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Importance: Governments worldwide have become increasingly cognizant of the spread of genetic discrimination (negative treatment or harm on the basis of actual or presumed genetic characteristics). Despite efforts by a number of governments to establish regulations addressing this phenomenon, public concern about genetic discrimination persists., Objective: To identify key elements of an optimal genetic nondiscrimination policy and inform policymakers as they seek to allay genetic nondiscrimination and related public anxieties., Evidence Review: Sixty multidisciplinary experts from 20 jurisdictions worldwide were consulted to understand their views on effective genetic nondiscrimination policies. Following standard requirements of the Delphi method, 3 rounds of surveys over the course of 1.5 years were conducted. Round 1 focused on assessing participants' understanding of the intricacies of existing genetic nondiscrimination policies, while rounds 2 and 3 invited participants to reflect on specific means of implementing a more effective regime. A total of 60 respondents participated in the first round, 53 participated in round 2, and 43 participated in round 3., Findings: While responses varied across disciplines, there was consensus that binding regulations that reach across various sectors are most useful in preventing genetic discrimination. Overall, experts agreed that human rights-based approaches are well suited to preventing genetic discrimination. Experts also agreed that explicit prohibition of genetic discrimination within nondiscrimination policies can highlight the importance of genetic nondiscrimination as a fundamental right and ensure robust protection at a national level. While most participants believed the international harmonization of genetic nondiscrimination laws would facilitate data sharing worldwide, they also recognized that regulations must reflect the sociocultural differences that exist among regions., Conclusions and Relevance: As the reach of genetic discrimination continues to evolve alongside developments in genomics, strategic policy responses that are harmonious at the international and state levels will be critical to address this phenomenon. In seeking to establish comprehensive frameworks, policymakers will need to be mindful of regional and local circumstances that influence the need for and efficacy of unique genetic nondiscrimination approaches across diverse contexts.

Genetic discrimination is an evolving phenomenon that impacts fundamental human rights such as dignity, justice and equity. Although, in the past, various definitions to better conceptualize genetic discrimination have been proposed, these have been unable to capture several key facets of the phenomenon. In this Perspective, we explore definitions of genetic discrimination across disciplines, consider criticisms of such definitions and show how other forms of discrimination and stigmatization can compound genetic discrimination in a way that affects individuals, groups and systems. We propose a nuanced and inclusive definition of genetic discrimination, which reflects its multifaceted impact that should remain relevant in the face of an evolving social context and advancing science. We argue that our definition should be adopted as a guiding academic framework to facilitate scientific and policy discussions about genetic discrimination and support the development of laws and industry policies seeking to address the phenomenon., (© 2024. Springer Nature America, Inc.)

Epigenetic research has brought several important technological achievements, including identifying epigenetic clocks and signatures, and developing epigenetic editing. The potential military applications of such technologies we discuss are stratifying soldiers' health, exposure to trauma using epigenetic testing, information about biological clocks, confirming child soldiers' minor status using epigenetic clocks, and inducing epigenetic modifications in soldiers. These uses could become a reality. This article presents a comprehensive literature review, and analysis by interdisciplinary experts of the scientific, legal, ethical, and societal issues surrounding epigenetics and the military. Notwithstanding the potential benefit from these applications, our findings indicate that the current lack of scientific validation for epigenetic technologies suggests a careful scientific review and the establishment of a robust governance framework before consideration for use in the military. In this article, we highlight general concerns about the application of epigenetic technologies in the military context, especially discrimination and data privacy issues if soldiers are used as research subjects. We also highlight the potential of epigenetic clocks to support child soldiers' rights and ethical questions about using epigenetic engineering for soldiers' enhancement and conclude with considerations for an ethical framework for epigenetic applications in the military, defense, and security contexts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Duke University School of Law, Harvard Law School, Oxford University Press, and Stanford Law School.)

