Mitochondria as a Target of Environmental Toxicants

Look into any cell today, and you’ll see remnants of ancient bacteria by the thousands. These mitochondria—tiny organelles in the cell that each possess their own DNA—have come under a growing scientific spotlight; scientists increasingly believe they play a central role in many, if not most, human illnesses. Exquisitely sensitive to environmental threats, mitochondria convert dietary sugars into a high-energy molecule—adenosine triphosphate (ATP)—that cells use as fuel. And when mitochondria falter, cells lose power, just as a flashlight dims when its batteries weaken. Now scientists are linking environmental interactions with the mitochondria to an array of metabolic and age-related maladies, including cancer, autism, type 2 diabetes, Alzheimer disease, Parkinson disease, and cardiovascular illness.

In this issue of Environmental Health Perspectives, Feingold et al. (2010) propose a unique step forward for toxicology: incorporating infectious disease agents and theory into the toxicological paradigm. The fields of infectious disease and toxicology intersect on many different levels. First, they can act concurrently, as when global bands of various tropical diseases widen due to increased atmospheric temperatures. For example, in A Human Health Perspective on Climate Change, the Interagency Working Group on Climate Change and Health (2010) identified health effects from climate change, as well as the health benefits from mitigating climate change. These various health effects range from respiratory and cardiovascular disease, to developmental and neurological disorders, to food- and waterborne illness, and vectorborne and zoonotic disease. It is increasingly clear that climate change—a marquee issue in the field of environmental health—and infectious disease are linked. Second, the two fields can also act antagonistically: For example, the newly renewed appeals for global use of DDT (dichlorodiphenyltrichloroethane) to combat malaria will pit the well-known hazardous effects of DDT against the scourge of malaria. In many countries DDT has been banned for agricultural use; it is considered a Class II or “moderately hazardous” pesticide by the World Health Organization (International Programme on Chemical Safety 2005), and its use is strictly limited by the 2001 Stockholm Convention. However, use of DDT is still permitted for vector control. This balance of risks and benefits is a conundrum for scientists and policy makers, but it reveals the serious issues raised when infectious disease and environmental health interests clash. Third, these two disciplines can act synergistically, as in the interactions between hepatitis B and aflatoxin in hepatic cancer. Both hepatitis B and aflatoxin are independent factors in liver cancer. However, when combined, they act powerfully to raise the risk of hepatic cancer up to 60 times that of unexposed individuals (Groopman et al. 2005). This National Institute of Environmental Health Sciences (NIEHS)-funded research is a primary example of the interaction between environmental health and infectious disease and can serve as a model for future research efforts. Supression of the immune response by polychlorinated biphenyls (PCBs) was first shown in mice and nonhuman primates. Recently, in another example of concurrent interaction, NIEHS-funded studies led by Philippe Grandjean have shown that perinatal and developmental exposure to PCBs adversely impact immune responses to childhood vaccinations (Heilmann et al. 2006, 2010). We have an opportunity at the NIEHS to embrace this new paradigm. As we have shown with our investment in research into the aflatoxin–hepatitis B and PCB–vaccine interactions, the NIEHS has a track record that could promote a wider interest in this field of inquiry. Ideas like these are supported not only at the institute level but also throughout the National Institutes of Health (NIH). Recently, NIH director Francis Collins (2010b) wrote, “NIH can play a major role in ramping up the discovery of novel targets in both pathogen and host and work to facilitate advances in prevention . . . .” Collins (2010a) also wrote, “the best outcomes are generally when you don’t have walls between parts of the organization that prevent people from learning from each other.” A recent presentation at the NIEHS outlined a vision for the institute that included the infectious disease and environmental health intersection within the context of the rapid evolution in the field of environmental health, specifically in epigenetics. As we recognize that our old assumptions about toxicants and how they affect our bodies are being changed by modern science (e.g., exposure effects are not only dose dependent but are also affected by both time and context), the field of environmental health is moving fast and the NIEHS needs to be at the front with innovative, bold ideas so we can participate and lead with the best science possible. The idea of incorporating infectious disease into the toxicological paradigm is exactly the kind of pioneering concept that can take environmental health to the next level. The NIEHS Office of the Director will be working with division leaders to develop an initiative on infectious disease and environmental health—to incorporate infectious disease into the toxicological paradigm. We look forward to the possibilities to strengthen the field of environmental health science.

