ABSTRACT
[This corrects the article DOI: 10.1016/j.toxrep.2020.04.011.].
ABSTRACT
Autoimmunity is a multifaceted disorder influenced by both genetic and environmental factors, and metal exposure has been implicated as a potential catalyst, especially in autoimmune diseases affecting the central nervous system. Notably, metals like mercury, lead, and aluminum exhibit well-established neurotoxic effects, yet the precise mechanisms by which they elicit autoimmune responses in susceptible individuals remain unclear. Recent studies propose that metal-induced autoimmunity may arise from direct toxic effects on immune cells and tissues, coupled with indirect impacts on the gut microbiome and the blood-brain barrier. These effects can activate self-reactive T cells, prompting the production of autoantibodies, inflammatory responses, and tissue damage. Diagnosing metal-induced autoimmunity proves challenging due to nonspecific symptoms and a lack of reliable biomarkers. Treatment typically involves chelation therapy to eliminate excess metals and immunomodulatory agents to suppress autoimmune responses. Prevention strategies include lifestyle adjustments to reduce metal exposure and avoiding occupational and environmental risks. Prognosis is generally favorable with proper treatment; however, untreated cases may lead to autoimmune disorder progression and irreversible organ damage, particularly in the brain. Future research aims to identify genetic and environmental risk factors, enhance diagnostic precision, and explore novel treatment approaches for improved prevention and management of this intricate and debilitating disease.
Subject(s)
Autoimmunity , Metals , Humans , Autoimmunity/drug effects , Autoimmunity/immunology , Metals/adverse effects , Metals/immunology , Nervous System Diseases/immunology , Animals , Autoimmune Diseases/immunologyABSTRACT
Glutamate, one of the most important excitatory neurotransmitters, acts as a signal transducer in peripheral tissues and endocrine cells. Excessive glutamate secretion has been shown to cause excitotoxicity and neurodegenerative disease. Cerebrolysin is a mixture of enzymatically treated peptides derived from pig brain including neurotrophic factors, like brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF). The present study investigated the protective effects of cerebrolysin on glutamate transporters (EAAT 1, EAAT 2) and cytokines (IL-1ß and IL-10) activity in glutamate-mediated neurotoxicity. Primary cortex neuron culture was exposed to glutamate and successively treated with various cerebrolysin concentrations for 24 and 48 h. Our data showed that cerebrolysin primarily protects neurons by decreasing glutamate concentration in the synaptic cleft. In addition, Cerebrolysin can decrease oxidative stress and neuron cell damage by increasing antioxidant activity and decreasing inflammation cytokine levels.
Subject(s)
Amino Acid Transport System X-AG , Neurodegenerative Diseases , Swine , Animals , Glutamic Acid/toxicity , Oxidative StressABSTRACT
This paper describes the synthesis of enamino carbonyl compounds by the copper(i)-catalyzed coupling of acceptor-substituted diazo compounds and tertiary thioamides. We plan to use this method to synthesize indolizidine (-)-237D analogs to find α6-selective antismoking agents. Therefore, we also performed in silico α6-nAchRs binding studies of selected products. Compounds with low root-mean-square deviation values showed more favorable binding free energies. We also report preliminary pharmacokinetic data on indolizidine (-)-237D and found it to have weak activity at CYP3A4. In addition, as enamino carbonyl compounds are also known for antimicrobial properties, we screened previously reported and new enamino carbonyl compounds for antibacterial, antimicrobial, and antifungal properties. Eleven compounds showed significant antimicrobial activities.
ABSTRACT
As our understanding of changes to the neurological system has improved, it has become clear that patients who have contracted human immunodeficiency virus type 1 (HIV-1) can potentially suffer from a cascade of neurological issues, including neuropathy, dementia, and declining cognitive function. The progression from mild to severe symptoms tends to affect motor function, followed by cognitive changes. Central nervous system deficits that are observed as the disease progresses have been reported as most severe in later-stage HIV infection. Examining the full spectrum of neuronal damage, generalized cortical atrophy is a common hallmark, resulting in the death of multiple classes of neurons. With antiretroviral therapy (ART), we can partially control disease progression, slowing the onset of the most severe symptoms such as, reducing viral load in the brain, and developing HIV-associated dementia (HAD). HAD is a severe and debilitating outcome from HIV-related neuropathologies. HIV neurotoxicity can be direct (action directly on the neuron) or indirect (actions off-site that affect normal neuronal function). There are two critical HIV-associated proteins, Tat and gp120, which bear responsibility for many of the neuropathologies associated with HAD and HIV-associated neurocognitive disorder (HAND). A cascade of systems is involved in HIV-related neurotoxicity, and determining a critical point where therapeutic strategies can be employed is of the utmost importance. This review will provide an overview of the existing hypotheses on HIV-neurotoxicity and the potential for the development of therapeutics to aid in the treatment of HIV-related nervous system dysfunction.