Background : Sex and gender are vitally important in the study of epigenetic mechanisms for various types of cancer. However, little has been done to assess the state of sex and gender-based analyses (SGBA) in this field. The aim was to undertake a critical evaluation of sex and gender representation, discussion, and data analysis within the cancer epigenetics field since 2010. Methods : A PRISMA-ScR scoping review was conducted with 111 peer-reviewed studies comprising of colorectal, gastric, head and neck, hepatocellular carcinoma, and lung cancers. Data extraction and a quality appraisal were performed by a team of epidemiologists and bioethicists. Results : Of the 111 included studies, only 17 studies (15.3%) explicitly stated sex and gender analysis to be their primary aim. A total of 103 studies (92.8%) provided a detailed analysis of sex/gender as a biological or social variable, while the remaining 8 studies (7.2%) only stratified results by sex/gender. Although sex and gender were a key facet in all the eligible studies, only 7 studies (6.3%) provided an explicit definition of the terms "sex" or "gender", while the remaining 104 studies (93.7%) used the words "sex" or "gender" without providing a definition. A total of 84 studies (75.7%) conflated the concepts of "sex" and "gender", while 44 studies (39.6%) were inconsistent with their usage of the "sex" and "gender" terms. Conclusions : Very few studies offered a robust analysis of sex/gender data according to SAGER guidelines. We call for clear and directed guidelines regarding the use of sex/gender as a variable in epigenetics research.

Over the past decade, bioethicists, legal scholars and social scientists have started to investigate the potential implications of epigenetic research and technologies on medicine and society. There is growing literature discussing the most promising opportunities, as well as arising ethical, legal and social issues (ELSI). This paper explores the views of epigenetic researchers about some of these discussions. From January to March 2020, we conducted an online survey of 189 epigenetic researchers working in 31 countries. We questioned them about the scope of their field, opportunities in different areas of specialization, and ELSI in the conduct of research and knowledge translation. We also assessed their level of concern regarding four emerging non-medical applications of epigenetic testing-i.e., in life insurance, forensics, immigration and direct-to-consumer testing. Although there was strong agreement on DNA methylation, histone modifications, 3D structure of chromatin and nucleosomes being integral elements of the field, there was considerable disagreement on transcription factors, RNA interference, RNA splicing and prions. The most prevalent ELSI experienced or witnessed by respondents were in obtaining timely access to epigenetic data in existing databases, and in the communication of epigenetic findings by the media. They expressed high levels of concern regarding non-medical applications of epigenetics, echoing cautionary appraisals in the social sciences and humanities literature., (© 2022. The Author(s).)

Non-invasive prenatal testing (NIPT) using cell-free DNA (cfDNA) offers numerous benefits to pregnant women and their families. It also raises ethical, legal and social concerns regarding, for instance, the possible effects of a routinization of prenatal genetic testing on free and informed decision-making by prospective parents, and the role of the state in governing its use. Technological advances are allowing cfDNA analyses to detect an increasing number of genetic risks and conditions in the fetus, potentially further exacerbating such concerns. From May 2015 to December 2016, we conducted a three-round Policy Delphi study (N R1  = 61, N R2  = 58, N R3  = 47; overall retention rate = 77.0%) to explore the social acceptability (SA) of current and potential future uses of NIPT in Canada according to participants with relevant professional, research or advocacy expertise. Participants came from four groups: healthcare professionals (N R3  = 14), social sciences and humanities researchers (N R3  = 13), patients/disability rights advocates (N R3  = 14), and cultural/religious communities advocates (N R3  = 6). This paper presents SA criteria and contextual contingencies relevant to the assessment of NIPT's SA according to the group. It also reports what uses (conditions or motives) participants thought should be banned, permitted, publicly funded, or promoted as a public health strategy. According to them, conditions resulting in severe pain or early death, as well as trisomies (13, 18, 21) and sex chromosome abnormalities, should be covered by Canadian public health insurance. However, there was wide agreement that direct-to-consumer NIPT should be legally banned, and that testing for fetal sex for non-medical reasons using NIPT should be either proscribed or discouraged. In addition to identifying areas of consensus, our results point to disagreement regarding, for instance, the required level of governance of whole-genome sequencing and testing for late onset conditions with low penetrance. This study also provides a model for exploring the SA of emerging technologies using the Policy Delphi method., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

While the accumulation and increased circulation of genomic data have captured much attention over the past decade, privacy risks raised by the diversification and integration of omics have been largely overlooked. In this paper, we propose the outline of a framework for assessing privacy risks in multi-omic research and databases. Following a comparison of privacy risks associated with genomic and epigenomic data, we dissect ten privacy risk-impacting omic data properties that affect either the risk of re-identification of research participants, or the sensitivity of the information potentially conveyed by biological data. We then propose a three-step approach for the assessment of privacy risks in the multi-omic era. Thus, we lay grounds for a data property-based, 'pan-omic' approach that moves away from genetic exceptionalism. We conclude by inviting our peers to refine these theoretical foundations, put them to the test in their respective fields, and translate our approach into practical guidance.