It has been more than 2 years since Environmental Health and Toxicology (EHT) was converted to an online, open access, English-only journal. EHT established an online submission system and was indexed successfully in the international database PubMed. Now, at least as a matter of form, EHT seems to have reached the first milestone on the way toward its goal of being a truly distinguished international academic journal in the field of environmental health and toxicology. However, EHT still has some tasks to accomplish in order to reach the final goal. EHT aims to be a place where multidisciplinary fields of science related to the environment, that is, toxicology, chemistry, risk assessment, biostatistics, exposure assessment, and epidemiology, converge and are integrated. In particular, we are dedicated to making it a leading academic journal in the Asian region. The topics we want EHT to deal with range broadly from ecotoxicology to climate change and health policy, from micro to macro science, from a regional to a global scale. To reach our target, EHT must overcome some obstacles. First, EHT needs more manuscript submissions. EHT welcomes not only original articles, but also diverse types of manuscripts, including systematic reviews or meta-analyses, reviews of meetings or conferences, brief reports, investigative reports, case reports, special topics, perspectives, editorials, letters to the editor, debates, and hypotheses. Specifically, EHT embraces descriptive studies in relation to basic indices of environmental exposure, health, and toxicology. Globalization of the members of the editorial board as well as the authorship of and topics of published articles is also very important. Timely article series dealing with environmental issues that are currently drawing a great deal of attention should be organized. Second, EHT should increase its visibility so that more readers worldwide can encounter the manuscripts we publish. For this, the journal needs to be indexed in more international academic databases. The unofficial impact factor of EHT during 2011-2012 was 0.38, which is not bad as a starting point within the international academic publishing community. Third, EHT should enforce the principles and screening system for publication ethics. Scientific journals are places where the three important stakeholders in the community of peer-reviewed science meet: editors and publishers, authors, and reviewers. Here, during the process of manuscript submission, reviewing, and publication of a journal, screening for scientific errors or ethical problems and checking and improving scientific soundness are performed. EHT needs to adopt up-to-date technology to screen for misconduct in scientific research and publication. In 2013, EHT is at a crossroads. We can fall behind or jump forward.

A workshop titled "Using Sentinel Species Data to Address the Potential Human Health Effects of Chemicals in the Environment," sponsored by the U.S. Army Center for Environmental Health Research, the National Center for Environmental Assessment of the EPA, and the Agency for Toxic Substances and Disease Registry, was held to consider the use of sentinel and surrogate animal species data for evaluating the potential human health effects of chemicals in the environment. The workshop took a broad view of the sentinel species concept, and included mammalian and nonmammalian species, companion animals, food animals, fish, amphibians, and other wildlife. Sentinel species data included observations of wild animals in field situations as well as experimental animal data. Workshop participants identified potential applications for sentinel species data derived from monitoring programs or serendipitous observations and explored the potential use of such information in human health hazard and risk assessments and for evaluating causes or mechanisms of effect. Although it is unlikely that sentinel species data will be used as the sole determinative factor in evaluating human health concerns, such data can be useful as for additional weight of evidence in a risk assessment, for providing early warning of situations requiring further study, or for monitoring the course of remedial activities. Attention was given to the factors impeding the application of sentinel species approaches and their acceptance in the scientific and regulatory communities. Workshop participants identified a number of critical research needs and opportunities for interagency collaboration that could help advance the use of sentinel species approaches.

