Neurotoxic Exposure Research Articles

Functional brain MRI in patients complaining of electrohypersensitivity after long term exposure to electromagnetic fields.

Ten adult patients with electromagnetic hypersensitivity underwent functional magnetic resonance imaging (fMRI) brain scans. All scans were abnormal with abnormalities which were consistent and similar. It is proposed that fMRI brain scans be used as a diagnostic aid for determining whether or not a patient has electromagnetic hypersensitivity. Over the years we have seen an increasing number of patients who had developed multi system complaints after long term repeated exposure to electromagnetic fields (EMFs). These complaints included headaches, intermittent cognitive and memory problems, intermittent disorientation, and also sensitivity to EMF exposure. Regular laboratory tests were within normal limits in these patients. The patients refused to be exposed to radioactivity. This of course ruled out positron emission tomography (PET) and single-photon emission computed tomography (SPECT) brain scanning. This is why we ordered fMRI brain scans on these patients. We hoped that we could document objective abnormalities in these patients who had often been labeled as psychiatric cases. Ten patients first underwent a regular magnetic resonance imaging (MRI) brain scan, using a 3 Tesla Siemens Verio MRI open system. A functional MRI study was then performed in the resting state using the following sequences: A three-dimensional, T1-weighted, gradient-echo (MPRAGE) Resting state network. The echo-planar imaging (EPI) sequences for this resting state blood oxygenation level dependent (BOLD) scan were then post processed on a 3D workstation and the independent component analysis was performed separating out the various networks. Arterial spin labeling. Tractography and fractional anisotropy. All ten patients had abnormal functional MRI brain scans. The abnormality was often described as hyper connectivity of the anterior component of the default mode in the medial orbitofrontal area. Other abnormalities were usually found. Regular MRI studies of the brain were mostly unremarkable in these patients. We propose that functional MRI studies should become a diagnostic aid when evaluating a patient who claims electrohypersensitivity (EHS) and has otherwise normal studies. Interestingly, the differential diagnosis for the abnormalities seen on the fMRI includes head injury. It turns out that many of our patients indeed had a history of head injury which was then followed sometime later by the development of EHS. Many of our patients also had a history of exposure to potentially neurotoxic chemicals, especially mold. Head injury and neurotoxic chemical exposure may make a patient more vulnerable to develop EHS.

Cognitive toxicity: from pesticides to pharmaceuticals

Impairment of cognitive functions following neurotoxic exposure is collectively termed cognitive toxicity. This oration is based on a series of studies carried out over last 12 years on cognitive toxicity of two groups of substances, viz. organophosphate (OP) pesticides and sedative psychotropic drugs. OP pesticide poisoning is a major clinical and public health problem in South Asia. OPs act as cholinesterase inhibitors, and bring about acute neurological deficits following exposure. Using neurophysiological and neuropsychological techniques, we assess long-term neurocognitive deficits of OPs, a less known yet important adverse effect of OP exposure. The findings hitherto indicate both acute large-dose poisoning and subclinical occupational exposure are associated with long-term cognitive impairment. In the same way the pesticide use and misuse are common in agricultural communities, use and misuse of sedative psychotropic medications are common in urbanised societies. Sedative drugs, even in therapeutic doses impair driving and underlying cognitive functions, and increase the risk of traffic accidents. When taken in overdose, these drugs have cognitively impairing effects that last beyond clinical recovery from acute poisoning. These patients are more prone to traffic crashes at least up to 4 weeks following exposure, and the cognitive recovery over this period mirrors the crash risk at different post-overdose time points. The above findings raise a number of clinical and medico legal implications in post-discharge management of patients with sedative drug overdose. As the agricultural communities transform into urban industrialised societies in Sri Lanka, the pattern of poisoning changes from agrochemicals into pharmaceuticals, particularly psychotropic dugs. The two lines of research discussed above highlight how this changing social fabric poses new challenges for the neurophysiologists, neurologists and psychiatrists who study cognition and apply their findings in clinical settings. Our latest work in generating age-, sex- and education-adjusted norms for cognitive tests for Sri Lankans, would set the foundation in interpreting the cognitive test results of clinical populations.

