Special Issue "Developmental Neurotoxicology"
A special issue of Toxics (ISSN 2305-6304).
Deadline for manuscript submissions: closed (15 May 2014)
Professor David R. Wallace
Oklahoma State University, Center for Health Sciences, 1111 West 17th Street, Tulsa, Oklahoma 74107-1898, USA
Phone: +918 561 1407 Cell: +918 230 8524
Fax: +918 561 5729 Lab: +918 561 5784
Interests: environmental toxins; heavy metals; pesticides; developmental neurotoxicity; neurochemical & cellular mechanisms of toxicity
There has been heightened awareness of neuroscience research since the “Decade of the Brain” which ran from 1990–2000. Significant advances have been made in many areas of brain research from behavioral to degenerative, yet work in developmental neurotoxicology (DNT) has lagged. First, there is the difficulty of translating animal/alternate model systems to the human condition that has slowed progress in this field. The developing brain is extremely sensitive to insult from exogenous xenobiotics. Of the 1,000’s of chemicals that are commercially available, only about 200–300 have known DNT properties. The list of nearly 100 well established toxic compounds includes compounds from heavy metals (cadmium and methylmercury), to prescription drugs (haloperidol and diazepam), and legal ‘drugs’ (caffeine and salicylate), as well as illicit drugs (cocaine and LSD). Approximately 100 compounds have minimal or incomplete evidence of DNT which includes some pesticides (organophosphates), prescription drugs and a variety of other chemicals. It is clear that the developing brain is highly susceptible to toxic insult, yet this sensitivity is not confined to in utero exposure, but also throughout infant, toddler, and pre-teen adolescent neurodevelopment. Contrary to mixtures of many different chemicals found in commercially available preparations or in the environment, neurotoxicity testing consists of examining a single compound. This is a confounding element that needs to be addressed in future studies. The possibility exists that two or more compounds alone have tested to be non-toxic, but when present in a mixture, they may have a potentiating or synergist effect. Additional research is needed to identify appropriate model systems to study DNT effects which will improve the translation from alternative to human model systems. Also, additional work is needed to identify and develop accurate biomarkers which will signal exposure to DNT compounds early in the exposure period, facilitating medical intervention.
Professor David R. Wallace
Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
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- animal models
- in vitro testing
- risk assessment
Toxics 2014, 2(2), 165-187; doi:10.3390/toxics2020165
Received: 24 February 2014; in revised form: 12 May 2014 / Accepted: 13 May 2014 / Published: 20 May 2014| PDF Full-text (632 KB)
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
Title: Developmental Exposure to Perfluorooctane Sulfonate (PFOS) and T Cell Indicators of Autoimmunity
Authors: Qing Hu, Jason N. Franklin, Ian Bryan, Erin Morris, Andrew Wood, and Jamie DeWitt
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC
Abstract: An immunopathology reported in some patients with neurodevelopmental disorders is development of autoantibodies against brain-specific proteins, suggesting impacts to regulatory T cells (Tregs). Perfluorooctane sultanate (PFOS) is an environmental pollutant that induces developmental immunotoxicity. Our hypothesis was that developmental exposure to PFOS would affect the number and/or function of Tregs and increase autoimmune risk in offspring. In immunocompetent male and female C57BL/6 mouse offspring exposed to 0.02, 0.2, or 2 mg/kg of PFOS during gestation and lactation, splenic Treg number and function, serum markers of autoreactivity, and levels of myelin basic protein and T cell infiltration in the cerebella were evaluated. Splenic Treg numbers from male offspring of dams exposed to all doses of PFOS were reduced by 25%, on average. Levels IL-10 released from splenic Tregs cultured ex vivo was elevated in male offspring of dams exposed to 0.02 mg/kg PFOS and in female offspring of dams exposed to 0.2 mg/kg PFOS. Oppositely, levels of IL-10 released from splenic Tregs cultured ex vivo was reduced in male offspring of dams exposed to 0.2 mg/kg PFOS and in female offspring of dams exposed to 0.02 mg/kg PFOS. No other endpoints were statistically different by dose for offspring of dams exposed to PFOS. Our data demonstrate that PFOS affects the number of Tregs and may affect the ability of ex vivo Tregs to release IL-10. While our results are far from predictive of risk, they do indicate that certain cells of the immune system can be altered by developmental exposure to PFOS. In genetically susceptible individuals who experience the “right” combination of causes and triggers, developmental exposure to PFOS may tip the balance from health to disease.
