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Xenobiotics in Developmental Neurotoxicity
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Xenobiotics in Developmental Neurotoxicity (Closed)

A topical collection in Toxics (ISSN 2305-6304). This collection belongs to the section "Reproductive and Developmental Toxicity".

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Editor

Prof. Dr. David R. Wallace

E-Mail Website
Collection Editor
Department of Pharmacology & Physiology, School of Biomedical Science, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107-1898, USA
Interests: pancreatic cancer; environmental toxicants; mitochondrial toxicity; apoptosis; cellular regulation; tryptophan-kynurenine pathway; indoleamine 2,3-dioxygenase
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

The role of xenobiotics in the development of the brain is a rapidly expanding field. A xenobiotic agent is a foreign substance found in a biological organism that would not be normally found in that organism, or found at much higher concentrations than expected. These agents can cover chemical pollutants, drugs, or other biological agents, such as viral particles. There have been significant advances in neuroscience research over the last two decades. The developing brain is extremely sensitive to insult from exogenous xenobiotics. This sensitivity is not confined to in utero exposure, but also throughout infant, toddler, and pre-teen adolescent neurodevelopment. Work in developmental neurotoxicology (DNT) has lagged. Reasons for this delay include; (1) difficulty in finding appropriate model systems, (2) lack of existing toxicology data on many of the chemicals that are commercially available, and (3) relative lack of information regarding mixtures of various chemicals that are commercially available. Most xenobiotics can be categorized based on their physiological/chemical agent. These categories include antioxidants, carcinogens, drugs (prescription/over-the-counter/illegal), environmental pollutants, food additives, hydrocarbons, and pesticides. Of the tens of thousands of compounds, only about 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 additional research is needed to identify appropriate model systems to study DNT effects that will improve the translation from alternative to human model systems. Also, additional work is needed to identify and develop accurate biomarkers that will signal exposure to DNT compounds early in the exposure period, facilitating medical intervention. The purpose of this Topical Collection is to provide a forum to develop a compendium of work spanning a variety of topics to further our understanding of DNT.

Prof. David R. Wallace
Collection Editor

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Keywords

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

Published Papers (6 papers)

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2021

Jump to: 2019, 2018, 2017, 2016

24 pages, 1410 KiB  
Review
Mechanisms of Neurotoxicity Associated with Exposure to the Herbicide Atrazine
by Sydney C. Stradtman and Jennifer L. Freeman
Toxics 2021, 9(9), 207; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics9090207 - 31 Aug 2021
Cited by 29 | Viewed by 5933
Abstract
Atrazine is an herbicide commonly used on crops to prevent broadleaf weeds. Atrazine is an endocrine-disrupting chemical mainly targeting the neuroendocrine system and associated axes, especially as a reproductive toxicant through attenuation of the luteinizing hormone (LH). Current regulatory levels for chronic exposure [...] Read more.
Atrazine is an herbicide commonly used on crops to prevent broadleaf weeds. Atrazine is an endocrine-disrupting chemical mainly targeting the neuroendocrine system and associated axes, especially as a reproductive toxicant through attenuation of the luteinizing hormone (LH). Current regulatory levels for chronic exposure are based on no observed adverse effect levels (NOAELs) of these LH alterations in rodent studies. Atrazine has also been studied for its effects on the central nervous system and neurotransmission. The European Union (EU) recognized the health risks of atrazine exposure as a public health concern with no way to contain contamination of drinking water. As such, the EU banned atrazine use in 2003. The United States recently reapproved atrazine’s use in the fall of 2020. Research has shown that there is a wide array of adverse health effects that are seen across multiple models, exposure times, and exposure periods leading to dysfunction in many different systems in the body with most pointing to a neuroendocrine target of toxicity. There is evidence of crosstalk between systems that can be affected by atrazine exposure, causing widespread dysfunction and leading to changes in behavior even with no direct link to the hypothalamus. The hypothetical mechanism of toxicity of atrazine endocrine disruption and neurotoxicity can therefore be described as a web of pathways that are influenced through changes occurring in each and their multiple feedback loops with further research needed to refine NOAELs for neurotoxic outcomes. Full article
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2019