Distributions and determinants of urinary biomarkers of organophosphate pesticide exposure in a prospective Spanish birth cohort study

BackgroundPrenatal exposure to organophosphate pesticides (OPs) has been associated with impaired child development. Pesticide exposure determinants need to be studied in order to identify sources and pathways of pesticide exposure. The aim of this paper is to describe prenatal exposure to OPs and evaluate the associated factors in pregnant women.MethodsThe study population consisted of pregnant women (n = 573) who participated in the INMA birth cohort study in Valencia (Spain, 2003–2006). OP metabolites were analyzed in maternal urine at the 32nd week of gestation using a liquid chromatography-high resolution mass spectrometry method. The analysis included non-specific (diethyl phosphate [DEP], diethyl thiophosphate [DETP], dimethyl thiophosphate [DMTP], dimethyl dithiophosphate [DMDTP]) and specific metabolites (2-diethylamino-6-methyl-4-pyrimidinol [DEAMPY], 2-isopropyl-4-methyl-6-hydroxypyrimidine [IMPY], para-nitrophenol [PNP], and 3,5,6-trichloro-2-pyridinol [TCPY]). Information about the sociodemographic, environmental, and dietary characteristics was obtained by questionnaire. The association between log-transformed OPs and covariates was analyzed using multivariable interval censored regression.ResultsThe detection frequencies were low, DMTP and TCPY being the most frequently detected metabolites (53.8% and 39.1%, respectively). All the OP metabolites were positively associated with maternal intake of fruits and vegetables. Other maternal characteristics related to the OPs were body mass index (BMI) before pregnancy and smoking habit during pregnancy. Women with lower BMI and those who did not smoke presented higher OP concentrations. Moreover, mothers who had a yard or garden with plants at home or who lived in an urban area were also more exposed to OPs.ConclusionsThe OP detection frequencies and the concentrations observed in our study population were low, compared with most of the previously published studies. Given the high vulnerability of the fetus to neurotoxicant exposure, further research on the determinants of the body burden of OPs during pregnancy would be necessary. The knowledge gained from such studies would enhance the effectiveness of public health control and future recommendations in order to reduce the risk to both the health of pregnant women and the health and development of their children.

Public health benefits of hair-mercury analysis and dietary advice in lowering methylmercury exposure in pregnant women.

To evaluate whether a public health intervention using focused dietary advice combined with a hair-mercury analysis can lower neurotoxic methylmercury exposure among pregnant women without decreasing their overall intake of seafood. A total of 146 pregnant women were consecutively recruited from the antenatal clinic at a Danish university hospital at their initial ultrasound scan. Dietary advice was provided on avoiding methylmercury exposure from large predatory fish and a hair sample from each participant was analysed for mercury, with the results being communicated shortly thereafter to the women. A dietary questionnaire was filled in. Follow-up three months later included a dietary questionnaire and a repeat hair-mercury analysis. In the follow-up group, 22% of the women had hair-mercury concentrations above a safe limit of 0.58 µg/g at enrolment, decreasing to 8% three months later. Average hair-mercury concentrations decreased by 21%. However, the total seafood intake remained at the same level after three months. Increased exposure to methylmercury among pregnant women is an important public health concern in Denmark. The observed lowering of hair-mercury concentrations associated with dietary advice corresponds to a substantial public health benefit that probably makes such an intervention highly profitable.

