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.     

Prenatal stress programs lipid metabolism enhancing cardiovascular risk in the female F1, F2, and F3 generation in the primate model common marmoset (Callithrix jacchus)

Background Many human diseases are modulated by intrauterine environment, which is called prenatal programming. This study investigated effects of prenatal glucocorticoids on the lipid metabolism of three filial generations of common marmosets. Methods Pregnant primates were treated with dexamethasone during pregnancy. Body weight and blood lipid parameters of adult female offspring (F1: n = 5, F2: n = 6, F3: n = 3) were compared with age‐related female controls (n = 12). Results F1, F2, and F3 offspring showed significantly lower percentage of plasma n3 fatty acids than controls. F2 and F3 presented higher cholesterol levels, with significantly more LDL cholesterol, significantly less HDL triglycerides and an enhanced cholesterol/HDL cholesterol ratio. Body weight was not significantly affected. Conclusions Prenatal dexamethasone led to higher amounts of cardiovascular risk factors and less protective parameters in female F1–F3 offspring. The intergenerational consequences suggest prenatal programming through epigenetic effects.     

How differing modes of non‐genetic inheritance affect population viability in fluctuating environments

Different modes of non‐genetic inheritance are expected to affect population persistence in fluctuating environments. We here analyse Caenorhabditis elegans density‐independent per capita growth rate time series on 36 populations experiencing six controlled sequences of challenging oxygen level fluctuations across 60 generations, and parameterise competing models of non‐genetic inheritance in order to explain observed dynamics. Our analysis shows that phenotypic plasticity and anticipatory maternal effects are sufficient to explain growth rate dynamics, but that a carryover model where ‘epigenetic’ memory is imperfectly transmitted and might be reset at each generation is a better fit to the data. We further find that this epigenetic memory is asymmetric since it is kept for longer when populations are exposed to the more challenging environment. Our analysis suggests that population persistence in fluctuating environments depends on the non‐genetic inheritance of phenotypes whose expression is regulated across multiple generations.     

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.     

Zika,contraception and the non‐identity problem

The 2016 outbreak of the Zika arbovirus was associated with large numbers of cases of the newly‐recognised Congenital Zika Syndrome (CZS). This novel teratogenic epidemic raises significant ethical and practical issues. Many of these arise from strategies used to avoid cases of CZS, with contraception in particular being one proposed strategy that is atypical in epidemic control. Using contraception to reduce the burden of CZS has an ethical complication: interventions that impact the timing of conception alter which people will exist in the future. This so‐called ‘non‐identity problem’ potentially has significant social justice implications for evaluating contraception, that may affect our prioritisation of interventions to tackle Zika. This paper combines ethical analysis of the non‐identity problem with empirical data from a novel survey about the general public's moral intuitions. The ethical analysis examines different perspectives on the non‐identity problem, and their implications for using contraception in response to Zika. The empirical section reports the results of an online survey of 93 members of the US general public exploring their intuitions about the non‐identity problem in the context of the Zika epidemic. Respondents indicated a general preference for a person‐affecting intervention (mosquito control) over an impersonal intervention (contraception). However, their responses did not appear to be strongly influenced by the non‐identity problem. Despite its potential philosophical significance, we conclude from both theoretical considerations and analysis of the attitudes of the community that the non‐identity problem should not affect how we prioritise contraception relative to other interventions to avoid CZS.     

Entangled lives: Implications of the developmental origins of health and disease hypothesis for bioarchaeology and the life course

Epidemiological research since the 1980s has highlighted the consequences of early life adversity, particularly during gestation and early infancy, for adult health (the “Barker hypothesis”). The fast‐evolving field of molecular epigenetics is providing explanatory mechanisms concerning phenotypic plasticity in response to developmental stressors and the accumulation of disease risk throughout life. In addition, there is now evidence for the heritability of poor health across generations via epigenetic modifications. This research has the potential to invoke a paradigmatic shift in how we interpret factors such as growth insults and immune response in past skeletal remains. It demonstrates that health cannot be understood in terms of immediate environmental circumstances alone. Furthermore, it requires both a theoretical and practical re‐evaluation of disease biographies and the life course more generally. Individual life courses can no longer be regarded as discrete, bounded, life histories, with clearly defined beginning and end points. If socioeconomic circumstances can have intergenerational effects, including disease susceptibility and growth stunting, then individual biographies should be viewed as nested or “embedded” within the lives of others. This commingling of life courses may prove problematic to unravel; nevertheless, this review aims to consider the potential consequences for bioarchaeological interpretations. These include a greater consideration of: the temporal power of human skeletons and a life course approach to past health; infant health and the implications for maternal well‐being; and the impact of non‐proximate stressors (e.g., early life and ancestral environments) on the presence of health indicators. Am J Phys Anthropol 158:530–540, 2015. © 2015 Wiley Periodicals, Inc.     