Type of Paper: Review
Title: Multifactorial Origin of Neurodevelopmental Disorders: Modeling Complexity in Laboratory Studies
Authors: Alessia De Felice, Laura Ricceri, Maria Luisa Scattoni, Aldina Venerosi, Flavia Chiarotti and Gemma Calamandrei
Affiliation: Unit of Neurotoxicology and neuroendocrinology, Dept. of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma (ITALY)
Abstract: A number of factors including heredity, gene expression, social environment, nutrition and synthetic chemicals contribute to typical brain development in complex ways. In this perspective, it has become increasingly clear that the genome is not the only actor playing a role in health and disease. A great body of data support the multifactorial etiology of major chronic human diseases, and among these, of neurodevelopmental disorders (NDDs) affecting children. In NDDs a number of genetic variations (e.g., polymorphisms, mutations, deletions and copy number variants) in different genes may confer higher vulnerability and/or interact with different kinds of environmental factors. In such model, diverse environmental agents (chemicals, drugs, nutritional factors, maternal infection, stress) may interfere with brain developmental trajectories, disturbing gene regulation in a permanent manner, and eventually increasing the risk of either subclinical neuropsychological alterations or clinical conditions such as learning disabilities, autism and ADHD.
Autism spectrum disorders (ASD) are paradigmatic in this respect: ASD encompass a broad spectrum of heterogeneous NDDs, with an estimated prevalence rate of 1: 88 in US and 1:150 in Europe and a 4:1 male: female ratio, characterized by social deficits, abnormalities in communication, repetitive behaviors, and cognitive inflexibility. Gene mutations, gene deletions, copy number variants are all persuasively linked to autism but no single candidate gene alone is sufficient to cause the full clinical phenotype. A significant contribution from environmental factors would provide a plausible explanation for the rapid increase in the incidence of ASD over the past few decades
Assessing the interaction between genes and environment in human populations remains a daunting task. A great body of data have linked low-dose chronic exposure to environmental chemicals during fetal and neonatal development to altered neurodevelopment. However it is unlikely that a single or even a few specific environmental agents are responsible for the majority of neurodevelopmental disorders that involve dysregulation of several developmental pathways. Recent evidences on mercury developmental neurotoxicity suggest that polymorphisms in a number of environmentally responsive genes can possibly explain variations in biomarker values and health outcomes. To complicate the picture further, the socioeconomic context and the rearing environment are important modifiers of the effects of environmental neurotoxicants, in a positive or negative way, as shown by experimental and clinical studies indicating maternal stress as modulator of toxicants’ adverse effects in the offspring.
In spite of this complexity, most knowledge of the health effects of environmental factors is derived from studies of single agents or single candidate genes. The simultaneous exposures to multiple risk factors, which may accumulate or interact synergistically, remain to be fully explained and defined.
Animal models are useful tools to identify potential gene–environment interactions that might contribute to neurodevelopment alterations and to test what gene–environment combinations produce the greatest neurobehavioral deficits. However, to date the neurobehavioral toxicity of environmental pollutants and the contribution of candidate genes to NDDs have typically been tested independently with very few attempts to identify their potential interaction. Therefore, future neurotoxicological research in animals must consider how different factors may work in combination to affect CNS development, in order to understand how genetic susceptibility, environmental pollutants and other environmental factors (e.g. psychosocial stress or infective diseases) interact to produce measureable deficits in brain and behavioral development. In vivo models, when taking advantage from the results of mechanistic in vitro studies in “simpler” systems as well as from the indication of epidemiological studies, may help to identify candidate biomarkers and pinpoint susceptible groups or lifestages to be then translated to large prospective studies.
This paper intends to review the major lines of evidence about environmental factors contributing to altered neurodevelopment in children, which have specifically addressed the role of genetic vulnerability. The presence of confounding and/or modifier factors will be also looked for. As for environmental chemicals, the focus will be on specific classes of compounds (metals, organophosphorous pesticides); as for non-chemical factors, maternal stress in pregnancy and the socioeconomic state will be considered. Laboratory rodent studies where either gene x environment or chemical agent x non-chemical (i.e. infective state, maternal stress, early deprivation) agent interaction have been concomitantly assessed will be described and discussed. Examples of in vitro studies evaluating the effects of two or more risk factors in simpler systems will be also presented. Finally the possible usefulness of such “more realistic” preclinical models for risk assessment will be discussed, as well as the new perspective posed by the “exposome” concept on preclinical research in environmental health.
Last update: 16 April 2014