UCH‐L1 as a Susceptibility Factor for Nigrostriatal and Mesolimbic Dopamine Neurons: Neurotoxicant Exposure and Aging

Parkinson disease (PD) is a debilitating neurodegenerative disorder in which nigrostriatal (NSDA) dopamine neurons die, affecting signaling within the basal ganglia pathway. Loss of dopamine input to the striatum (ST) results in the motor symptoms required to diagnose PD. Although the majority of cases are idiopathic, genes mutated in familial PD can provide clues to highlight important pathways important in pathogenesis and progression of PD. One such pathway is the ubiquitin proteasome system (UPS) which degrades proteins tagged with ubiquitin (Ub) chains. Since accumulation and aggregation of misfolded proteins such as alpha synuclein is a hallmark of PD, enhancing degradation of key substrates is a lucrative target for therapy. One UPS‐related protein mutated in familial PD is UCH‐L1, a deubiquitinating enzyme responsible for maintaining available pools of free monomeric Ub. UCH‐L1 is an abundant neuron‐specific protein that is critical for normal synaptic function and to maintain the structure of the neuromuscular junction. In a mouse model of oxidative damage specific to dopamine neurons, systemic administration of neurotoxicant MPTP resulted in loss of UCH‐L1 expression and function in the substantia nigra after 24 h. Since loss of UCH‐L1 and loss of phenotypic markers both occur concurrently in NSDA neurons, we hypothesized that loss of UCH‐L1 contributes to susceptibility to neurotoxicant administration. Not all dopamine neurons are equally susceptible in PD: mesolimbic dopamine neurons (MLDA) are spared while NSDA neurons degenerate. We compared NSDA to MLDA neurons and found that MLDA neurons are less susceptible to MPTP‐induced loss of ST dopamine and tyrosine hydroxylase (TH), which coincides with maintenance of UCH‐L1 expression in the ventral tegmental area. In addition, we performed an aging study to determine if UCH‐L1 is lost in aged mice versus young mice and if aged mice are more sensitive to loss of UCH‐L1 after MPTP. Finally, we hypothesized that overexpression of UCH‐L1 in NSDA neurons via rAAV 2/5 will be protective against proteasome impairment and loss of dopamine phenotypic markers after MPTP. Preliminary results indicate that aged mice are more sensitive to MPTP‐induced loss of dopamine in the ST compared to young mice, but not more sensitive to loss of TH and dopamine transporter expression. However, aged mice show decreased metabolism of dopamine as evidenced by lower levels of one of its metabolites, DOPAC. Aged mice also show similar levels of UPS impairment compared to young mice. Further study will determine if UCH‐L1 expression is influenced by aging in NSDA neurons, and if UCH‐L1 overexpression rescues UPS impairment in young mice.Support or Funding InformationInstitute for Integrative Toxicology T32 Predoctoral Fellowship National Institutes of Health NINDS

Noise and neurotoxic chemical exposure relationship to workplace traumatic injuries: A review

IntroductionMore than 5,000 fatalities and eight million injuries occurred in the workplace in 2007 at a cost of $6 billion and $186 billion, respectively. Neurotoxic chemicals are known to affect central nervous system functions among workers, which include balance and hearing disorders. However, it is not known if there is an association between exposure to noise and solvents and acute injuries. Method: A thorough review was conducted of the literature on the relationship between noise or solvent exposures and hearing loss with various health outcomes. Results: The search resulted in 41 studies. Health outcomes included: hearing loss, workplace injuries, absence from work due to sickness, fatalities, hospital admissions due to workplace accidents, traffic accidents, hypertension, balance, slip, trips, or falls, cognitive measures, or disability retirement. Important covariates in these studies were age of employee, type of industry or occupation, or length of employment. Discussion: Most authors that evaluated noise exposure concluded that higher exposure to noise resulted in more of the chosen health effect but the relationship is not well understood. Studies that evaluated hearing loss found that hearing loss was related to occupational injury, disability retirement, or traffic accidents. Studies that assessed both noise exposure and hearing loss as risk factors for occupational injuries reported that hearing loss was related to occupational injuries as much or more than noise exposure. Evidence suggests that solvent exposure is likely to be related to accidents or other health consequences such balance disorders. Conclusions: Many authors reported that noise exposures and hearing loss, respectively, are likely to be related to occupational accidents. Practical applications: The potential significance of the study is that findings could be used by managers to reduce injuries and the costs associated with those injures.

