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Machine learning and artificial intelligence approaches have revolutionized multiple disciplines, including toxicology. This review summarizes representative recent applications of machine learning and artificial intelligence approaches in different areas of toxicology, including physiologically based pharmacokinetic (PBPK) modeling, quantitative structure-activity relationship modeling for toxicity prediction, adverse outcome pathway analysis, high-throughput screening, toxicogenomics, big data, and toxicological databases. By leveraging machine learning and artificial intelligence approaches, now it is possible to develop PBPK models for hundreds of chemicals efficiently, to create in silico models to predict toxicity for a large number of chemicals with similar accuracies compared with in vivo animal experiments, and to analyze a large amount of different types of data (toxicogenomics, high-content image data, etc.) to generate new insights into toxicity mechanisms rapidly, which was impossible by manual approaches in the past. To continue advancing the field of toxicological sciences, several challenges should be considered: (1) not all machine learning models are equally useful for a particular type of toxicology data, and thus it is important to test different methods to determine the optimal approach; (2) current toxicity prediction is mainly on bioactivity classification (yes/no), so additional studies are needed to predict the intensity of effect or dose-response relationship; (3) as more data become available, it is crucial to perform rigorous data quality check and develop infrastructure to store, share, analyze, evaluate, and manage big data; and (4) it is important to convert machine learning models to user-friendly interfaces to facilitate their applications by both computational and bench scientists.

Big data approaches have profoundly influenced state-of-the-art in many fields of research, with toxicology being no exception. Here, we use Parkinson’s disease as a window through which to explore the challenges of a dual explosion of metabolomic data addressing the myriad environmental exposures individuals experience and genetic analyses implicating many different loci as risk factors for disease. We argue that new experimental approaches are needed to convert the growing body of omics data into molecular mechanisms of disease that can be therapeutically targeted in specific patients. We outline one attractive strategy, which capitalizes on the rapid generation time and advanced molecular tools available in the fruit fly, Drosophila, to provide a platform for mechanistic dissection and drug discovery.

Environmental factors and gene-environment interactions modify the variable expressivity, progression, severity, and onset of some classic (monogenic) Mendelian-inherited genetic diseases. Cystic fibrosis, Huntington disease, Parkinson’s disease, and sickle cell disease are examples of well-known Mendelian disorders that are influenced by exogenous exposures. Environmental factors may act by direct or indirect mechanisms to modify disease severity, timing, and presentation, including through epigenomic influences, protein misfolding, miRNA alterations, transporter activity, and mitochondrial effects. Because pathological features of early-onset Mendelian diseases can mimic later onset complex diseases, we propose that studies of environmental exposure vulnerabilities using monogenic model systems of rare Mendelian diseases have high potential to provide insight into complex disease phenotypes arising from multi-genetic/multi-toxicant interactions. Mendelian disorders can be modeled by homologous mutations in animal model systems with strong recapitulation of human disease etiology and natural history, providing an important advantage for study of these diseases. Monogenic high penetrant mutations are ideal for toxicant challenge studies with a wide variety of environmental stressors, because background genetic variability may be less able to alter the relatively strong phenotype driving disease-causing mutations. These models promote mechanistic understandings of gene-environment interactions and biological pathways relevant to both Mendelian and related sporadic complex disease outcomes by creating a sensitized background for relevant environmental risk factors. Additionally, rare disease communities are motivated research participants, creating the potential of strong research allies among rare Mendelian disease advocacy groups and disease registries and providing a variety of translational opportunities that are under-utilized in genetic or environmental health science.

Recent studies implicate mitochondrial dysfunction in the development and progression of numerous chronic diseases, which may be partially due to modifications in mitochondrial DNA (mtDNA). There is also mounting evidence that epigenetic modifications to mtDNA may be an additional layer of regulation that controls mitochondrial biogenesis and function. Several environmental factors (eg, smoking, air pollution) have been associated with altered mtDNA methylation in a handful of mechanistic studies and in observational human studies. However, little is understood about other environmental contaminants that induce mtDNA epigenetic changes. Numerous environmental toxicants are classified as endocrine disrupting chemicals (EDCs). Beyond their actions on hormonal pathways, EDC exposure is associated with elevated oxidative stress, which may occur through or result in mitochondrial dysfunction. Although only a few studies have assessed the impacts of EDCs on mtDNA methylation, the current review provides reasons to consider mtDNA epigenetic disruption as a mechanism of action of EDCs and reviews potential limitations related to currently available evidence. First, there is sufficient evidence that EDCs (including bisphenols and phthalates) directly target mitochondrial function, and more direct evidence is needed to connect this to mtDNA methylation. Second, these and other EDCs are potent modulators of nuclear DNA epigenetics, including DNA methylation and histone modifications. Finally, EDCs have been shown to disrupt several modulators of mtDNA methylation, including DNA methyltransferases and the mitochondrial transcription factor A/nuclear respiratory factor 1 pathway. Taken together, these studies highlight the need for future research evaluating mtDNA epigenetic disruption by EDCs and to detail specific mechanisms responsible for such disruptions.

