Current Opinion in Toxicology

With extensive use in industrial and agriculture applications, overexposure to heavy metals has become a global public health concern. The nervous system is vulnerable to many heavy metals, including cadmium, lead, and mercury. However, the knowledge about the underlying mechanisms of these metals' neurotoxicity is still very limited. Adult neurogenesis is a process of generating functional neurons from adult neural progenitor/stem cells (aNPCs), which plays an important role in cognitive function and olfaction...

Children are constantly exposed to a wide range of environmental factors including essential and non-essential metals. In recent years, the mixtures paradigm has emerged to foster the examination of combined effects that emerge from exposures to multiple elements. In this review, we summarized recent literature studying the relationship between prenatal and childhood metal mixtures with neurodevelopmental outcomes. Our review highlights two basic principles to emerge from this approach. First, recent findings emphasize that the effect of a given exposure is contextual and may be dependent on past or concurrent metal exposures...

Lead (Pb2+ ) exposure is a global public health problem of major proportion with an alarming number of children with blood Pb2+ levels > 10 >g/dL, twice the current CDC reference level for Pb2+ exposure. Mounting evidence from population-based studies suggests an association between chronic early life Pb2+ exposure (CELLE) and psychiatric disorders, specifically schizophrenia (SZ). Preclinical studies suggest a common mechanism in the pathophysiology of CELLE and SZ, NMDA receptor hypofunction. Here we describe human and experimental animal studies providing the evidence for such an association...

Toxic and essential elements are widely distributed in the Earth's crust and individuals may be exposed to several of them. Indeed, exposure to toxic elements such as mercury (Hg) can be a potential health risk factor of health, mainly by ingestion of fish containing methylmercury (MeHg). On the other hand, essential elements such as manganese (Mn) play an important role in physiological process in human body. However, Mn overexposure may cause toxic effects. In this respect, the neurotoxic effects of MeHg and Mn on the developing brain are well recognized...

Neurological symptoms occur in approximately one-third of hospitalized patients with coronavirus disease 2019 (COVID-19). Among these symptoms, hypoxic encephalopathy develops in one-fifth of severe cases, while ischemic strokes due to thrombotic complications are common in one-third of COVID-19 intensive care patients. Brain involvement of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is eventuated by several routes, including hematogenous spread, transsynaptic entry through infected neurons, olfactory nerve, ocular epithelium, vascular endothelium, and impaired blood-brain barrier...

New approach methodologies (NAMs) refer to any non-animal technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment that avoids the use of intact animals. A spectrum of in silico models is needed for the integrated analysis of various domains in toxicology to improve predictivity and reduce animal testing. This review focuses on in silico approaches, computer models, and computational intelligence for developmental and reproductive toxicity (predictive DART), providing a means to measure toxicodynamics in simulated systems for quantitative prediction of adverse outcomes phenotypes...

A major goal of translational toxicology is to identify adverse chemical effects and determine whether they are conserved or divergent across experimental systems. Translational toxicology encompasses assessment of chemical toxicity across multiple life stages, determination of toxic mode-of-action, computational prediction modeling, and identification of interventions that protect or restore health following toxic chemical exposures. The zebrafish is increasingly used in translational toxicology because it combines the genetic and physiological advantages of mammalian models with the higher-throughput capabilities and genetic manipulability of invertebrate models...

Cytochrome P4501A (CYP1A) enzymes play important roles in xenobiotic and endobiotic metabolism. Due to uncoupling reactions during the enzymatic cycle, CYP1A enzymes can release reactive oxidative species (ROS) in the form of superoxide radical, hydrogen peroxide, hydroxyl radical etc. An imbalance between production of free radicals and the ability of antioxidants to detoxify the free radicals can lead to accumulation of ROS, which in turn can lead to oxidative stress. Oxidative stress can lead to inflammation and toxicity, which in turn can cause human diseases such as bronchopulmonary disease (BPD), ARDS, renal hypertension, etc...

Acetaminophen is a widely used analgesic and antipyretic, which can cause liver injury after an overdose. Although a controversial topic for some time, solid evidence for a critical role of oxidative and nitrosative stress has emerged during the last two decades. This review will discuss the cellular sources, amplification mechanisms and the consequences of the excessive formation of reactive oxygen and nitrogen species in the clinically relevant mouse model of acetaminophen hepatotoxicity. This new mechanistic insight contributes to the better understanding of the mechanism of action of N-acetylcysteine, the only clinically approved antidote...

The human gut microbiome is considered critical for establishing and maintaining intestinal function and homeostasis throughout life. Evidence for bidirectional communication with the immune and nervous systems has spawned interest in the microbiome as a key factor for human and animal health. Consequently, appreciation of the microbiome as a target of xenobiotics, including environmental pollutants such as heavy metals, has risen steadily because disruption of a healthy microbiome (dysbiosis) has been linked to unfavorable health outcomes...