Evaluation of the neurotoxic effects of chronic embryonic exposure with inorganic mercury on motor and anxiety-like responses in zebrafish (Danio rerio) larvae

Chronic exposure to mercury (Hg) can lead to cumulative impairments in motor and cognitive functions including alteration in anxiety responses. Although several risk factors have been identified in recent year, little is known about the environmental factors that either due exposure toward low level of inorganic mercury that may led to the developmental disorders. The present study investigated the effects of embryonic exposure of mercury chloride on motor function and anxiety-like behavior. The embryo exposed to 6 different concentrations of HgCl2 (7.5, 15, 30, 100, 125, 250nM) at 5hpf until hatching (72hpf) in a semi-static condition. The mortality rate increased in a dose dependent manner where the chronic embryonic exposure to 100nM decreased the number of tail coiling, heartbeat, and swimming activity. Aversive stimulus was used to examine the effects of 100nM interferes with the development of anxiety-related behavior. No elevation in both thigmotaxis and avoidance response of 6dpf larvae exposed with 100nM were found. Biochemical analysis showed HgCl2 exposure affects proteins, lipids, carbohydrates and nucleic acids of the zebrafish larvae. These results showed that implication of HgCl2 on locomotor and biochemical defects affects motor performance and anxiety-like responses. Yet, the potential underlying mechanisms these responses need to be further investigated which is crucial to prevent potential hazards on the developing organism due to neurotoxicant exposure.

High content imaging quantification of multiple in vitro human neurogenesis events after neurotoxin exposure.

BackgroundOur objective was to test neural active compounds in a human developmental neurotoxicity (DNT) model that represents neural tube stages of vulnerability. Previously we showed that 14 days in vitro (DIV 14) was sufficient to generate cryopreserved neuronal cells for post thaw neurite recovery assays. However, short exposure and assessment may not detect toxicants that affect an early neurogenesis continuum, from a mitotic human neural progenitor (hNP) cell population through the course of neurite outgrowth in differentiating neurons. Therefore, we continuously exposed differentiating hNP cells from DIV 0 through DIV 14 to known toxicants and endocrine active compounds in order to assess at DIV 14 effects of these compounds in a human DNT maturation model for neurogenesis.MethodsThe Human DNT continuum (DIV 0 to DIV 14) was determined using immunocytochemistry for SOX1+ (proliferating hNP) and HuC/D+ (post mitotic neurons). The cumulative effects of five compounds was observed on neurite outgrowth in (βIII-tubulin+) and (HuC/D+) cells using high content imaging. All data were analyzed using a one-way ANOVA with a significance threshold of p < 0.05.ResultsDuring maturation in vitro, the neural cultures transitioned from uniform hNP cells (DIV 0) to predominantly mature post mitotic neuronal neurons (HuC/D+, 65%; DIV14) but also maintained a smaller population of hNP cells (SOX1+). Using this DNT maturation model system, Bis-1, testosterone, and β-estradiol inhibited neuronal maturation at micromolar levels but were unaffected by acetaminophen. β-estradiol also disrupted neurite extension at 10 μM. Treating cells in this window with Bisphenol A (BPA) significantly inhibited neurite outgrowth and branching in these continuum cultures but only at the highest concentrations tested (10 μM).ConclusionsCumulative effects of neurotoxicant exposure during a maturation continuum altered human neurogenesis at lower exposure levels than observed in acute exposure of static cryopreserved neurite recovery neurons cultures. Unlike prior acute studies, β-estradiol was highly toxic when present throughout the continuum and cytotoxicity was manifested starting early in the continuum via a non-estrogen receptor α (ER α) mechanism. Therefore, the effect of neural developmental neurotoxins can and should be determined during the dynamic process of human neural maturation.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-016-0107-4) contains supplementary material, which is available to authorized users.