Cigarette smoking during pregnancy is associated with numerous obstetrical, fetal, and developmental complications, as well as an increased risk of adverse health consequences in the adult offspring. Nicotine replacement therapy and electronic nicotine delivery systems (e-cigarettes) have been developed as a pharmacotherapy for smoking cessation and are considered safer alternatives for women to smoke during pregnancy. The safety of nicotine replacement therapy use during pregnancy has been evaluated in a limited number of short-term human trials, but there is currently no information on the long-term effects of developmental nicotine exposure in humans. However, animal studies suggest that nicotine alone may be a key chemical responsible for many of the long-term effects associated with maternal cigarette smoking on the offspring and increases the risk of adverse neurobehavioral outcomes, dysmetabolism, respiratory illness, and cancer. This review will examine the long-term effects of fetal and neonatal nicotine exposure on postnatal health.

The development of the exposome concept has been one of the hallmarks of environmental and health research for the last decade. The exposome encompasses the life course environmental exposures including lifestyle factors from the prenatal period onwards. It has inspired many research programs and is expected to influence environmental and health research, practices, and policies. Yet, the links bridging toxicology and the exposome concept have not been well developed. In this review, we describe how the exposome framework can interface with and influence the field of toxicology, as well as how the field of toxicology can help advance the exposome field by providing the needed mechanistic understanding of the exposome impacts on health. Indeed, exposome-informed toxicology is expected to emphasize several orientations including (1) developing approaches integrating multiple stressors, in particular chemical mixtures, as well as the interaction of chemicals with other stressors, (2) using mechanistic frameworks such as the adverse outcome pathways to link the different stressors with toxicity outcomes, (3) characterizing the mechanistic basis of long-term effects by distinguishing different patterns of exposures and further exploring the environment-DNA interface through genetic and epigenetic studies, and (4) improving the links between environmental and human health, in particular through a stronger connection between alterations in our ecosystems and human toxicology. The exposome concept provides the linkage between the complex environment and contemporary mechanistic toxicology. What toxicology can bring to exposome characterization is a needed framework for mechanistic understanding and regulatory outcomes in risk assessment.

The majority of embolic strokes in patients with nonvalvular atrial fibrillation are caused by thrombi in the left atrial appendage. It is projected that strokes related to atrial fibrillation will markedly increase in the future unless effective mitigation strategies are implemented. Systemic anticoagulation has been known to be highly effective in reducing stroke risk in patients with atrial fibrillation. However, bleeding complications and nonadherence are barriers to effective anticoagulation therapy. Surgical and percutaneous left atrial appendage occlusion devices are nonpharmacologic strategies to mitigate the challenges of drug therapy. We present a contemporary review of left atrial appendage occlusion for stroke prevention in nonvalvular atrial fibrillation. A thorough review of the history of surgical and percutaneous left atrial appendage occlusion devices, recent trials, and US Food and Drug Administration milestones of current left atrial appendage occlusion devices are discussed.

Irisin, a novel hormone like polypeptide, is cleaved and secreted by an unknown protease from a membrane‐spanning protein, FNDC5 (fibronectin type III domain‐containing protein 5). The current knowledge on the biological functions of irisin includes browning white adipose tissue, regulating insulin use, and anti‐inflammatory and antioxidative properties. Dysfunction of irisin has shown to be involved in cardiovascular diseases such as hypertension, coronary artery disease, myocardial infarction, and myocardial ischemia–reperfusion injury. Moreover, irisin gene variants are also associated with cardiovascular diseases. In this review, we discuss the current knowledge on irisin‐mediated regulatory mechanisms and their roles in the pathogenesis of cardiovascular diseases.