Obesity, diabetes, and their cardiovascular and hepatic comorbidities are alarming public health issues of the twenty-first century, which share mitochondrial dysfunction, oxidative stress, and chronic inflammation as common pathophysiological mechanisms. An increasing body of evidence links the combined exposure to multiple environmental toxicants with the occurrence and severity of metabolic diseases. Endocrine disruptors (EDs) are ubiquitous chemicals or mixtures with persistent deleterious effects on the living organisms beyond the endocrine system impairment; in particular, those known as metabolism-disrupting chemicals (MDCs), increase the risk of the metabolic pathologies in adult organism or its progeny. Being largely lipophilic, MDCs mainly target the adipose tissue and elicit mitochondrial dysfunction by interfering with mitochondrial bioenergetics, biogenesis, dynamics and/or other functions. Plastics, when broken down into micro- and nano-plastics (MNPs), have been detected in several human tissues, including the liver. The harmful interplay between inflammatory and redox processes, which mutually interact in a positive feed-back loop, hence the term oxidative inflammation ("OxInflammation"), occurs both at systemic and organ level. In both liver and adipose tissue, oxinflammation contributes to the progression of the metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, it has been reported that individuals with MASLD may be more susceptible to the harmful effects of toxicants (mainly, those related to mitochondria) and that chronic exposure to EDs/MDCs or MNPs may play a role in the development of the disease. While liver has been systematically investigated as major target organ for ambient chemicals, surprisingly, less information is available in the literature with respect to the adipose tissue. In this narrative review, we delve into the current literature on the most studied environmental toxicants (bisphenols, polychlorinated biphenyls, phthalates, tolylfluanid and tributyltin, per-fluoroalkyl and polyfluoroalkyl substances, heavy metals and MNPs), summarize their deleterious effects on adipose tissue, and address the role of dysregulated mitochondria and oxinflammation, particularly in the setting of MASLD.

Advancing Knowledge on the Environment and Its Impact on Health, and Meeting the Challenges of Global Environmental Change

Guest Editorial: Global Perspective on Environmental Health

Hemispheres of Influence: Bridging the Disconnect between Environmental Neurotoxicology and Clinical Practice.

Human Exposure Estimates for Phthalates

Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: executive summary

Background: Even in the field of climate change and environmental health there is a need to for robust, systematic and transparent methods of research synthesis to define policy and support decision makers. Environmental and research agencies have started to translate methods from evidence-based medicine into environmental health. In the field of exposure to heatwaves, public health interventions have been implemented in several countries with a poor or lacking evidence-base. This systematic review is focused on public health interventions aimed to reduce, in the short or in the long-term, the adverse effects of high temperatures and heatwaves. Methods: We searched Pubmed, Embase and other bibliographic databases to identify relevant studies (inception-July 2015) using a detailed search strategies. Inclusion criteria were: RCT and observational studies with a control group and quantitative effect measures. Two reviewers extracted data independently and assessed risk of bias using a modified version of the Cochrane risk of bias tool. Results: We identified 6323 records of which 8 studies met all inclusion criteria. Included studies had a very high risk of selection bias, contamination and heterogeneity in study design prohibited a meta-analysis. They showed weak evidence on effectiveness for educational and home interventions (2 RCT); limited evidence on cooling measures (2 cohort studies), and urban interventions (4 CBA). Conclusions: Evidence on the effectiveness of interventions in the field of heat prevention is limited and not conclusive due to the exposure characteristics and the risk of bias associated to nonrandomized studies. Despite the uptake of systematic methods is promising in the field of environmental health, the process for the synthesis of evidence needs improvements and discussion.