FosB and ΔFosB expression in brain regions containing differentially susceptible dopamine neurons following acute neurotoxicant exposure

Parkinson disease (PD) is characterized by progressive neuronal degeneration, in particular nigrostriatal dopamine (NSDA) neurons and consequent deficits in movement. In mice and non-human primates, NSDA neurons preferentially degenerate following exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tuberoinfundibular (TI) DA neurons, in contrast, appear to be unaffected in PD and recover following acute MPTP exposure-induced injury (Behrouz et al., 2007; Benskey et al., 2012). The recovery of the TIDA neurons is dependent on de novo protein synthesis and positively correlated with an increase in parkin mRNA and protein expression (Benskey et al., 2012, 2015). Inhibition of parkin upregulation renders TIDA neurons susceptible to degeneration following MPTP exposure. In addition to parkin, other potentially protective proteins are likely to be differentially regulated in TIDA and NSDA neurons following neurotoxicant exposure. The regulation of potential transcription factors for parkin and other neuroprotective pathway genes are of interest since they may provide novel targets for PD disease modifying therapies. As such, we sought to determine if there are time-dependent differences in the expression of AP-1 transcription factors c-Fos, c-Jun, FosB, ΔFosB and JunD in TIDA and NSDA neurons of mice following acute MPTP exposure. We observed that both FosB and ΔFosB expression increase in brain regions containing TIDA, but not NSDA neurons. Furthermore, the nuclear and long-term expression of ΔFosB is consistent with its role as a transcription factor that may influence parkin transcription, which may underlie the unique ability of TIDA neurons to recovery from an injury that leads NSDA neurons to degeneration.

Differential epigenetic effects of chlorpyrifos and arsenic in proliferating and differentiating human neural progenitor cells.

Understanding the underlying temporal and mechanistic responses to neurotoxicant exposures during sensitive periods of neuronal development are critical for assessing the impact of these exposures on developmental processes. To investigate the importance of timing of neurotoxicant exposure for perturbation of epigenetic regulation, we exposed human neuronal progenitor cells (hNPCs) to chlorpyrifos (CP) and sodium arsenite (As; positive control) during proliferation and differentiation. CP or As treatment effects on hNPCs morphology, cell viability, and changes in protein expression levels of neural differentiation and cell stress markers, and histone H3 modifications were examined. Cell viability, proliferation/differentiation status, and epigenetic results suggest that hNPCs cultures respond to CP and As treatment with different degrees of sensitivity. Histone modifications, as measured by changes in histone H3 phosphorylation, acetylation and methylation, varied for each toxicant and growth condition, suggesting that differentiation status can influence the epigenetic effects of CP and As exposures.

Turing Revisited: Decoding the microRNA Messages in Brain Extracellular Vesicles for Early Detection of Neurodevelopmental Disorders.

The prevention of neurodevelopmental disorders (NDD) of prenatal origin suffers from the lack of objective tools for early detection of susceptible individuals and the long time lag, usually in years, between the neurotoxic exposure and the diagnosis of mental dysfunction. Human data on the effects of alcohol, lead, and mercury and experimental data from animals on developmental neurotoxins and their long-term behavioral effects have achieved a critical mass, leading to the concept of the Developmental Origin of Health and Disease (DOHaD). However, there is currently no way to evaluate the degree of brain damage early after birth. We propose that extracellular vesicles (EVs) and particularly exosomes, released by brain cells into the fetal blood, may offer us a non-invasive means of assessing brain damage by neurotoxins. We are inspired by the strategy applied by Alan Turing (a cryptanalyst working for the British government), who created a first computer to decrypt German intelligence communications during World War II. Given the growing evidence that microRNAs (miRNAs), which are among the molecules carried by EVs, are involved in cell-cell communication, we propose that decrypting messages from EVs can allow us to detect damage thus offering an opportunity to cure, reverse, or prevent the development of NDD. This review summarizes recent findings on miRNAs associated with selected environmental toxicants known to be involved in the pathophysiology of NDD.

