epigenetic biomarkers within environmental risk assessment frameworks are the objectives of this review. We first compile evidence from human health studies supporting the use of epigenetic exposure‐associated changes as reliable biomarkers of exposure. Then, specifically focusing on environmental science, we examine the potential and challenges of developing epigenetic biomarkers for environmental fields, and discuss useful organisms and appropriate sequencing techniques to foster their development in this context. Finally, we discuss the practical incorporation of epigenetic biomarkers in the environmental risk assessment of chemicals, highlighting critical data gaps and making key recommendations for future research within a regulatory context.     

Prioritizing risks and uncertainties from intentional release of selected Category A pathogens

This paper synthesizes available information on five Category A pathogens (Bacillus anthracis, Yersinia pestis, Francisella tularensis, Variola major and Lassa) to develop quantitative guidelines for how environmental pathogen concentrations may be related to human health risk in an indoor environment. An integrated model of environmental transport and human health exposure to biological pathogens is constructed which 1) includes the effects of environmental attenuation, 2) considers fomite contact exposure as well as inhalational exposure, and 3) includes an uncertainty analysis to identify key input uncertainties, which may inform future research directions. The findings provide a framework for developing the many different environmental standards that are needed for making risk-informed response decisions, such as when prophylactic antibiotics should be distributed, and whether or not a contaminated area should be cleaned up. The approach is based on the assumption of uniform mixing in environmental compartments and is thus applicable to areas sufficiently removed in time and space from the initial release that mixing has produced relatively uniform concentrations. Results indicate that when pathogens are released into the air, risk from inhalation is the main component of the overall risk, while risk from ingestion (dermal contact for B. anthracis) is the main component of the overall risk when pathogens are present on surfaces. Concentrations sampled from untracked floor, walls and the filter of heating ventilation and air conditioning (HVAC) system are proposed as indicators of previous exposure risk, while samples taken from touched surfaces are proposed as indicators of future risk if the building is reoccupied. A Monte Carlo uncertainty analysis is conducted and input-output correlations used to identify important parameter uncertainties. An approach is proposed for integrating these quantitative assessments of parameter uncertainty with broader, qualitative considerations to identify future research priorities.     

Left upper quadrant presentation of Fitz-Hugh-Curtis syndrome in an adolescent.

The National Energy Plan proposed by President Carter provides for the rapid development of coal resources in the United States, particularly in the West. The potential consequences for health of this development were considered by the Advisory Committee on Health and Environmental Effects of Increased Coal Utilization, reporting to the Department of Energy. Their report recommended rigid adherence to pertinent existing regulations, improved environmental monitoring, expanded research in selected relevant topics and development of procedures for selecting the sites of new coal-fired power plants. Although the report was a major exercise in technology assessment, it is fundamentally a cautious document that proposes no new solutions or approaches. A review of occupational and community health problems associated with coal mining and coal utilization suggests that lessons from past experiences, especially in Appalachia, cannot be applied to the West uncritically. The two regions are fundamentally different in scale, topography and social development. In the West, future problems related to coal are likely to derive from unknown risks associated with coal processing technologies, land reclamation and water quality at the sites of power generation, and extensive social and demographic changes at centers of industrial activity that may have secondary effects on health. Additional considerations should supplement the recommendations of the Advisory Committee report.     

Maternal caregiving and DNA methylation in human infants and children: Systematic review

The integration of behavioral epigenetics' principles (eg, DNA methylation) into the study of human infants' development has mainly focused on the effects of early adverse exposures, paying less attention to protective caregiving experiences. The present review focused on DNA methylation linked to variations in maternal behavior in human infants and children. Literature search occurred on three databases (PubMed, Scopus and Web of Science) and 11 records were selected. Key variables were abstracted from each article including: sample size and characteristics, time and type of maternal caregiving behavior exposure, time and locus of methylation biomarker, presence/absence, time and type of adverse exposure. Six out of eleven records documented the predictive effect of maternal caregiving on DNA methylation, whereas the remaining five reported on the role of maternal behavior as an influencing factor of the adversity‐to‐methylation link. Consistent with evidence from the animal model, the quality of maternal caregiving in humans (a) might be associated with variations in DNA methylation status of specific genes involved in socio‐emotional development and (b) might partially buffer the association between early adversities and epigenetic variations in infants and children. Current evidence suggests that the quality of maternal caregiving can contribute to behavioral development trajectories of human infants and children at least partially through epigenetic regulation. Open questions and methodological aspects are discussed to guide future human developmental research in behavioral epigenetics.     