Geroscience and climate science: Oppositional or complementary?

Two of this century's most significant public health challenges are climate change and healthy aging. The future of humanity will be both warmer and older than it is today. Is it socially responsible, in a warming planet of a population exceeding 8 billion people, for science to aspire to develop gerotherapeutic drugs that aim to reduce the burden of aging-related diseases that may also increase lifespan? This question is the “elephant in the room” for geroscience advocacy. Science communication concerning what constitutes empirically valid and morally defensible ways of navigating the dual public health predicaments of climate change and healthy aging must be sensitive to both the interdependence of the environment (including planetary health) and the mechanisms of aging, as well as the common (mis)perceptions about the potential conflict between the goals of climate science and geroscience. Geroscience advocacy can transcend narratives of intergenerational conflict by highlighting the shared aspirations of climate science and geroscience, such as the goals of promoting health across the lifespan, redressing health disparities, and improving the economic prospects of current and future generations.     

Epigenetically facilitated mutational assimilation: epigenetics as a hub within the inclusive evolutionary synthesis

After decades of debate about the existence of non‐genetic inheritance, the focus is now slowly shifting towards dissecting its underlying mechanisms. Here, we propose a new mechanism that, by integrating non‐genetic and genetic inheritance, may help build the long‐sought inclusive vision of evolution. After briefly reviewing the wealth of evidence documenting the existence and ubiquity of non‐genetic inheritance in a table, we review the categories of mechanisms of parent–offspring resemblance that underlie inheritance. We then review several lines of argument for the existence of interactions between non‐genetic and genetic components of inheritance, leading to a discussion of the contrasting timescales of action of non‐genetic and genetic inheritance. This raises the question of how the fidelity of the inheritance system can match the rate of environmental variation. This question is central to understanding the role of different inheritance systems in evolution. We then review and interpret evidence indicating the existence of shifts from inheritance systems with low to higher transmission fidelity. Based on results from different research fields we propose a conceptual hypothesis linking genetic and non‐genetic inheritance systems. According to this hypothesis, over the course of generations, shifts among information systems allow gradual matching between the rate of environmental change and the inheritance fidelity of the corresponding response. A striking conclusion from our review is that documented shifts between types of inherited non‐genetic information converge towards epigenetics (i.e. inclusively heritable molecular variation in gene expression without change in DNA sequence). We then interpret the well‐documented mutagenicity of epigenetic marks as potentially generating a final shift from epigenetic to genetic encoding. This sequence of shifts suggests the existence of a relay in inheritance systems from relatively labile ones to gradually more persistent modes of inheritance, a relay that could constitute a new mechanistic basis for the long‐proposed, but still poorly documented, hypothesis of genetic assimilation. A profound difference between the genocentric and the inclusive vision of heredity revealed by the genetic assimilation relay proposed here lies in the fact that a given form of inheritance can affect the rate of change of other inheritance systems. To explore the consequences of such inter‐connection among inheritance systems, we briefly review published theoretical models to build a model of genetic assimilation focusing on the shift in the engraving of environmentally induced phenotypic variation into the DNA sequence. According to this hypothesis, when environmental change remains stable over a sufficient number of generations, the relay among inheritance systems has the potential to generate a form of genetic assimilation. In this hypothesis, epigenetics appears as a hub by which non‐genetically inherited environmentally induced variation in traits can become genetically encoded over generations, in a form of epigenetically facilitated mutational assimilation. Finally, we illustrate some of the major implications of our hypothetical framework, concerning mutation randomness, the central dogma of molecular biology, concepts of inheritance and the curing of inherited disorders, as well as for the emergence of the inclusive evolutionary synthesis.     