Background: Noninvasive prenatal testing (NIPT) provides important benefits yet raises ethical concerns. We surveyed Canadian pregnant women and their partners to explore their views regarding pressure to test and terminate a pregnancy, as well as other societal impacts that may result from the routinization of NIPT., Methods: A questionnaire was offered (March 2015 to July 2016) to pregnant women and their partners at five healthcare facilities in four Canadian provinces., Results: 882 pregnant women and 395 partners completed the survey. 64% of women anticipated feeling no pressure to take the test if it were offered routinely, and 39% were not concerned about routinization leading to increased pressure to terminate a pregnancy of a fetus with Down Syndrome. Regarding other social concerns possibly resulting from routinization, pregnant women were most concerned regarding a reduction in resources available for people with Down Syndrome and their families and least concerned regarding a decrease in the population of people with Down Syndrome., Conclusions: Our findings reflect the concerns expressed by pregnant women and their partners, both personal (pressure to test, pressure to terminate) and societal (e.g., regarding potential negative impact on people with disabilities and their families). Even if most women were not concerned about feeling pressured to test due to NIPT routinization, a large minority express concerns that should not be taken lightly. Moreover, a majority of respondents were concerned regarding pressure to terminate pregnancies due to NIPT routinization as well as regarding most societal impacts they were queried on, especially the possible future reduction in resources available for people with DS and their families. Canadian policy-makers should consider these potential negative ramifications of NIPT and ensure that appropriate social policies accompany its implementation.

Concerns about genetic discrimination (GD) often surface when discussing research and innovation in genetics. Over recent decades, countries around the world have attempted to address GD using various policy measures. In this article, we survey these approaches and provide a critical commentary on their advantages and disadvantages. Our examination begins with regions featuring extensive policy-making activities (North America and Europe), followed by regions with moderate policy-making activities (Australia, Asia, and South America) and regions with minimal policy-making activities (the Middle East and Africa). Our analysis then turns to emerging issues regarding genetic testing and GD, including the expansion of multiomics sciences and direct-to-consumer genetic tests outside the health context. We additionally survey the shortcomings of current normative approaches addressing GD. Finally, we conclude by highlighting the evolving nature of GD and the need for more innovative policy-making in this area.

Epigenetics, defined as 'the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence', has emerged as a promissory yet controversial field of scientific inquiry over the past decade. Scholars from many disciplines have formulated both optimistic and cautionary claims regarding its potential normative implications. This article provides a comprehensive review of the nascent literature at the crossroads of epigenetics, ethics, law and society. It describes nine emerging areas of discussion, relating to (1) the impact of epigenetics on the nature versus nurture dualism, (2) the potential resulting biologization of the social, (3) the meaning of epigenetics for public health, its potential influence on (4) reproduction and parenting, (5) political theory and (6) legal proceedings, and concerns regarding (7) stigmatization and discrimination, (8) privacy protection and (9) knowledge translation. While there is some degree of similarity between the nature and content of these areas and the abundant literature on ethical, legal and social issues in genetics, the potential implications of epigenetics ought not be conflated with the latter. Critical studies on epigenetics are emerging within a separate space of bioethical and biopolitical investigations and claims, with scholars from various epistemological standpoints utilizing distinct yet complementary analytical approaches.

Objective: This study sought to assess Canadian pregnant women's and their partners' preferences for information about non-invasive prenatal testing (NIPT)., Methods: Pregnant women and their partners across Canada were surveyed as part of the Personalized Genomics for prenatal Aneuploidy Screening Using maternal blood (PEGASUS) study., Results: A total of 882 pregnant women and 395 partners participated. Women preferred being informed by a physician (77.2%). They preferred getting information ahead of time, except for information about resources for families with Down syndrome, which they preferred getting with test results. More than half thought that written consent is important (63.7%) and could decide whether to do NIPT on the day they received the information (54.9%). Women preferred to be informed of results by telephone (43.7%) or in person (28%), but they preferred in person if they were considered at high risk for Down syndrome on the basis of the results (76%). The partner was the person whose input was considered most important (62.6%). Partners' preferences were similar, except that partners tended to want information later (at the time of the test or with the results) and felt that their opinion was not considered as highly by health professionals., Conclusion: Canadian women want information about NIPT early, in person, by a knowledgeable physician. Partners also want to be informed and involved in the decision-making process., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