Folic acid supplementation in pregnancy and implications in health and disease

Maternal exposure to dietary factors during pregnancy can influence embryonic development and may modulate the phenotype of offspring through epigenetic programming. Folate is critical for nucleotide synthesis, and preconceptional intake of dietary folic acid (FA) is credited with reduced incidences of neural tube defects in infants. While fortification of grains with FA resulted in a positive public-health outcome, concern has been raised for the need for further investigation of unintended consequences and potential health hazards arising from excessive FA intakes, especially following reports that FA may exert epigenetic effects. The objective of this article is to discuss the role of FA in human health and to review the benefits, concerns and epigenetic effects of maternal FA on the basis of recent findings that are important to design future studies.     

Lamarck rises from his grave: parental environment‐induced epigenetic inheritance in model organisms and humans

Organisms can change their physiological/behavioural traits to adapt and survive in changed environments. However, whether these acquired traits can be inherited across generations through non‐genetic alterations has been a topic of debate for over a century. Emerging evidence indicates that both ancestral and parental experiences, including nutrition, environmental toxins, nurturing behaviour, and social stress, can have powerful effects on the physiological, metabolic and cellular functions in an organism. In certain circumstances, these effects can be transmitted across several generations through epigenetic (i.e. non‐DNA sequence‐based rather than mutational) modifications. In this review, we summarize recent evidence on epigenetic inheritance from parental environment‐induced developmental and physiological alterations in nematodes, fruit flies, zebrafish, rodents, and humans. The epigenetic modifications demonstrated to be both susceptible to modulation by environmental cues and heritable, including DNA methylation, histone modification, and small non‐coding RNAs, are also summarized. We particularly focus on evidence that parental environment‐induced epigenetic alterations are transmitted through both the maternal and paternal germlines and exert sex‐specific effects. The thought‐provoking data presented here raise fundamental questions about the mechanisms responsible for these phenomena. In particular, the means that define the specificity of the response to parental experience in the gamete epigenome and that direct the establishment of the specific epigenetic change in the developing embryos, as well as in specific tissues in the descendants, remain obscure and require elucidation. More precise epigenetic assessment at both the genome‐wide level and single‐cell resolution as well as strategies for breeding at relatively sensitive periods of development and manipulation aimed at specific epigenetic modification are imperative for identifying parental environment‐induced epigenetic marks across generations. Considering their diverse epigenetic architectures, the conservation and prevalence of the mechanisms underlying epigenetic inheritance in non‐mammals require further investigation in mammals. Interpretation of the consequences arising from epigenetic inheritance on organisms and a better understanding of the underlying mechanisms will provide insight into how gene–environment interactions shape developmental processes and physiological functions, which in turn may have wide‐ranging implications for human health, and understanding biological adaptation and evolution.     

Social Capital, Narratives of Fragmentation, and Schizophrenia: An Ethnographic Exploration of Factors Shaping African-Caribbeans’ Social Capital and Mental Health in a North London Community

Recent research studies have proposed the concept of social capital—broadly defined as social networks, community cohesion, and participation—as a social risk factor for health disparities and the high rates of schizophrenia among individuals of Caribbean heritage in England. However, many of the existing studies lack sociohistorical contexts and do not capture the experiential dimensions of individuals’ social capital. This paper adds to the debate by examining the mechanisms and sociocultural processes that shape the understandings and experiences of social capital in a sample of British African-Caribbeans. Drawing on ethnographic and survey data collected over 2 years in a North London community, the paper focuses on participants’ every day experiences and the stories they tell about their community and social fragmentation. These stories suggest that social changes and historical forces interact to affect the social capital and emotional well-being of local African-Caribbean residents. I argue that my participants’ collective narratives about their social environment contribute to the emotional tone of the community, and create added stressors that may impact their mental health.     

Epigenetics and Future Generations

Recent evidence of intergenerational epigenetic programming of disease risk broadens the scope of public health preventive interventions to future generations, i.e. non existing people. Due to the transmission of epigenetic predispositions, lifestyles such as smoking or unhealthy diet might affect the health of populations across several generations. While public policy for the health of future generations can be justified through impersonal considerations, such as maximizing aggregate well‐being, in this article we explore whether there are rights‐based obligations supervening on intergenerational epigenetic programming despite the non‐identity argument, which challenges this rationale in case of policies that affect the number and identity of future people. We propose that rights based obligations grounded in the interests of non‐existing people might fall upon existing people when generations overlap. In particular, if environmental exposure in F0 (i.e. existing people) will affect the health of F2 (i.e. non‐existing people) through epigenetic programming, then F1 (i.e. existing and overlapping with both F0 and F2) might face increased costs to address F2's condition in the future: this might generate obligations upon F0 from various distributive principles, such as the principle of equal opportunity for well being.     