A neurotoxic alcohol exposure paradigm does not induce hepatic encephalopathy

Alcohol abuse is associated with neurological dysfunction, brain morphological deficits and frank neurotoxicity. Although these disruptions may be a secondary effect due to hepatic encephalopathy, no clear evidence of causality is available. This study examined whether a 72h period of alcohol intoxication known to induce physical dependence, followed by a single withdrawal, was sufficient to induce signs of hepatic encephalopathy in male and female mice. Animals were continuously intoxicated via alcohol vapor inhalation, a procedure previously shown to induce significant neurotoxicity in female mice. At peak synchronized withdrawal (8h following the end of alcohol exposure), blood samples were taken and levels of several liver-regulated markers and brain swelling were characterized. Glutathione levels were also determined in the medial frontal cortex (mFC) and hippocampus. Results revealed elevated levels of cholesterol, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and decreased levels of blood urea nitrogen and total bilirubin in alcohol-exposed male and female groups compared to controls. Brain water weight was not affected by alcohol exposure, though males tended to have slightly more water weight overall. Alcohol exposure led to reductions in tissue levels of glutathione in both the hippocampus and mFC which may indicate increased oxidative stress. Combined, these results suggest that hepatic encephalopathy does not appear to play a significant role in the neurotoxicity observed following alcohol exposure in this model.

Research Review: Environmental exposures, neurodevelopment, and child mental health - new paradigms for the study of brain and behavioral effects.

Environmental exposures play a critical role in the genesis of some child mental health problems. We open with a discussion of children's vulnerability to neurotoxic substances, changes in the distribution of toxic exposures, and cooccurrence of social and physical exposures. We address trends in prevalence of mental health disorders, and approaches to the definition of disorders that are sensitive to the subtle effects of toxic exposures. We suggest broadening outcomes to include dimensional measures of autism spectrum disorders, attention-deficit hyperactivity disorder, and child learning capacity, as well as direct assessment of brain function. We consider the impact of two important exposures on children's mental health: lead and pesticides. We argue that longitudinal research designs may capture the cascading effects of exposures across biological systems and the full-range of neuropsychological endpoints. Neuroimaging is a valuable tool for observing brain maturation under varying environmental conditions. A dimensional approach to measurement may be sensitive to subtle subclinical toxic effects, permitting the development of exposure-related profiles and testing of complex functional relationships between brain and behavior. Questions about the neurotoxic effects of chemicals become more pressing when viewed through the lens of environmental justice. Reduction in the burden of child mental health disorders will require longitudinal study of neurotoxic exposures, incorporating dimensional approaches to outcome assessment, and measures of brain function. Research that seeks to identify links between toxic exposures and mental health outcomes has enormous public health and societal value.

Vascular-directed responses of microglia produced by methamphetamine exposure: indirect evidence that microglia are involved in vascular repair?

BackgroundBrain microglial activations and damage responses are most commonly associated with neurodegeneration or systemic innate immune system activation. Here, we used histological methods to focus on microglial responses that are directed towards brain vasculature, previously undescribed, after a neurotoxic exposure to methamphetamine.MethodsMale rats were given doses of methamphetamine that produce pronounced hyperthermia, hypertension, and toxicity. Identification of microglia and microglia-like cells (pericytes and possibly perivascular cells) was done using immunoreactivity to allograft inflammatory factor 1 (Aif1 a.k.a Iba1) and alpha M integrin (Itgam a.k.a. Cd11b) while vasculature endothelium was identified using rat endothelial cell antigen 1 (RECA-1). Regions of neuronal, axonal, and nerve terminal degeneration were determined using Fluoro-Jade C.ResultsDual labeling of vasculature (RECA-1) and microglia (Iba1) showed a strong association of hypertrophied cells surrounding and juxtaposed to vasculature in the septum, medial dorsal hippocampus, piriform cortex, and thalamus. The Iba1 labeling was more pronounced in the cell body while Cd11b more so in the processes of activated microglia. These regions have been previously identified to have vascular leakage after neurotoxic methamphetamine exposure. Dual labeling with Fluoro-Jade C and Iba1 indicated that there was minimal or no evidence of neuronal damage in the septum and hippocampus where many hypertrophied Iba1-labeled cells were found to be associated with vasculature. Although microglial activation around the prominent neurodegeneration was found in the thalamus, there were also many examples of activated microglia associated with vasculature.ConclusionsThe data implicate microglia, and possibly related cell types, in playing a major role in responding to methamphetamine-induced vascular damage, and possibly repair, in the absence of neurodegeneration. Identifying brain regions with hypertrophied/activated microglial-like cells associated with vasculature has the potential for identifying regions of more subtle examples of vascular damage and BBB compromise.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0526-6) contains supplementary material, which is available to authorized users.