As epigenetic studies become more common and lead to new insights into health and disease, the return of individual epigenetic results to research participants, in particular in large-scale epigenomic studies, will be of growing importance. Members of the International Human Epigenome Consortium (IHEC) Bioethics Workgroup considered the potential ethical, legal, and social issues (ELSI) involved in returning epigenetic research results and incidental findings in order to produce a set of 'Points-to-consider' (P-t-C) for the epigenetics research community. These P-t-C draw on existing guidance on the return of genetic research results, while also integrating the IHEC Bioethics Workgroup's ELSI research on and discussion of the issues associated with epigenetic data as well as the experience of a return of results pilot study by the Personal Genome Project UK (PGP-UK). Major challenges include how to determine the clinical validity and actionability of epigenetic results, and considerations related to environmental exposures and epigenetic marks, including circumstances warranting the sharing of results with family members and third parties. Interdisciplinary collaboration and good public communication regarding epigenetic risk will be important to advance the return of results framework for epigenetic science.

Background: Canadian policies regarding the implementation and public coverage of non-invasive prenatal testing (NIPT) are heterogeneous and shifting, with NIPT being publicly covered for high-risk pregnancies in some provinces, but not others. Such a diverse and evolving policy landscape provides fertile ground for examining the preferences of pregnant women, their partners, and health professionals regarding the implementation and coverage of NIPT by the public healthcare system, as well as the factors influencing their preferences, which is what the present study does., Methods: In this paper, we report the results of three-large scale Canadian surveys, in which 882 pregnant women, 395 partners of pregnant women, and 184 healthcare professionals participated., Results: The paper focuses on preferences regarding how and when NIPT should be used, as well as the factors influencing these preferences, and how coverage for NIPT should be provided. These are correlated with respondents' levels of knowledge about Down syndrome and testing technologies and with their stated intended use of NIPT results., Conclusion: Salient is the marked difference between the preferences of prospective parents and those of healthcare professionals, which has potential implications for Canadian policy regarding NIPT implementation and insurance coverage.

Background: Noninvasive prenatal testing is a recent technology that provides some genetic information about the fetus through the analysis of cell-free fetal DNA circulating in maternal blood. We aimed to identify the benefits, challenges and guiding ethical principles most relevant to the clinical integration of noninvasive prenatal testing in Canada, according to experts throughout the country., Methods: We conducted a 3-round Delphi study involving Canadian experts of contemporary discussions about the ethical and societal implications of prenatal testing and genomic technologies. In round 1, we asked participants to identify clinical benefits and challenges related to the implementation of noninvasive prenatal testing in Canada, and the ethical principles they think should guide it. In round 2, we asked participants to select the most important elements stated by their peers. In round 3, participants were informed of the aggregated results from round 2, and invited to revise or confirm their selection., Results: Round 1 had a participation rate of 20.2%, and involved 61 participants. Subsequent rounds 2 and 3 had retention rates of 95.1% ( n = 58) and 84.5% ( n = 49), respectively. Through these discussions, we identified 3 lists of benefits ( n = 10), challenges ( n = 27), and ethical principles ( n = 16) prioritized by Canadian experts as being most relevant to the implementation of noninvasive prenatal testing in Canada., Interpretation: Although multiple and diverse potential issues were identified, Canadian experts agreed on 2 sets of requirements for the responsible implementation of noninvasive prenatal testing in Canada. Interdisciplinary appraisals may be instrumental to responsible policy-making related to the implementation of noninvasive prenatal testing in Canada., Competing Interests: Competing interests: None declared., (Copyright 2018, Joule Inc. or its licensors.)

Over more than two decades, various policies have been adopted worldwide to restrict the use of individual genetic information for non-medical reasons by third parties and prevent 'genetic discrimination'. In this paper, we bring attention to the growing interest for individual epigenetic information by insurers and forensic scientists. We question whether such interest could lead to 'epigenetic discrimination' - the differential adverse treatment or abusive profiling of individuals or groups based on their actual or presumed epigenetic characteristics - and argue that we might already be facing the limitations of recently adopted normative approaches against genetic discrimination. First, we highlight some similarities and differences between genetic and epigenetic modifications, and stress potential challenges to regulating epigenetic discrimination. Second, we argue that most existing normative approaches against genetic discrimination fall short in providing oversight into the field of epigenetics. We conclude with a call for discussion on the issue, and the development of comprehensive and forward-looking preventive strategies against epigenetic discrimination.

