Special Issue "Developmental Neurotoxicology"

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A special issue of Toxics (ISSN 2305-6304).

Deadline for manuscript submissions: closed (15 May 2014)

Special Issue Editor

Guest Editor
Prof. Dr. David R. Wallace

Oklahoma State University, Center for Health Sciences, 1111 West 17th Street, Tulsa, Oklahoma 74107-1898, USA
Website | E-Mail
Phone: +1-918-561-1407
Fax: +1-918-561-5729 Lab: +1-918-561-5784
Interests: environmental toxins; heavy metals; pesticides; developmental neurotoxicity; neurochemical and cellular mechanisms of toxicity

Special Issue Information

Dear Colleagues,

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
Guest Editor

Submission

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Keywords

  • biomarkers
  • animal models
  • in vitro testing
  • neurodevelopment
  • risk assessment

Published Papers (7 papers)

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Editorial

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Open AccessEditorial Current State of Developmental Neurotoxicology Research
Toxics 2015, 3(4), 370-372; doi:10.3390/toxics3040370
Received: 25 September 2015 / Revised: 29 September 2015 / Accepted: 29 September 2015 / Published: 1 October 2015
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Abstract We have been witness to significant research advances in areas such as neuroscience, neurodegeneration, cancer therapy, etc., yet, investigation in developmental neurotoxicology (DNT) has fallen behind [1]. [...] Full article
(This article belongs to the Special Issue Developmental Neurotoxicology)