Evaluating the Usefulness of Compulsory Licensing in Developing Countries: A Comparative Study of Thai and Brazilian Experiences Regarding Access to Aids Treatments

While compulsory licensing (CL) is described in the TRIPS agreement as flexibility to protect public health by improving access to medicines in developing countries, a recent literature contends adversely that CL may harm public health. Therefore, this article intends to evaluate the usefulness of CL in the South through the prism of obligations and goals entrusted to patent holders (the effective and non‐abusive exploitation of patents in order to achieve industrial and health developments) and in light of experiences in Thailand and Brazil regarding access to antiretroviral drugs. In this way, it shows that the obligations assigned to patent holders were better served by the recipients of CL and brought significant health and industrial benefits in the two high middle‐income countries. In particular, CL allowed the scaling‐up of free and universal access to antiretroviral drugs by assuring the financial sustainability of these public health programs endangered by monopolistic practices from patent holders.     

Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats

Epidemiological studies linking low birth weight and subsequent cardiometabolic disease have given rise to the hypothesis that events in fetal life permanently program subsequent cardiovascular risk. The effects of fetal programming may not be limited to the first-generation offspring. We have explored intergenerational effects in the dexamethasone-programmed rat, a model in which fetal exposure to excess glucocorticoid results in low birth weight with subsequent adult hyperinsulinemia and hyperglycemia underpinned by increased activity of the key hepatic gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK). We found that the male offspring of female rats that had been exposed prenatally to dexamethasone, but were not manipulated in their own pregnancy, also had reduced birth weight (5.66 +/- 0.06 vs. 6.12 +/- 0.06 g, P < 0.001), glucose intolerance, and elevated hepatic PEPCK activity (5.7 +/- 0.6 vs. 3.3 +/- 0.2 nmol.min(-1).mg protein(-1), P < 0.001). These effects resolved in a third generation. Similar intergenerational programming was observed in offspring of male rats exposed prenatally to dexamethasone mated with control females. The persistence of such programming effects through several generations, transmitted by either maternal or paternal lines, indicates the potential importance of epigenetic factors in the intergenerational inheritance of the "programming phenotype" and provides a basis for the inherited association between low birth weight and cardiovascular risk factors.     

Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms

This paper reviews the research evidence concerning the intergenerational transmission of trauma effects and the possible role of epigenetic mechanisms in this transmission. Two broad categories of epigenetically mediated effects are highlighted. The first involves developmentally programmed effects. These can result from the influence of the offspring's early environmental exposures, including postnatal maternal care as well as in utero exposure reflecting maternal stress during pregnancy. The second includes epigenetic changes associated with a preconception trauma in parents that may affect the germline, and impact fetoplacental interactions. Several factors, such as sex‐specific epigenetic effects following trauma exposure and parental developmental stage at the time of exposure, explain different effects of maternal and paternal trauma. The most compelling work to date has been done in animal models, where the opportunity for controlled designs enables clear interpretations of transmissible effects. Given the paucity of human studies and the methodological challenges in conducting such studies, it is not possible to attribute intergenerational effects in humans to a single set of biological or other determinants at this time. Elucidating the role of epigenetic mechanisms in intergenerational effects through prospective, multi‐generational studies may ultimately yield a cogent understanding of how individual, cultural and societal experiences permeate our biology.     

Rights, indirect harms and the non-identity problem

The non‐identity problem is the problem of grounding moral wrongdoing in cases in which an action affects who will exist in the future. Consider a woman who intentionally conceives while on medication that is harmful for a fetus. If the resulting child is disabled as a result of the medication, what makes the woman's action morally wrong? I argue that an explanation in terms of harmful rights violations fails, and I focus on Peter Markie's recent rights‐based defense. Markie's analysis rests on the notion of an indirect harm, and I show that the calculation of an indirect harm relies on an improper baseline for the determination of whether or not an action adversely affects a patient's interests. I also defend an impersonal duty‐based analysis of the wrongdoing in non‐identity cases against an objection by Markie. I close by arguing that the rights‐based analysis is insensitive to context and that context is morally relevant in the determination of the moral valence of actions in cases of non‐identity. This failure provides a pro tanto reason to favor an impersonal duty‐based analysis of the wrongdoing in non‐identity cases.     