Daily oral exposure to vast numbers (>1013 /adult/day) of micron or nano-sized persistent particles has become the norm for many populations. Significant airborne particle exposure is deleterious, so what about ingestion? Titanium dioxide in food grade form (fgTiO2 ) , which is an additive to some foods, capsules, tablets and toothpaste, may provide clues. Certainly, exposed human populations accumulate these particles in specialised intestinal cells at the base of large lymphoid follicles (Peyer's patches) and it's likely that a degree of absorption goes beyond this- i...

We are continuously exposed to large numbers of non-biological, persistent particulates through dermal, oral and inhalation routes. At sizes perfect for cell interactions, such modern particle exposures are derived from human engineering either purposefully (e.g. additives/excipients) or inadvertently (e.g. pollution). Whether oral or dermal exposure to common particles has significantly adverse effects is not yet known. However, relationships between increased morbidity or mortality and airborne particle exposure are well established...

Epigenetics refers to the study of mitotically heritable and potentially reversible changes in gene expression unrelated to the DNA sequence itself, influenced by epigenetic marks including chromatin modifications, non-coding RNA and alterations to DNA itself via methylation and hydroxymethylation. Epigenetics has taken center stage in the study of diseases such as cancer, diabetes, and neurodegeneration; however, its integration into the field of environmental health sciences and toxicology (e.g. Toxicoepigenetics) is in its infancy...

The nature and types of genome editing tools are rapidly expanding and becoming increasingly incorporated into research efforts aimed at understanding human disease. The majority of research involving genome editing has been driven by medical research, with a limited but increasing number of studies currently published in the field of environmental health and toxicology. This review aims to address this research gap by providing a high-level summary of current genome editing techniques and presenting examples of how some of these techniques have been used toxicologically to evaluate environmental exposure-induced disease...

Next generation sequencing (NGS) represents several powerful platforms that have revolutionized RNA and DNA analysis. The parallel sequencing of millions of DNA molecules can provide mechanistic insights into toxicology and provide new avenues for biomarker discovery with growing relevance for risk assessment. The evolution of NGS technologies has improved over the last decade with increased sensitivity and accuracy to foster new biomarker assays from tissue, blood and other biofluids. NGS sequencing technologies can identify transcriptional changes and genomic targets with base pair precision in response to chemical exposure...

Public databases provide a wealth of freely available information about chemicals, genes, proteins, biological networks, phenotypes, diseases, and exposure science that can be integrated to construct pathways for systems toxicology applications. Relating this disparate information from public repositories, however, can be challenging since databases use a variety of ways to represent, describe, and make available their content. The use of standard vocabularies to annotate key data concepts, however, allows the information to be more easily exchanged and combined for discovery of new findings...

Currently, there is no single taxonomy for organizing data on the various types of chemical interactions that may affect risks from combined exposures. A taxonomy of chemical interactions is proposed that is based on a combination of the aggregate exposure pathways (AEPs) and adverse outcome pathways (AOPs) (AEP-AOP framework). The AEP-AOP framework organizes data on the causal events that ocur over the entire source-exposure-response continuum of a chemical's release. The proposed taxonomy uses this framework in two ways...

Research consortia play a key role in our understanding of how environmental exposures influence health and wellbeing, especially in the case of catastrophic events such as the Deepwater Horizon oil spill. A common challenge that prevents the optimal use of these data is the difficulty of harmonizing data regarding the environmental exposures and health effects across the studies within and among consortia. A review of the measures used by members of the Deepwater Horizon Research Consortia highlights the challenges associated with balancing timely implementation of a study to support disaster relief with optimizing the long-term value of the data...

As systems biology expands its multi-omic spectrum to increasing resolutions, distinguishing cells based on single-cell profiles becomes feasible. Unlike traditional bulk assays that average cellular responses and blur the distinct identities of responsive cells, single-cell technologies enable sensitive detection of small cellular changes and precise identification of those cells perturbed by toxicants. Among the suite of omic technologies that continue to expand and become affordable, single-cell RNA sequencing (scRNA-seq) is at the cutting edge and leading the way to transform systems toxicology...

The more than 80,000 chemicals in commerce present a challenge for hazard assessments that toxicity testing in the 21st century strives to address through high-throughput screening (HTS) assays. Assessing chemical effects on human development adds an additional layer of complexity to the screening, with a need to capture complex and dynamic events essential for proper embryo-fetal development. HTS data from ToxCast/Tox21 informs systems toxicology models, which incorporate molecular targets and biological pathways into mechanistic models describing the effects of chemicals on human cells, 3D organotypic culture models, and small model organisms...