Research

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Open AccessArticle Comparison of Neurological Function in Males and Females from Two Substrains of C57BL/6 Mice
Toxics 2015, 3(1), 1-17; doi:10.3390/toxics3010001
Received: 12 June 2014 / Accepted: 17 December 2014 / Published: 25 December 2014
Cited by 1 | PDF Full-text (592 KB) | HTML Full-text | XML Full-text
Abstract
The C57BL/6 (B6) mouse is the background strain most frequently used for genetically-modified mice. Previous studies have found significant behavioral and genetic differences between the B6J (The Jackson Laboratory) and B6N substrains (National Institutes of Health); however, most studies employed only male mice.
[...] Read more.
The C57BL/6 (B6) mouse is the background strain most frequently used for genetically-modified mice. Previous studies have found significant behavioral and genetic differences between the B6J (The Jackson Laboratory) and B6N substrains (National Institutes of Health); however, most studies employed only male mice. We performed a comprehensive battery of motor function and learning and memory tests on male and female mice from both substrains. The B6N male mice had greater improvement in the rotarod test. In contrast, B6J female mice had longer latencies to falling from the rotarod. In the Morris water maze (MWM), B6J males had significantly shorter latencies to finding the hidden platform. However, B6N females had significantly shorter path lengths in the reversal and shifted-reduced phases. In open field locomotor activity, B6J males had higher activity levels, whereas B6N females took longer to habituate. In the fear conditioning test, B6N males had a significantly longer time freezing in the new context compared with B6J males, but no significant differences were found in contextual or cued tests. In summary, our findings demonstrate the importance of testing both males and females in neurobehavioral studies. Both factors (sex and substrain) must be taken into account when designing developmental neurotoxicology studies. Full article
(This article belongs to the Special Issue Developmental Neurotoxicology)
Open AccessArticle Developmental Neurotoxicity of 3,3',4,4'-Tetrachloroazobenzene with Thyroxine Deficit: Sensitivity of Glia and Dentate Granule Neurons in the Absence of Behavioral Changes
Toxics 2014, 2(3), 496-532; doi:10.3390/toxics2030496
Received: 1 August 2014 / Revised: 2 September 2014 / Accepted: 4 September 2014 / Published: 24 September 2014
Cited by 5 | PDF Full-text (2851 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Thyroid hormones (TH) regulate biological processes implicated in neurodevelopmental disorders and can be altered with environmental exposures. Developmental exposure to the dioxin-like compound, 3,3',4,4'-tetrachloroazobenzene (TCAB), induced a dose response deficit in serum T4 levels with no change in 3,5,3'-triiodothyronine or thyroid stimulating hormone.
[...] Read more.
Thyroid hormones (TH) regulate biological processes implicated in neurodevelopmental disorders and can be altered with environmental exposures. Developmental exposure to the dioxin-like compound, 3,3',4,4'-tetrachloroazobenzene (TCAB), induced a dose response deficit in serum T4 levels with no change in 3,5,3'-triiodothyronine or thyroid stimulating hormone. Female Sprague-Dawley rats were orally gavaged (corn oil, 0.1, 1.0, or 10 mg TCAB/kg/day) two weeks prior to cohabitation until post-partum day 3 and male offspring from post-natal day (PND) 4–21. At PND21, the high dose showed a deficit in body weight gain. Conventional neuropathology detected no neuronal death, myelin disruption, or gliosis. Astrocytes displayed thinner and less complex processes at 1.0 and 10 mg/kg/day. At 10 mg/kg/day, microglia showed less complex processes, unbiased stereology detected fewer hippocampal CA1 pyramidal neurons and dentate granule neurons (GC) and Golgi staining of the cerebellum showed diminished Purkinje cell dendritic arbor. At PND150, normal maturation of GC number and Purkinje cell branching area was not observed in the 1.0 mg/kg/day dose group with a diminished number and branching suggestive of effects initiated during developmental exposure. No effects were observed on post-weaning behavioral assessments in control, 0.1 and 1.0 mg/kg/day dose groups. The demonstrated sensitivity of hippocampal neurons and glial cells to TCAB and T4 deficit raises support for considering additional anatomical features of brain development in future DNT evaluations. Full article
(This article belongs to the Special Issue Developmental Neurotoxicology)
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Open AccessArticle Changes in miRNA Expression Profiling during Neuronal Differentiation and Methyl Mercury-Induced Toxicity in Human in Vitro Models
Toxics 2014, 2(3), 443-463; doi:10.3390/toxics2030443
Received: 4 June 2014 / Revised: 31 July 2014 / Accepted: 5 August 2014 / Published: 29 August 2014
Cited by 1 | PDF Full-text (1090 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs (miRNAs) are implicated in the epigenetic regulation of several brain developmental processes, such as neurogenesis, neuronal differentiation, neurite outgrowth, and synaptic plasticity. The main aim of this study was to evaluate whether miRNA expression profiling could be a useful approach to detect
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MicroRNAs (miRNAs) are implicated in the epigenetic regulation of several brain developmental processes, such as neurogenesis, neuronal differentiation, neurite outgrowth, and synaptic plasticity. The main aim of this study was to evaluate whether miRNA expression profiling could be a useful approach to detect in vitro developmental neurotoxicity. For this purpose, we assessed the changes in miRNA expression caused by methyl mercury chloride (MeHgCl), a well-known developmental neurotoxicant, comparing carcinoma pluripotent stem cells (NT-2) with human embryonic stem cells (H9), both analyzed during the early stage of neural progenitor commitment into neuronal lineage. The data indicate the activation of two distinct miRNA signatures, one activated upon neuronal differentiation and another upon MeHgCl-induced toxicity. Particularly, exposure to MeHgCl elicited, in both neural models, the down-regulation of the same six out of the ten most up-regulated neuronal pathways, as shown by the up-regulation of the corresponding miRNAs and further assessment of gene ontology (GO) term and pathway enrichment analysis. Importantly, some of these common miRNA-targeted pathways defined in both cell lines are known to play a role in critical developmental processes, specific for neuronal differentiation, such as axon guidance and neurotrophin-regulated signaling. The obtained results indicate that miRNAs expression profiling could be a promising tool to assess developmental neurotoxicity pathway perturbation, contributing towards improved predictive human toxicity testing. Full article
(This article belongs to the Special Issue Developmental Neurotoxicology)