EXISTENCE: WHO NEEDS IT? THE NON‐IDENTITY PROBLEM AND MERELY POSSIBLE PEOPLE

In formulating procreative principles, it makes sense to begin by thinking about whose interests ought to matter to us. Obviously, we care about those who exist. Less obviously, but still uncontroversially, we care about those who will exist. Ought we to care about those who might possibly, but will not actually, exist? Recently, unusual positions have been taken regarding merely possible people and the non‐identity problem. David Velleman argues that what might have happened to you – an existent person – often doesn't merit moral consideration since the alternative person one would have been had what might have happened actually happened is a merely possible person about whom one has no reason to care. He argues that his way of thinking can eliminate the non‐identity problem. Caspar Hare argues that merely possible people have interests and are morally relevant. He argues that we can solve the non‐identity problem by rejecting the view that merely possible people are morally irrelevant. Both Hare and Velleman argue that focusing on one's de dicto rather than on one's de re children can help us avoid the non‐identity problem. I analyze the role that merely possible, nonexistent hypothetical entities ought to play in our moral reasoning, especially with regard to procreation. I refute both Velleman's and Hare's views and demonstrate the difficulties we encounter when we try to apply their views to common non‐identity cases. I conclude with the common‐sense view regarding who matters, morally: only those who do, did, or will exist.     

Direct but No Transgenerational Effects of Decitabine and Vorinostat on Male Fertility

Establishment and maintenance of the correct epigenetic code is essential for a plethora of physiological pathways and disturbed epigenetic patterns can provoke severe consequences, e.g. tumour formation. In recent years, epigenetic drugs altering the epigenome of tumours actively have been developed for anti-cancer therapies. However, such drugs could potentially also affect other physiological pathways and systems in which intact epigenetic patterns are essential. Amongst those, male fertility is one of the most prominent. Consequently, we addressed possible direct effects of two epigenetic drugs, decitabine and vorinostat, on both, the male germ line and fertility. In addition, we checked for putative transgenerational epigenetic effects on the germ line of subsequent generations (F1–F3). Parental adult male C57Bl/6 mice were treated with either decitabine or vorinostat and analysed as well as three subsequent untreated generations derived from these males. Treatment directly affected several reproductive parameters as testis (decitabine & vorinostat) and epididymis weight, size of accessory sex glands (vorinostat), the height of the seminiferous epithelium and sperm concentration and morphology (decitabine). Furthermore, after decitabine administration, DNA methylation of a number of loci was altered in sperm. However, when analysing fertility of treated mice (fertilisation, litter size and sex ratio), no major effect of the selected epigenetic drugs on male fertility was detected. In subsequent generations (F1–F3 generations) only subtle changes on reproductive organs, sperm parameters and DNA methylation but no overall effect on fertility was observed. Consequently, in mice, decitabine and vorinostat neither affected male fertility per se nor caused marked transgenerational effects. We therefore suggest that both drugs do not induce major adverse effects—in terms of male fertility and transgenerational epigenetic inheritance—when used in anti-cancer-therapies.     

Pesticide Methoxychlor Promotes the Epigenetic Transgenerational Inheritance of Adult-Onset Disease through the Female Germline

Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.     

Disorders related to sexuality and gender identity in the ICD‐11: revising the ICD‐10 classification based on current scientific evidence,best clinical practices,and human rights considerations

In the World Health Organization's forthcoming eleventh revision of the International Classification of Diseases and Related Health Problems (ICD‐11), substantial changes have been proposed to the ICD‐10 classification of mental and behavioural disorders related to sexuality and gender identity. These concern the following ICD‐10 disorder groupings: F52 Sexual dysfunctions, not caused by organic disorder or disease; F64 Gender identity disorders; F65 Disorders of sexual preference; and F66 Psychological and behavioural disorders associated with sexual development and orientation. Changes have been proposed based on advances in research and clinical practice, and major shifts in social attitudes and in relevant policies, laws, and human rights standards. This paper describes the main recommended changes, the rationale and evidence considered, and important differences from the DSM‐5. An integrated classification of sexual dysfunctions has been proposed for a new chapter on Conditions Related to Sexual Health, overcoming the mind/body separation that is inherent in ICD‐10. Gender identity disorders in ICD‐10 have been reconceptualized as Gender incongruence, and also proposed to be moved to the new chapter on sexual health. The proposed classification of Paraphilic disorders distinguishes between conditions that are relevant to public health and clinical psychopathology and those that merely reflect private behaviour. ICD‐10 categories related to sexual orientation have been recommended for deletion from the ICD‐11.     