Linking inter-individual variability to endocrine disruptors: insights for epigenetic inheritance

Endocrine disrupting chemicals (EDCs) can induce a myriad of adverse health effects. An area of active investigation is the multi- and transgenerational inheritance of EDC-induced adverse health effects referring to the transmission of phenotypes across multiple generations via the germline. The inheritance of EDC-induced adverse health effects across multiple generations can occur independent of genetics, spurring much research into the transmission of underlying epigenetic mechanisms. Epigenetic mechanisms play important roles in the development of an organism and are responsive to environmental exposures. To date, rodent studies have demonstrated that acquired epigenetic marks, particularly DNA methylation, that are inherited following parental EDC exposure can escape embryonic epigenome reprogramming. The acquired epimutations can lead to subsequent adult-onset diseases. Increasing studies have reported inter-individual variations that occur with epigenetic inheritance. Factors that underlie differences among individuals could reveal previously unidentified mechanisms of epigenetic transmission. In this review, we give an overview of DNA methylation and posttranslational histone modification as the potential mechanisms for disease transmission, and define the requirements for multi- and transgenerational epigenetic inheritance. We subsequently evaluate rodent studies investigating how acquired changes in epigenetic marks especially DNA methylation across multiple generations can vary among individuals following parental EDC exposure. We also discuss potential sources of inter-individual variations and the challenges in identifying these variations. We conclude our review discussing the challenges in applying rodent generational studies to humans.

     

Artificial light at night: melatonin as a mediator between the environment and epigenome

The adverse effects of excessive use of artificial light at night (ALAN) are becoming increasingly evident and associated with several health problems including cancer. Results of epidemiological studies revealed that the increase in breast cancer incidents co-distribute with ALAN worldwide. There is compiling evidence that suggests that melatonin suppression is linked to ALAN-induced cancer risks, but the specific genetic mechanism linking environmental exposure and the development of disease is not well known. Here we propose a possible genetic link between environmental exposure and tumorigenesis processes. We discuss evidence related to the relationship between epigenetic remodelling and oncogene expression. In breast cancer, enhanced global hypomethylation is expected in oncogenes, whereas in tumour suppressor genes local hypermethylation is recognized in the promoter CpG chains. A putative mechanism of action involving epigenetic modifications mediated by pineal melatonin is discussed in relation to cancer prevalence. Taking into account that ALAN-induced epigenetic modifications are reversible, early detection of cancer development is of great significance in the treatment of the disease. Therefore, new biomarkers for circadian disruption need to be developed to prevent ALAN damage.     

Focus: Health Equity: Lung Disease in Central Appalachia: It’s More than Coal Dust that Drives Disparities

The population living in Central Appalachia is disproportionately impacted by lung disease. This is driven, in part, by occupational hazards and environmental exposures. However, it is more than coal dust that is driving the ongoing disparity of lung disease in the region. This review describes how the decline of the coal mine industry and subsequent rise of unemployment, poverty, and educational disparities have increased risk for worse pulmonary health outcomes in the region. Additional challenges related to healthcare access, substance use, cultural characteristics, and social capital are highlighted in their relation to pulmonary health within Central Appalachia. Lastly, the review describes strategies that hold promise to reduce regional health disparities. Several healthcare and community-centered initiatives are highlighted as successful examples of collaborative efforts working towards improving pulmonary health outcomes in the region. However, significant challenges related to social, economic, and environmental factors remain. Addressing these social determinants of health must be a paramount concern for healthcare, community and political leaders seeking to impact change and improve the health and well-being of this vulnerable population.     

Perception of residential crowding,classroom experiences,and student health

The present research is based on a typology of crowding experiences incorporating two main dimensions: neutral-personal thwartings and primary-secondary environments. The thwarting dimension concerns the degree to which crowding experiences are associated with spatial inconveniences, alone, or with spatial as well as social constraints. The environmental dimension relates to the type of setting in which crowding experiences occur. A major assumption of this typology is that crowding experiences involving social conflict will be more intense and disruptive to the individual than those in which interpersonal conflict is minimal. The reported study examined the relationship between college students' evaluations of the physical amenity, social climate, and crowdedness of their residential environments, on the one hand, and their sensitivity to crowding in a classroom situation, their academic performance, and the frequency of their visits to the campus health center, on the other. Results indicated that perceived residential crowding and negative perceptions of residential social climate were strongly associated with increased sensitivity to crowding in a classroom situation, impaired course performance, and visits to the student health center. The implications of these correlational findings for future field-experimental research are discussed.     

Childhood Adversity Is Associated with Adult Theory of Mind and Social Affiliation,but Not Face Processing

People vary substantially in their ability to acquire and maintain social ties. Here, we use a combined epidemiological and individual differences approach to understand the childhood roots of adult social cognitive functioning. We assessed exposure to 25 forms of traumatic childhood experiences in over 5000 adults, along with measures of face discrimination, face memory, theory of mind, social motivation, and social support. Retrospectively-reported experiences of parental maltreatment in childhood (particularly physical abuse) were the most broadly and robustly associated with adult variations in theory of mind, social motivation, and social support. Adult variations in face discrimination and face memory, on the other hand, were not significantly associated with exposure to childhood adversity. Our findings indicate domains of social cognition that may be particularly vulnerable to the effects of adverse childhood environments, and suggest mechanisms whereby environmental factors might influence the development of social abilities.     