Non-invasive prenatal testing (NIPT) is an exciting technology with the potential to provide a variety of clinical benefits, including a reduction in miscarriages, via a decline in invasive testing. However, there is also concern that the economic and near-future clinical benefits of NIPT have been overstated and the potential limitations and harms underplayed. NIPT, therefore, presents an opportunity to explore the ways in which a range of social pressures and policies can influence the translation, implementation, and use of a health care innovation. NIPT is often framed as a potential first tier screen that should be offered to all pregnant women, despite concerns over cost-effectiveness. Multiple forces have contributed to a problematic translational environment in Canada, creating pressure towards first tier implementation. Governments have contributed to commercialization pressure by framing the publicly funded research sector as a potential engine of economic growth. Members of industry have an incentive to frame clinical value as beneficial to the broadest possible cohort in order to maximize market size. Many studies of NIPT were directly funded and performed by private industry in laboratories lacking strong independent oversight. Physicians' fear of potential liability for failing to recommend NIPT may further drive widespread uptake. Broad social endorsement, when combined with these translation pressures, could result in the "routinization" of NIPT, thereby adversely affecting women's reproductive autonomy. Policymakers should demand robust independent evidence of clinical and public health utility relevant to their respective jurisdictions before making decisions regarding public funding for NIPT., (Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Over the past decade, epigenetic studies have been providing further evidence of the molecular interplay between gene expression and its health outcomes on one hand, and the physical and social environments in which individuals are conceived, born and live on the other. As knowledge of epigenetic programming expands, a growing body of literature in social sciences and humanities is exploring the implications of this new field of study for contemporary societies. Epigenetics has been mobilised to support political claims, for instance, with regard to collective obligations to address socio-environmental determinants of health. The idea of a moral 'epigenetic responsibility' has been proposed, meaning that individuals and/or governments should be accountable for the epigenetic programming of children and/or citizens. However, these discussions have largely overlooked important biological nuances and ambiguities inherent in the field of epigenetics. In this paper, we argue that the identification and assignment of moral epigenetic responsibilities should reflect the rich diversity and complexity of epigenetic mechanisms, and not rely solely on a gross comparison between epigenetics and genetics. More specifically, we explore how further investigation of the ambiguous notions of epigenetic normality and epigenetic plasticity should play a role in shaping this emerging debate., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Recent findings in epigenetics have been attracting much attention from social scientists and bioethicists because they reveal the molecular mechanisms by which exposure to socioenvironmental factors, such as pollutants and social adversity, can influence the expression of genes throughout life. Most surprisingly, some epigenetic modifications may also be heritable via germ cells across generations. Epigenetics may be the missing molecular evidence of the importance of using preventive strategies at the policy level to reduce the incidence and prevalence of common diseases. But while this "policy translation" of epigenetics introduces new arguments in favor of public health strategies and policy-making, a more "clinical translation" of epigenetics is also emerging. It focuses on the biochemical mechanisms and epigenetic variants at the origin of disease, leading to novel biomedical means of assessing epigenetic susceptibility and reversing detrimental epigenetic variants. In this paper, we argue that the impetus to create new biomedical interventions to manipulate and reverse epigenetic variants is likely to garner more attention than effective social and public health interventions and therefore also to garner a greater share of limited public resources. This is likely to happen because of the current biopolitical context in which scientific findings are translated. This contemporary neoliberal "regime of truth," to use a term from Michel Foucault, greatly influences the ways in which knowledge is being interpreted and implemented. Building on sociologist Thomas Lemke's Foucauldian "analytics of biopolitics" and on literature from the field of science and technology studies, we present two sociological trends that may impede the policy translation of epigenetics: molecularization and biomedicalization. These trends, we argue, are likely to favor the clinical translation of epigenetics-in other words, the development of new clinical tools fostering what has been called "personalized" or "precision" medicine. In addition, we argue that an overemphasized clinical translation of epigenetics may further reinforce this biopolitical landscape through four processes closely related to neoliberal pathways of thinking: the internalization and isolation (aspects of liberal individualism) of socioenvironmental determinants of health and increased opportunities for commodification and technologicalization (aspects of economic liberalism) of health care interventions., (© 2015 The Hastings Center.)