Subject(s)
AIDS Dementia Complex , Cognitive Dysfunction , HIV Infections , HIV-1 , Neurotoxicity Syndromes , AIDS Dementia Complex/drug therapy , AIDS Dementia Complex/metabolism , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/etiology , HIV Infections/complications , HIV Infections/drug therapy , HIV-1/metabolism , Humans , Neurons/metabolism , Neurotoxicity Syndromes/drug therapy , Neurotoxicity Syndromes/etiologyABSTRACT
Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as α6ß2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block α6ß2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for α6ß2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of α6ß2 nAChR that we derived from the recent crystal structure of α4ß2 nAChR. We also screened the crystal structure of α4ß2 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards α6ß2* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction.
Subject(s)
Drug Discovery , Indolizidines/chemistry , Molecular Dynamics Simulation , Receptors, Nicotinic/chemistry , Humans , Nicotinic Antagonists/chemistry , Protein Binding , Receptors, Nicotinic/metabolism , Smoking CessationABSTRACT
Living organisms have an innate ability to regulate the synthesis of inorganic materials, such as bones and teeth in humans. Cadmium sulfide (CdS) can be utilized as a quantum dot that functions as a unique light-emitting semiconductor nanocrystal. The increased use in CdS has led to an increased inhalation and ingestion rate of CdS by humans which requires a broader appreciation for the acute and chronic toxicity of CdS. We investigated the toxic effects of CdS on cerebellar cell cultures and rat brain. We employed a 'green synthesis' biosynthesis process to obtain biocompatible material that can be used in living organisms, such as Viridibacillus arenosi K64. Nanocrystal formation was initiated by adding CdCl2 (1â¯mM) to the cell cultures. Our in vitro results established that increased concentrations of CdS (0.1⯵g/mL) lead to decreased cell viability as assessed using 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT), total antioxidant capacity (TAC), and total oxidant status (TOS). The in vivo studies showed that exposure to CdS (1â¯mg/kg) glial fibrillary acidic protein (GFAP) and 8-hydroxy-2' -deoxyguanosine (8-OHdG) were increased. Collectively, we describe a model system that addresses the process from the synthesis to the neurotoxicity assessment for CdS both in vitro and in vivo. These data will be beneficial in establishing a more comprehensive pathway for the understanding of quantum dot-induced neurotoxicity.
ABSTRACT
Toxic metals are extensively found in the environment, households, and workplaces and contaminate food and drinking water. The crosstalk between environmental exposure to toxic metals and human diseases has been frequently described. The toxic mechanism of action was classically viewed as the ability to dysregulate the redox status, production of inflammatory mediators and alteration of mitochondrial function. Recently, growing evidence showed that heavy metals might exert their toxicity through microRNAs (miRNA)-short, single-stranded, noncoding molecules that function as positive/negative regulators of gene expression. Aberrant alteration of the endogenous miRNA has been directly implicated in various pathophysiological conditions and signaling pathways, consequently leading to different types of cancer and human diseases. Additionally, the gene-regulatory capacity of miRNAs is particularly valuable in the brain-a complex organ with neurons demonstrating a significant ability to adapt following environmental stimuli. Accordingly, dysregulated miRNAs identified in patients suffering from neurological diseases might serve as biomarkers for the earlier diagnosis and monitoring of disease progression. This review will greatly emphasize the effect of the toxic metals on human miRNA activities and how this contributes to progression of diseases such as cancer and neurodegenerative disorders (NDDs).
Subject(s)
Heavy Metal Poisoning/genetics , MicroRNAs/biosynthesis , Animals , Early Diagnosis , Gene Expression/drug effects , Heavy Metal Poisoning/metabolism , Humans , Metals, Heavy/pharmacology , Metals, Heavy/toxicity , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Rats , Risk AssessmentABSTRACT
Tauopathies are a disease group characterized by either pathological accumulation or release of fragments of hyperphosphorylated tau proteins originating from the central nervous system. The tau hypotheses of Parkinson's and Alzheimer's diseases contain a clinically diverse spectrum of tauopathies. Studies of case records of various tauopathies may reveal clinical phenotype characteristics of the disease. In addition, improved understanding of different tauopathies would disclose environmental factors, such as xenobiotics and trace metals, that can precipitate or modify the progression of the disorder. Important for diagnostics and monitoring of these disorders is a further development of adequate biomarkers, including refined neuroimaging, or proteomics. Our goal is to provide an in-depth review of the current literature regarding the pathophysiological roles of tau proteins and the pathogenic factors leading to various tauopathies, with the perspective of future advances in potential therapeutic strategies.