Brain maturation in neonatal rodents is impeded by sevoflurane anesthesia.

A wealth of data shows neuronal demise after general anesthesia in the very young rodent brain. Herein, the authors apply proton magnetic resonance spectroscopy (1HMRS), testing the hypothesis that neurotoxic exposure during peak synaptogenesis can be tracked via changes in neuronal metabolites. 1HMRS spectra were acquired in the brain (thalamus) of neonatal rat pups 24 and 48 h after sevoflurane exposure on postnatal day (PND) 7 and 15 and in unexposed, sham controls. A repeated measure ANOVA was performed to examine whether changes in metabolites were different between exposed and unexposed groups. Sevoflurane-induced neurotoxicity on PND7 was confirmed by immunohistochemistry. In unexposed PND7 pups (N = 21), concentration of N-acetylaspartate (NAA; [NAA]) increased by 16% from PND8 to PND9, whereas in exposed PND7 pups (N = 19), [NAA] did not change and concentration of glycerophosphorylcholine and phosphorylcholine ([GPC + PCh]) decreased by 25%. In PND15 rats, [NAA] increased from PND16 to PND17 for both the exposed (N = 14) and the unexposed (N = 16) groups. Two-way ANOVA for PND7 pups demonstrated that changes over time observed in [NAA] (P = 0.031) and [GPC + PCh] (P = 0.024) were different between those two groups. The authors demonstrated that normal [NAA] increase from PND8 to PND9 was impeded in sevoflurane-exposed rats when exposed at PND7; however, not impeded when exposed on PND15. Furthermore, the authors showed that noninvasive 1HMRS is sufficiently sensitive to detect subtle differences in developmental time trajectory of [NAA]. This is potentially clinically relevant because 1HMRS can be applied across species and may be useful in providing evidence of neurotoxicity in the human neonatal brain.

Neurotoxicant exposure during pregnancy is a confounder for assessment of iodine supplementation on neurodevelopment outcome

ContextThe developing brain is vulnerable to iodine deficiency (ID) and environmental neuro-toxicants. ObjectivesTo assess neurocognitive development of children whose mothers have received (or not) iodine supplementation during pregnancy, in an area of borderline ID, while assessing in utero exposure to environmental neuro-toxicants. Design/patientsAmong 86 children born from normal euthyroid women who participated in our prospective interventional study on iodine supplementation (150μg/day) started early in pregnancy, 44 (19 with iodine supplementation, 25 controls) were assessed at two years using the Bayley test. Information on parents' education and habits (smoking), and on child development was recorded. Thyroid tests at each trimester of pregnancy and on cord blood (CB) were available, as well as milk concentrations of selected environmental compounds known for their neurotoxicity, including heavy metals and PCBs. ResultsThere was no difference in Bayley tests for children born to mothers with and without iodine supplementation, but sample size was small. Language and Social-Emotional Scales were negatively correlated with TBG at all times tested, while PCB 118 correlated negatively with all Language scales. Among maternal and CB thyroid tests, only CB thyroglobulin, the best marker of iodine status, correlated (negatively) with neurodevelopment scales (Motor and Expressive Language). ConclusionsThis pilot study suggests that PCB118 has a negative impact on neurocognitive development, possibly mitigating the benefit of iodine supplementation in an area of borderline ID. We propose that exposure to environmental neurotoxicants should be taken into account when designing studies on the benefit of iodine supplementation in pregnancy. The potential interactions between TBG, environmental neurotoxicants and brain development warrant further studies.