A rich literature in public health has demonstrated that health is strongly influenced by a host of environmental factors that can vary according to social, economic, geographic, cultural or physical contexts. Bioethicists should, we argue, recognize this and--where appropriate--work to integrate environmental concerns into their field of study and their ethical deliberations. In this article, we present an argument grounded in scientific research at the molecular level that will be familiar to--and so hopefully more persuasive for--the biomedically-inclined in the bioethics community. Specifically, we argue that the relatively new field of molecular epigenetics provides novel information that should serve as additional justification for expanding the scope of bioethics to include environmental and public health concerns. We begin by presenting two distinct visions of bioethics: the individualistic and rights-oriented and the communitarian and responsibility-oriented. We follow with a description of biochemical characteristics distinguishing epigenetics from genetics, in order to emphasize the very close relationship that exists between the environment and gene expression. This then leads to a discussion of the importance of the environment in determining individual and population health, which, we argue, should shift bioethics towards a Potterian view that promotes a communitarian-based sense of responsibility for the environment, in order to fully account for justice considerations and improve public health., (© 2012 John Wiley & Sons Ltd.)

Trust between the lay public and scientific experts is a key element to ensuring the efficient implementation of emergency public health measures. In modern risk societies, the management and elimination of risk have become preeminent drivers of public policy. In this context, the protection of public trust is a complex task. Those actors involved in public health decision-making and implementation (e.g., mass vaccination for influenza A virus) are confronted with growing pressures and responsibility to act. However, they also need to accept the limits of their own expertise and recognize the ability of lay publics to understand and be responsible for public health. Such a shared responsibility for risk management, if grounded in participative public debates, can arguably strengthen public trust in public health authorities and interventions.

Glucocorticoids (GC) are steroid hormones that modulate T cell functions and restrain their hyperresponsiveness following stimulation. Naive T lymphocytes are sensitive to GC but become more resistant when they are activated. A balance between activation and inhibition signals is important for a targeted and effective T cell response. Thermal injury is characterized by an immune dysfunction and hyperactive T cells visible at day 10 postburn. In this study, our objective was to evaluate T cell sensitivity to GC following thermal injury and to identify mechanisms that could modulate their sensitivity. One mechanism that we hypothesized was increased p38 mitogen-activated protein kinase (MAPK) activity that could lead to GC resistance. Male C57BL/6 mice underwent a full-thickness 20% total body surface area. At 10 days postinjury, splenic T cells were isolated. Glucocorticoid receptor (GR) expression was higher in T cells from burn-injured mice. Interestingly, these cells were also less sensitive to GC-induced apoptosis prior to and poststimulation. Furthermore, anti-CD3-activated T cells from burn-injured mice showed increased proliferation and CD25 expression, which resisted corticosterone's (CORT) suppressive effect. Anti-CD3-activated CD4(+)CD44(+) memory cells from burn-injured mice expressed the highest level of CD25 and were resistant to CORT. Increased phosphorylation of p38 MAPK was also noted in activated T cells from burn-injured mice. Pharmacological inhibition of p38 MAPK decreased cell proliferation and normalized interferon-gamma (IFNgamma) production. In conclusion, we demonstrate that a unique event like burn injury induces a loss of sensitivity to GC in splenic T cells and have identified p38 MAPK as a key modulator for this resistance.

System x(c)(-) transporter, formed by the association of CD98 and xCT proteins, regulates the import of cystine into cells and is poorly expressed in T lymphocytes. Thermal injury is associated with high oxidative stress, decreased levels of glutathione (GSH) and protein deficiency, all described as promoters of xCT expression and system x(c)(-) activity. T cell dysfunction is a consequence of thermal injury and has been related to oxidative stress. In order to evaluate if thermal injury induced system x(c)(-) expression in splenic T lymphocytes, cells were isolated from sham- and burn-injured mice at day 10 post-burn and cultured in 2-mercaptoethanol (2-ME)-rich and -free media. Isolated splenic T cells were stimulated and cell proliferation, system x(c)(-) expression and cystine transport activity were measured. Our results demonstrate that only burn-injured T cells express xCT and proliferate in (2-ME)-free media. In these cells, viability and CD25 expression was higher than control T cells. x(c)(-) system expression was responsible for significantly higher (14)C-cystine uptake by burn-injured T cells and its inhibition by sulfasalazine (SASP) decreased significantly their proliferation. Overall, these results demonstrate that xCT expression is induced by thermal injury in T lymphocytes and that cystine import by x(c)(-) leads to T cell dysfunction.