The congenital heart care community faces a myriad of public health issues that act as barriers toward optimum patient outcomes. In this article, we attempt to define advocacy and policy initiatives meant to spotlight and potentially address these challenges. Issues are organized into the following 3 key facets of our community: patient population, health care delivery, and workforce. We discuss the social determinants of health and health care disparities that affect patients in the community that require the attention of policy makers. Furthermore, we highlight the many needs of the growing adults with congenital heart disease and those with comorbidities, highlighting concerns regarding the inequities in access to cardiac care and the need for multidisciplinary care. We also recognize the problems of transparency in outcomes reporting and the promising application of telehealth. Finally, we highlight the training of providers, measures of productivity, diversity in the workforce, and the importance of patient–family centered organizations in advocating for patients. Although all of these issues remain relevant to many subspecialties in medicine, this article attempts to illustrate the unique needs of this population and highlight ways in which to work together to address important opportunities for change in the cardiac care community and beyond. This article provides a framework for policy and advocacy efforts for the next decade.

Criteria for diagnosis of arrhythmogenic cardiomyopathy (ACM) were first proposed in 1994 and revised in 2010 by a Task Force. Although the Task Force criteria demonstrated a good accuracy for diagnosis of the original right ventricular phenotype (arrhythmogenic right ventricular cardiomyopathy), they lacked sensitivity for identification of the expanding phenotypic spectrum of ACM, which includes left‐sided variants and did not incorporate late‐gadolinium enhancement findings by cardiac magnetic resonance. The 2020 International criteria (“Padua criteria”) have been developed by International experts with the aim to improve the diagnosis of ACM by providing new criteria for the diagnosis of left ventricular phenotypic features. The key upgrade was the incorporation of tissue characterization findings by cardiac magnetic resonance for noninvasive detection of late‐gadolinium enhancement/myocardial fibrosis that are determinants for characterization of arrhythmogenic biventricular and left ventricular cardiomyopathy. The 2020 International criteria are heavily dependent on cardiac magnetic resonance, which has become mandatory to characterize the ACM phenotype and to exclude other diagnoses. New criteria regarding left ventricular depolarization and repolarization ECG abnormalities and ventricular arrhythmias of left ventricular origin were also provided. This article reviews the evolving approach to diagnosis of ACM, going back to the 1994 and 2010 International Task Force criteria and then grapple with the modern 2020 International criteria.

Radiation therapy demonstrates a clear survival benefit in the treatment of several malignancies. However, cancer survivors can develop a wide array of cardiotoxic complications related to radiation. This pathology is often underrecognized by clinicians and there is little known on how to manage this population. Radiation causes fibrosis of all components of the heart and significantly increases the risk of coronary artery disease, cardiomyopathy, valvulopathy, arrhythmias, and pericardial disease. Physicians should treat other cardiovascular risk factors aggressively in this population and guidelines suggest obtaining regular imaging once symptomatology is established. Patients with radiation‐induced cardiovascular disease tend to do worse than their traditional counterparts for the same interventions. However, there is a trend toward fewer complications and lower mortality with catheter‐based rather than surgical approaches, likely because radiation makes these patients poor surgical candidates. When appropriate, these patients should be referred for percutaneous management of valvulopathy and coronary disease.

Delayed cerebral ischemia is a major predictor of poor outcomes in patients who suffer subarachnoid hemorrhage. Treatment options are limited and often ineffective despite many years of investigation and clinical trials. Modern advances in basic science have produced a much more complex, multifactorial framework in which delayed cerebral ischemia is better understood and novel treatments can be developed. Leveraging this knowledge to improve outcomes, however, depends on a holistic understanding of the disease process. We conducted a review of the literature to analyze the current state of investigation into delayed cerebral ischemia with emphasis on the major themes that have emerged over the past decades. Specifically, we discuss microcirculatory dysfunction, glymphatic impairment, inflammation, and neuroelectric disruption as pathological factors in addition to the canonical focus on cerebral vasospasm. This review intends to give clinicians and researchers a summary of the foundations of delayed cerebral ischemia pathophysiology while also underscoring the interactions and interdependencies between pathological factors. Through this overview, we also highlight the advances in translational studies and potential future therapeutic opportunities.