Regional (spinal, epidural, caudal) versus general anaesthesia in preterm infants undergoing inguinal herniorrhaphy in early infancy.

Regional (spinal, epidural, caudal) versus general anaesthesia in preterm infants undergoing inguinal herniorrhaphy in early infancy.

Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish.

Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25-0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3-72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development.

Alterations in Global DNA Methylation/Hydroxymethylation and MicroRNA Expression in a Rat Model of Gulf War Illness

Gulf War Illness (GWI) is a chronic, multisymptom illness that affects 25% of the 700,000 US veterans deployed to the Persian Gulf during the 1990-1991 Gulf War. Central nervous system impairments are among the most common symptoms reported, including memory dysfunction and depression. Epidemiological studies have consistently identified neurotoxic chemical exposures during deployment as the strongest risk factors for the persistent symptoms affecting GW veterans, but after nearly 25 years, treatments are lacking and underlying cellular and molecular mechanisms involved in its pathobiology remain poorly understood. Epigenetic changes including DNA methylation and altered microRNA (miRNA) expression play an important role in in learning, memory, and emotion regulation and have been implicated in various neurological disorders. The aim of this study was to determine in a rat model of GWI whether chronic alterations in global DNA methylation/hydroxymethylation and miRNA expression are mechanisms involved in the pathobiology of GWI. One year after a 28-day exposure regimen of GW chemicals and stress, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) content and expression of 84 mature miRNAs were analyzed in the brains of GWI rats and vehicle controls by ELISA and PCR array, respectively. In GWI rats, hippocampal 5mC content increased 46%, while 5hmC content increased 29% in the cerebellum and decreased 45% in the cortex (p<0.01 for all). Ten miRNAs known to be involved in synaptic plasticity and memory function, DNA methylation, or adult neurogenesis were differentially expressed (>1.5 fold change, p<0.01) in the hippocampus. Results from this study implicate a role for epigenetic alterations in GWI.

The role of astrocyte mitochondria in differential regional susceptibility to environmental neurotoxicants: tools for understanding neurodegeneration.

In recent decades, there has been a significant expansion in our understanding of the role of astrocytes in neuroprotection, including spatial buffering of extracellular ions, secretion of metabolic coenzymes, and synaptic regulation. Astrocytic neuroprotective functions require energy, and therefore require a network of functional mitochondria. Disturbances to astrocytic mitochondrial homeostasis and their ability to produce ATP can negatively impact neural function. Perturbations in astrocyte mitochondrial function may accrue as the result of physiological aging processes or as a consequence of neurotoxicant exposure. Hydrophobic environmental neurotoxicants, such as 1,3-dinitrobenzene and α-chlorohydrin, cause regionally specific spongiform lesions mimicking energy deprivation syndromes. Astrocyte involvement includes mitochondrial damage that either precedes or is accompanied by neuronal damage. Similarly, environmental neurotoxicants that are implicated in the etiology of age-related neurodegenerative conditions cause regionally specific damage in the brain. Based on the regioselective nature of age-related neurodegenerative lesions, chemically induced models of regioselective lesions targeting astrocyte mitochondria can provide insight into age-related susceptibilities in astrocyte mitochondria. Most of the available research to date focuses on neuronal damage in cases of age-related neurodegeneration; however, there is a body of evidence that supports a central mechanistic role for astrocyte mitochondria in the expression of neural injury. Regional susceptibility to neuronal damage induced by aging by exposure to neurotoxicants may be a reflection of highly variable regional energy requirements. This review identifies region-specific vulnerabilities in astrocyte mitochondria in examples of exposure to neurotoxicants and in age-related neurodegeneration.