In the preface1 to this supplement, we pointed out that pediatricians and other clinicians have made major contributions to the discovery of environmental toxicants. Many acute illnesses that are caused by high exposures to some toxicants are clinically diagnosable or at least are commonly in the differential diagnosis, eg, organophosphate poisoning, infant botulism, acute lead encephalopathy, carbon monoxide poisoning, acrodynia, hypervitaminosis A and some cases of aplastic anemia, convulsions, asthma, respiratory distress, methemoglobinemia, Reyes syndrome, kernicterus, and many of the recognizable syndromes that result from exposures to teratogenic drugs and chemicals. In contrast to the obvious effects of high exposures to environmental toxicants, there is less information and less certainty concerning the magnitude of the contribution of many low exposures of environmental toxicants to morbidity, mortality, and subtle alterations in children as well as adults or how the effects of these exposures vary with age or chronicity of exposure. We also informed the readership that we were going to address the issue of environmental toxicology from both a clinical and a toxicologic viewpoint. Very low exposures to environmental toxicants may lead to diseases that resemble many common illnesses that have other causes, or they may lead to decrements in functioning that are subtle or nonspecific. It is an almost insurmountable task for individual practitioners to conclude a cause-and-effect relationship from low exposures to environmental toxicants among patients in the physician’s patient population. Only well-planned, sophisticated epidemiologic and animal studies can answer the questions that pertain to the toxicity of low-level exposures to environmental toxicants, given that not all individuals will be affected equally, if at all, at any particular level of exposure. Many of the previous multi-authored compendia that have been published by groups of scientists have been unified in their conclusions that environmental toxicants are a very serious … Reprint requests to (R.L.B.) Rm 308, R/A, Alfred I. duPont Hospital for Children, Box 269, Wilmington, DE 19899. E-mail rbrent{at}nemours.org

BackgroundControl of leishmaniasis in the Mediterranean Basin relies on the active contributions from researchers in the fields of animal, human and environmental health. The application of knowledge, perceptions and practices (KPP) questionnaires to health students and professionals in Europe could be fundamental to identify and explore gaps in KPP, highlighting the diversity of conceptions related to this disease between students and professionals active in (One) Health. The objective of this study was to characterize and compare the current knowledge, perceptions and practices regarding leishmaniasis among subgroups of students and health professionals in Portugal through the application of an online questionnaire.MethodsA cross-sectional study targeted the population of health students and professionals in Portugal, including students in medicine, veterinary medicine and environmental health, physicians, veterinarians and environmental health technicians. Potential participants were approached by email via universities and professional societies and organizations and provided with the link to access the online questionnaire. Answers to the self-administered sociodemographic and KPP questionnaire were collected between July and December 2022. Individual KPP scores were calculated by summing grades defined for each question. Logistic regression models were used to search for potential associations, and the results were expressed at estimated crude and adjusted odds ratios with 95% confidence intervals.ResultsIn total, 486 participants were included in this study: 254 students and 232 professionals. Overall, 75% of the participants reported having heard of both human and animal leishmaniasis, and > 80% reported hearing about the disease during their course work (although this was significantly lower among those in the field of environmental health). Around 90% of participants identified the pathogenic agent as a parasite, and an arthropod bite was identified as the main route of transmission by > 95%. Animal leishmaniasis was considered to be diagnosed in Portugal by 87% of participants and human leishmaniasis by only 69%. The main barriers pointed out by professionals to the control of leishmaniasis were: lack of knowledge in the general population, failures in the early diagnosis and treatment of diseased animals, absence/inefficacy of vector control programs and lack of knowledge in human health professionals. Median knowledge and perception scores were higher among professionals in the animal health field and higher in professionals than in students. Median practice scores were not significantly different between groups and subgroups. The multivariate analysis revealed that a longer period of study (for students) and having seen cases of leishmaniasis (for physicians) were associated with above-mentioned median knowledge score.ConclusionsMost health students and professionals are knowledgeable about the cause and transmission route of leishmaniasis. However, recognition of the disease as autochthonous in humans is less common, highlighting the importance of promoting an approach to this infection through a One-Health lens. A national structured plan to control leishmaniasis could overcome some of the barriers pointed out by professionals, namely by implementing systematic phlebotomine surveillance and integrated reporting of animal and human cases of disease.Graphical abstract

Use of genome editing tools in environmental health research

Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: executive summary