Review

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Open AccessReview Multifactorial Origin of Neurodevelopmental Disorders: Approaches to Understanding Complex Etiologies
Toxics 2015, 3(1), 89-129; doi:10.3390/toxics3010089
Received: 29 September 2014 / Revised: 6 March 2015 / Accepted: 18 March 2015 / Published: 23 March 2015
Cited by 3 | PDF Full-text (641 KB) | HTML Full-text | XML Full-text
Abstract
A significant body of evidence supports the multifactorial etiology of neurodevelopmental disorders (NDDs) affecting children. The present review focuses on early exposure to environmental chemicals as a risk factor for neurodevelopment, and presents the major lines of evidence derived from epidemiological studies, underlying
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A significant body of evidence supports the multifactorial etiology of neurodevelopmental disorders (NDDs) affecting children. The present review focuses on early exposure to environmental chemicals as a risk factor for neurodevelopment, and presents the major lines of evidence derived from epidemiological studies, underlying key uncertainties and research needs in this field. We introduce the exposome concept that, encompassing the totality of human environmental exposures to multiple risk factors, aims at explaining individual vulnerability and resilience to early chemical exposure. In this framework, we synthetically review the role of variable gene backgrounds, the involvement of epigenetic mechanisms as well as the function played by potential effect modifiers such as socioeconomic status. We describe laboratory rodent studies where the neurodevelopmental effects of environmental chemicals are assessed in the presence of either a “vulnerable” gene background or adverse pregnancy conditions (i.e., maternal stress). Finally, we discuss the need for more descriptive and “lifelike” experimental models of NDDs, to identify candidate biomarkers and pinpoint susceptible groups or life stages to be translated to large prospective studies within the exposome framework. Full article
(This article belongs to the Special Issue Developmental Neurotoxicology)
Open AccessReview Zebrafish as a Model for Developmental Neurotoxicity Assessment: The Application of the Zebrafish in Defining the Effects of Arsenic, Methylmercury, or Lead on Early Neurodevelopment
Toxics 2014, 2(3), 464-495; doi:10.3390/toxics2030464
Received: 15 May 2014 / Revised: 22 August 2014 / Accepted: 25 August 2014 / Published: 10 September 2014
Cited by 6 | PDF Full-text (453 KB) | HTML Full-text | XML Full-text
Abstract
Developmental exposure to neurotoxic chemicals presents significant health concerns because of the vulnerability of the developing central nervous system (CNS) and the immature brain barrier. To date, a short list of chemicals including some metals have been identified as known developmental neurotoxicants; however,
[...] Read more.
Developmental exposure to neurotoxic chemicals presents significant health concerns because of the vulnerability of the developing central nervous system (CNS) and the immature brain barrier. To date, a short list of chemicals including some metals have been identified as known developmental neurotoxicants; however, there are still numerous chemicals that remain to be evaluated for their potential developmental neurotoxicity (DNT). To facilitate evaluation of chemicals for DNT, the zebrafish vertebrate model system has emerged as a promising tool. The zebrafish possesses a number of strengths as a test species in DNT studies including an abundance of embryos developing ex utero presenting ease in chemical dosing and microscopic assessment at all early developmental stages. Additionally, rapid neurodevelopment via conserved molecular pathways supports the likelihood of recapitulating neurotoxic effects observed in other vertebrates. In this review, we describe the biological relevance of zebrafish as a complementary model for assessment of DNT. We then focus on a metalloid and two metals that are known developmental neurotoxicants (arsenic, methylmercury, and lead). We summarize studies in humans and traditional vertebrate models and then detail studies defining the toxicity of these substances using the zebrafish to support application of this model system in DNT studies. Full article
(This article belongs to the Special Issue Developmental Neurotoxicology)
Open AccessReview Delayed Behavioral Effects of Early Life Toxicant Exposures in Aquatic Biota
Toxics 2014, 2(2), 165-187; doi:10.3390/toxics2020165
Received: 24 February 2014 / Revised: 12 May 2014 / Accepted: 13 May 2014 / Published: 20 May 2014
Cited by 9 | PDF Full-text (632 KB) | HTML Full-text | XML Full-text
Abstract
Behavioral development occurs together with the development of the nervous system. Studies on mammals indicate that exposures to some chemicals during embryonic development at concentrations that do not produce anatomical malformations may nevertheless produce behavioral deficits later in life, an example of delayed
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Behavioral development occurs together with the development of the nervous system. Studies on mammals indicate that exposures to some chemicals during embryonic development at concentrations that do not produce anatomical malformations may nevertheless produce behavioral deficits later in life, an example of delayed effects. There have been reports of delayed effects in aquatic organisms. Delayed behavioral effects of mercury, chlorinated and other pesticides, polycyclic aromatic hydrocarbons (PAHs), and some synthetic hormones in the environment have been reported in fishes and invertebrates; in some cases behavioral effects are manifested years after the exposure. Another type of delayed behavioral effect results from exposure of mature females before fertilization (maternal exposure). Even when embryos and larvae are reared in clean water, offspring may manifest abnormal behaviors following maternal exposure. The reported behavioral changes are generally deleterious and compromise the fitness of the animal in its natural environment. Delayed effects and their impacts on fitness are not considered in standard short-term embryo bioassays, which will therefore underestimate neurotoxicity. The literature in the field is scattered and has not been reviewed. The objective of this paper is to review and synthesize what is known about delayed behavioral effects in aquatic biota. Full article
(This article belongs to the Special Issue Developmental Neurotoxicology)
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