Jump to: 2021, 2018, 2017, 2016

24 pages, 2668 KiB  
Article
A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure
by Aimée I. Vester, Merry Chen, Carmen J. Marsit and W. Michael Caudle
Toxics 2019, 7(2), 24; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics7020024 - 02 May 2019
Cited by 7 | Viewed by 5030
Abstract
Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood and previous studies indicate the dopamine system plays a major role in ADHD pathogenesis. Two environmental exposures independently associated with dopaminergic dysfunction and ADHD risk include exposure to deltamethrin, [...] Read more.
Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood and previous studies indicate the dopamine system plays a major role in ADHD pathogenesis. Two environmental exposures independently associated with dopaminergic dysfunction and ADHD risk include exposure to deltamethrin, a pyrethroid insecticide, and chronic stress. We hypothesized that combined neurodevelopmental exposure to both deltamethrin and corticosterone (CORT), the major stress hormone in rodents, would result in additive changes within the dopamine system. To study this, we developed a novel dual exposure paradigm and exposed pregnant C57BL/6 dams to 3 mg/kg deltamethrin through gestation and weaning, and their offspring to 25 μg/mL CORT dissolved in the drinking water through adulthood. Midbrain RNA expression as well as striatal and cortical protein expression of key dopaminergic components were investigated, in addition to ADHD-like behavioral tasks and electrochemical dopamine dynamics via fast-scan cyclic voltammetry. Given the well-described sexual dimorphism of ADHD, males and females were assessed separately. Males exposed to deltamethrin had significantly decreased midbrain Pitx3 expression, decreased cortical tyrosine hydroxylase (TH) expression, increased activity in the Y maze, and increased dopamine uptake rate in the dorsal striatum. These effects did not occur in males exposed to CORT only, or in males exposed to both deltamethrin and CORT, suggesting that CORT may attenuate these effects. Additionally, deltamethrin- and CORT-exposed females did not display these dopaminergic features, which indicates these changes are sex-specific. Our results show dopaminergic changes from the RNA through the functional level. Moreover, these data illustrate the importance of testing multiple environmental exposures together to better understand how combined exposures that occur in certain vulnerable populations could affect similar neurodevelopmental systems, as well as the importance of studying sex differences of these alterations. Full article
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2018

Jump to: 2021, 2019, 2017, 2016

17 pages, 5736 KiB  
Article
Chlorpyrifos- and Dichlorvos-Induced Oxidative and Neurogenic Damage Elicits Neuro-Cognitive Deficits and Increases Anxiety-Like Behavior in Wild-Type Rats
by Aminu Imam, Nafeesah Abdulkareem Sulaiman, Aboyeji Lukuman Oyewole, Samson Chengetanai, Victoria Williams, Musa Iyiola Ajibola, Royhaan Olamide Folarin, Asma’u Shehu Muhammad, Sheu-Tijani Toyin Shittu and Moyosore Salihu Ajao
Toxics 2018, 6(4), 71; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics6040071 - 01 Dec 2018
Cited by 25 | Viewed by 4945
Abstract
The execution of agricultural activities on an industrial scale has led to indiscriminate deposition of toxic xenobiotics, including organophosphates, in the biome. This has led to intoxication characterized by deleterious oxidative and neuronal changes. This study investigated the consequences of oxidative and neurogenic [...] Read more.
The execution of agricultural activities on an industrial scale has led to indiscriminate deposition of toxic xenobiotics, including organophosphates, in the biome. This has led to intoxication characterized by deleterious oxidative and neuronal changes. This study investigated the consequences of oxidative and neurogenic disruptions that follow exposure to a combination of two organophosphates, chlorpyrifos (CPF) and dichlorvos (DDVP), on neuro-cognitive performance and anxiety-like behaviors in rats. Thirty-two adult male Wistar rats (150–170 g) were randomly divided into four groups, orally exposed to normal saline (NS), DDVP (8.8 mg/kg), CPF (14.9 mg/kg), and DDVP + CPF for 14 consecutive days. On day 10 of exposure, anxiety-like behavior and amygdala-dependent fear learning were assessed using open field and elevated plus maze paradigms, respectively, while spatial working memory was assessed on day 14 in the Morris water maze paradigm, following three training trials on days 11, 12, and 13. On day 15, the rats were euthanized, and their brains excised, with the hippocampus and amygdala removed. Five of these samples were homogenized and centrifuged to analyze nitric oxide (NO) metabolites, total reactive oxygen species (ROS), and acetylcholinesterase (AChE) activity, and the other three were processed for histology (cresyl violet stain) and proliferative markers (Ki67 immunohistochemistry). Marked (p ≤0.05) loss in body weight, AChE depletion, and overproduction of both NO and ROS were observed after repeated exposure to individual and combined doses of CPF and DDVP. Insults from DDVP exposure appeared more severe owing to the observed greater losses in the body weights of exposed rats. There was also a significant (p ≤0.05) effect on the cognitive behaviors recorded from the exposed rats, and these deficits were related to the oxidative damage and neurogenic cell loss in the hippocampus and the amygdala of the exposed rats. Taken together, these results provided an insight that oxidative and neurogenic damage are central to the severity of neuro-cognitive dysfunction and increased anxiety-like behaviors that follow organophosphate poisoning. Full article
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2017