Allocation of scarce resources in Africa during COVID‐19: Utility and justice for the bottom of the pyramid?

The COVID‐19 pandemic has raised important universal public health challenges. Conceiving ethical responses to these challenges is a public health imperative but must take context into account. This is particularly important in sub‐Saharan Africa (SSA). In this paper, we examine how some of the ethical recommendations offered so far in high‐income countries might appear from a SSA perspective. We also reflect on some of the key ethical challenges raised by the COVID‐19 pandemic in low‐income countries suffering from chronic shortages in health care resources, and chronic high morbidity and mortality from non‐COVID‐19 causes. A parallel is drawn between the distribution of severity of COVID‐19 disease and the classic “Fortune at the bottom of the pyramid” model that is relevant in SSA. Focusing allocation of resources during COVID‐19 on the ‘thick’ part of the pyramid in Low‐to‐Middle Income Countries (LMICs) could be ethically justified on utilitarian and social justice grounds, since it prioritizes a large number of persons who have been economically and socially marginalized. During the pandemic, importing allocation frameworks focused on the apex of the pyramid from the global north may therefore not always be appropriate. In a post‐COVID‐19 world, we need to think strategically about how health care systems can be financed and structured to ensure broad access to adequate health care for all who need it. The root problems underlying health inequity, exposed by COVID‐19, must be addressed, not just to prepare for the next pandemic, but to care for people in resource poor settings in non‐pandemic times.     

The Identity Objection to the future‐like‐ours argument

Some critics of Don Marquis's ‘future‐like‐ours’ anti‐abortion argument launch what has been called the Identity Objection. The upshot of this objection is that under a psychological theory of personal identity, a non‐sentient fetus lacks precisely what Marquis believes gives it a right to life – a future like ours. However, Eric Vogelstein, in a recent article, has argued that under this theory of personal identity a non‐sentient fetus, in fact, has a future like ours, which he believes dissolves the Identity Objection. But Vogelstein is mistaken. Even if he is correct that there is a sense in which a non‐sentient fetus has a future of value under a psychological theory of personal identity, the sense in which it has one is importantly different from the sense in which we have one, meaning that, under such a theory, a non‐sentient fetus does not have a future like ours.     

Progressive, transgenerational changes in offspring phenotype and epigenotype following nutritional transition

Induction of altered phenotypes during development in response to environmental input involves epigenetic changes. Phenotypic traits can be passed between generations by a variety of mechanisms, including direct transmission of epigenetic states or by induction of epigenetic marks de novo in each generation. To distinguish between these possibilities we measured epigenetic marks over four generations in rats exposed to a sustained environmental challenge. Dietary energy was increased by 25% at conception in F0 female rats and maintained at this level to generation F3. F0 dams showed higher pregnancy weight gain, but lower weight gain and food intake during lactation than F1 and F2 dams. On gestational day 8, fasting plasma glucose concentration was higher and β-hydroxybutyrate lower in F0 and F1 dams than F2 dams. This was accompanied by decreased phosphoenolpyruvate carboxykinase (PEPCK) and increased PPARα and carnitine palmitoyl transferase-1 mRNA expression. PEPCK mRNA expression was inversely related to the methylation of specific CpG dinucleotides in its promoter. DNA methyltransferase (Dnmt) 3a2, but not Dnmt1 or Dnmt3b, expression increased and methylation of its promoter decreased from F1 to F3 generations. These data suggest that the regulation of energy metabolism during pregnancy and lactation within a generation is influenced by the maternal phenotype in the preceding generation and the environment during the current pregnancy. The transgenerational effects on phenotype were associated with altered DNA methylation of specific genes in a manner consistent with induction de novo of epigenetic marks in each generation.