Disparities in Adverse Childhood Experiences among Sexual Minority and Heterosexual Adults: Results from a Multi-State Probability-Based Sample

Background

Adverse childhood experiences (e.g., physical, sexual and emotional abuse, neglect, exposure to domestic violence, parental discord, familial mental illness, incarceration and substance abuse) constitute a major public health problem in the United States. The Adverse Childhood Experiences (ACE) scale is a standardized measure that captures multiple developmental risk factors beyond sexual, physical and emotional abuse. Lesbian, gay, and bisexual (i.e., sexual minority) individuals may experience disproportionately higher prevalence of adverse childhood experiences.

Purpose

To examine, using the ACE scale, prevalence of childhood physical, emotional, and sexual abuse and childhood household dysfunction among sexual minority and heterosexual adults.

Methods

Analyses were conducted using a probability-based sample of data pooled from three U.S. states’ Behavioral Risk Factor Surveillance System (BRFSS) surveys (Maine, Washington, Wisconsin) that administered the ACE scale and collected information on sexual identity (n = 22,071).

Results

Compared with heterosexual respondents, gay/lesbian and bisexual individuals experienced increased odds of six of eight and seven of eight adverse childhood experiences, respectively. Sexual minority persons had higher rates of adverse childhood experiences (IRR = 1.66 gay/lesbian; 1.58 bisexual) compared to their heterosexual peers.

Conclusions

Sexual minority individuals have increased exposure to multiple developmental risk factors beyond physical, sexual and emotional abuse. We recommend the use of the Adverse Childhood Experiences scale in future research examining health disparities among this minority population.     

Environmental epigenetics in metal exposure

Although it is widely accepted that chronic exposure to arsenite, nickel, chromium and cadmium increases cancer incidence in individuals, the molecular mechanisms underlying their ability to transform cells remain largely unknown. Carcinogenic metals are typically weak mutagens, suggesting that genetic-based mechanisms may not be primarily responsible for metal-induced carcinogenesis. Growing evidence shows that environmental metal exposure involves changes in epigenetic marks, which may lead to a possible link between heritable changes in gene expression and disease susceptibility and development. Here, we review recent advances in the understanding of metal exposure affecting epigenetic marks and discuss establishment of heritable gene expression in metal-induced carcinogenesis.Key words: environmental metal, epigenetic, metal carcinogenesis, histone modification, DNA methylation, chromatin, gene expression     

Adolescent idiopathic scoliosis (AIS), environment, exposome and epigenetics: a molecular perspective of postnatal normal spinal growth and the etiopathogenesis of AIS with consideration of a network approach and possible implications for medical therapy

ABSTRACT: Genetic factors are believed to play an important role in the etiology of adolescent idiopathic scoliosis (AIS). Discordant findings for monozygotic (MZ) twins with AIS show that environmental factors including different intrauterine environments are important in etiology, but what these environmental factors may be is unknown. Recent evidence for common chronic non-communicable diseases suggests epigenetic differences may underlie MZ twin discordance, and be the link between environmental factors and phenotypic differences. DNA methylation is one important epigenetic mechanism operating at the interface between genome and environment to regulate phenotypic plasticity with a complex regulation across the genome during the first decade of life. The word exposome refers to the totality of environmental exposures from conception onwards, comprising factors in external and internal environments. The word exposome is used here also in relation to physiologic and etiopathogenetic factors that affect normal spinal growth and may induce the deformity of AIS. In normal postnatal spinal growth we propose a new term and concept, physiologic growth-plate exposome for the normal processes particularly of the internal environments that may have epigenetic effects on growth plates of vertebrae. In AIS, we propose a new term and concept pathophysiologic scoliogenic exposome for the abnormal processes in molecular pathways particularly of the internal environment currently expressed as etiopathogenetic hypotheses; these are suggested to have deforming effects on the growth plates of vertebrae at cell, tissue, structure and/or organ levels that are considered to be epigenetic. New research is required for chromatin modifications including DNA methylation in AIS subjects and vertebral growth plates excised at surgery. In addition, consideration is needed for a possible network approach to etiopathogenesis by constructing AIS diseasomes. These approaches may lead through screening, genetic, epigenetic, biochemical, metabolic phenotypes and pharmacogenomic research to identify susceptible individuals at risk and modulate abnormal molecular pathways of AIS. The potential of epigenetic-based medical therapy for AIS cannot be assessed at present, and must await new research derived from the evaluation of epigenetic concepts of spinal growth in health and deformity. The tenets outlined here for AIS are applicable to other musculoskeletal growth disorders including infantile and juvenile idiopathic scoliosis.