Jump to: 2021, 2019, 2018, 2016

269 KiB  
Review
EDCs Mixtures: A Stealthy Hazard for Human Health?
by Edna Ribeiro, Carina Ladeira and Susana Viegas
Toxics 2017, 5(1), 5; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics5010005 - 07 Feb 2017
Cited by 100 | Viewed by 8305
Abstract
Endocrine disrupting chemicals (EDCs) are exogenous chemicals that may occur naturally (e.g., phytoestrogens), while others are industrial substances and plasticizers commonly utilized worldwide to which human exposure, particularly at low-doses, is omnipresent, persistent and occurs in complex mixtures. EDCs can interfere with/or mimic [...] Read more.
Endocrine disrupting chemicals (EDCs) are exogenous chemicals that may occur naturally (e.g., phytoestrogens), while others are industrial substances and plasticizers commonly utilized worldwide to which human exposure, particularly at low-doses, is omnipresent, persistent and occurs in complex mixtures. EDCs can interfere with/or mimic estrogenic hormones and, consequently, can simultaneously trigger diverse signaling pathways which result in diverse and divergent biological responses. Additionally, EDCs can also bioaccumulate in lipid compartments of the organism forming a mixed “body burden” of contaminants. Although the independent action of chemicals has been considered the main principle in EDCs mixture toxicity, recent studies have demonstrated that numerous effects cannot be predicted when analyzing single compounds independently. Co-exposure to these agents, particularly in critical windows of exposure, may induce hazardous health effects potentially associated with a complex “body burden” of different origins. Here, we performed an exhaustive review of the available literature regarding EDCs mixtures exposure, toxicity mechanisms and effects, particularly at the most vulnerable human life stages. Although the assessment of potential risks to human health due to exposure to EDCs mixtures is a major topic for consumer safety, information regarding effective mixtures effects is still scarce. Full article
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2016

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964 KiB  
Communication
Hair Microelement Profile as a Prognostic Tool in Parkinson’s Disease
by Ferraro Stefano, Nasuti Cinzia, Piangerelli Marco, Guidi Marco, Giovannetti Rita, Ferri Augusto and Gabbianelli Rosita
Toxics 2016, 4(4), 27; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics4040027 - 16 Nov 2016
Cited by 6 | Viewed by 4893
Abstract
Changes in the homeostasis of metals and microelements have been demonstrated in Parkinson’s disease, whose etiology includes both a genetic and environmental basis. We studied the difference of microelements in the hair of Parkinson’s disease subjects (n = 46) compared with healthy [...] Read more.
Changes in the homeostasis of metals and microelements have been demonstrated in Parkinson’s disease, whose etiology includes both a genetic and environmental basis. We studied the difference of microelements in the hair of Parkinson’s disease subjects (n = 46) compared with healthy controls (n = 24). Hair was chosen as a representative matrix to measure microelements, since it is a vehicle of substance excretion from the human body and it allows for long-term evaluation of metal exposure. An inductively coupled plasma mass spectrometry (ICP-MS) analysis of hair collected from 24 Parkinson’s patients compared with their healthy relatives used as controls shows a significant decrease in Ca (U = 166, p = 0.012),), Mg (U = 187, p = 0.037), and Sr (U = 183, p = 0.030). Cd and Ca/Mg were decreased, and Cu was increased, in patients with respect to their healthy related controls at the limit of significance (p = 0.0501). Principal Component Analysis (PCA) of these microelements in hair shows a clustering into two groups according to gender, disease severity according to the Hoehn–Yahr scale, and pharmacological therapy. This pilot study represents a starting point for future investigations where a larger group of subjects will be involved to define other microelements useful when screening for early biomarkers of Parkinson’s disease. Full article
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570 KiB  
Review
The Synapse as a Central Target for Neurodevelopmental Susceptibility to Pesticides
by Aimee Vester and W. Michael Caudle
Toxics 2016, 4(3), 18; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics4030018 - 26 Aug 2016
Cited by 20 | Viewed by 7232
Abstract
The developmental period of the nervous system is carefully orchestrated and highly vulnerable to alterations. One crucial factor of a properly-functioning nervous system is the synapse, as synaptic signaling is critical for the formation and maturation of neural circuits. Studies show that genetic [...] Read more.
The developmental period of the nervous system is carefully orchestrated and highly vulnerable to alterations. One crucial factor of a properly-functioning nervous system is the synapse, as synaptic signaling is critical for the formation and maturation of neural circuits. Studies show that genetic and environmental impacts can affect diverse components of synaptic function. Importantly, synaptic dysfunction is known to be associated with neurologic and psychiatric disorders, as well as more subtle cognitive, psychomotor, and sensory defects. Given the importance of the synapse in numerous domains, we wanted to delineate the effects of pesticide exposure on synaptic function. In this review, we summarize current epidemiologic and molecular studies that demonstrate organochlorine, organophosphate, and pyrethroid pesticide exposures target the developing synapse. We postulate that the synapse plays a central role in synaptic vulnerability to pesticide exposure during neurodevelopment, and the synapse is a worthy candidate for investigating more subtle effects of chronic pesticide exposure in future studies. Full article
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