Subject(s)
Alzheimer Disease , Tauopathies , Xenobiotics , Alzheimer Disease/chemically induced , Humans , Metals , Tauopathies/chemically induced , Xenobiotics/toxicity , tau ProteinsABSTRACT
Humans are exposed to multiple chemicals on a daily basis instead of to just a single chemical, yet the majority of existing toxicity data comes from single-chemical exposure. Multiple factors must be considered such as the route, concentration, duration, and the timing of exposure when determining toxicity to the organism. The need for adequate model systems (in vivo, in vitro, in silico and mathematical) is paramount for better understanding of chemical mixture toxicity. Currently, shortcomings plague each model system as investigators struggle to find the appropriate balance of rigor, reproducibility and appropriateness in mixture toxicity studies. Significant questions exist when comparing single-to mixture-chemical toxicity concerning additivity, synergism, potentiation, or antagonism. Dose/concentration relevance is a major consideration and should be subthreshold for better accuracy in toxicity assessment. Previous work was limited by the technology and methodology of the time, but recent advances have resulted in significant progress in the study of mixture toxicology. Novel technologies have added insight to data obtained from in vivo studies for predictive toxicity testing. These include new in vitro models: omics-related tools, organs-on-a-chip and 3D cell culture, and in silico methods. Taken together, all these modern methodologies improve the understanding of the multiple toxicity pathways associated with adverse outcomes (e.g., adverse outcome pathways), thus allowing investigators to better predict risks linked to exposure to chemical mixtures. As technology and knowledge advance, our ability to harness and integrate separate streams of evidence regarding outcomes associated with chemical mixture exposure improves. As many national and international organizations are currently stressing, studies on chemical mixture toxicity are of primary importance.
Subject(s)
Chemical Safety/methods , Risk Assessment/methods , Toxicity Tests/methods , Animals , Computer Simulation , Environmental Exposure/adverse effects , Humans , Models, Biological , Models, Theoretical , Reproducibility of ResultsABSTRACT
Pancreatic cancer (PC) is insidious with a high mortality rate due to the lack of symptomology prior to diagnosis. Mitochondrial involvement in PC development is becoming accepted, and exposure to cadmium (Cd) is suspected of being a risk factor for the development of PC; however, the mechanisms involved remain unclear. In this study, we examined the role of Cd as a mitochondrial toxicant and whether alterations in mitochondrial function may be an underlying cause for the development of PC. In this study, cadmium chloride (CdCl2)mediated toxicity in hTERTHPNE and AsPC1 pancreatic cell lines was determined by MTT assay. We also investigated the release of LDH and the generation of free radicals. Mitochondrial toxicity assays were performed in media containing glucose (25 mM) or galactose (10 mM) and following exposure to CdCl2 (0100 µM) followed by MTT assay. For the confirmation of mitochondrial toxicity, we measured the release of ATP following exposure to CdCl2. Initial experiments confirmed that exposure to CdCl2 did not reduce the viability of either cell line until a concentration of >10 µM was used. Nonlinear analysis of the response curves revealed lethal concentration 50% (LC50) values for CdCl2 in the HPNE cells of 77 µM compared to 42 µM in the AsPC1 cells (P<0.01). The CdCl2mediated mitochondrial toxic effects were greater in the HPNE cells, suggesting a heightened sensitivity to the effects of CdCl2, not due to elevated oxidative stress. Increased mitochondrial toxic sensitivity was indicated by a 73.4% reduction in IC50 values in the HPNE cells cultured in galactose compared to culture in glucose media, whereas the AsPC1 cells exhibited a 58.8% reduction in IC50 values. In addition, the higher concentration of CdCl2 elicited a significant celldependent effect on ATP release in both cell lines, suggestive of CdCl2 being a mitochondrial toxicant. Cell survival was unaffected following exposure to low concentrations of CdCl2; however, exposure did alter mitochondrial function (control cells > tumor cells). Therefore, the findings of this study indicate that the mitochondria may be a site of action for cadmium in promoting tumor development.
Subject(s)
Cadmium Chloride/pharmacology , Cytotoxins/pharmacology , Mitochondria/metabolism , Oxidative Stress/drug effects , Pancreas/metabolism , Pancreatic Neoplasms/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Mitochondria/pathology , Pancreas/pathology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathologyABSTRACT
Although profoundly studied, etiology of pancreatic cancer (PC) is still rather scarce. Some of established risk factors of PC are connected to an increased cadmium (Cd) body burden. Hence, the aim of this study was to investigate the role of this environmental pollutant in PC development by conducting human observational, experimental and in vitro studies. The case-control study included 31 patients with a histologically based diagnosis of exocrine PC subjected to radical surgical intervention as cases and 29 accidental fatalities or subjects who died of a nonmalignant illness as controls. Animal study included two treated groups of Wistar rats (15 and 30â¯mg Cd/kg b.w) and untreated control group, sacrificed 24â¯h after single oral exposure. In in vitro study pancreas hTERT-HPNE and AsPC-1 cells were exposed to different Cd concentrations corresponding to levels measured in human cancerous pancreatic tissue. Cd content in cancer tissue significantly differed from the content in healthy controls. Odds ratio levels for PC development were 2.79 (95% CI 0.91-8.50) and 3.44 (95% CI 1.19-9.95) in the third and fourth quartiles of Cd distribution, respectively. Animal study confirmed Cd deposition in pancreatic tissue. In vitro studies revealed that Cd produces disturbances in intrinsic pathway of apoptotic activity and the elevation in oxidative stress in pancreatic cells. This study presents three different lines of evidence pointing towards Cd as an agent responsible for the development of PC.
Subject(s)
Cadmium/metabolism , Environmental Exposure/analysis , Pancreas/chemistry , Adult , Aged , Animals , Cadmium/toxicity , Case-Control Studies , Cell Line , Environmental Exposure/adverse effects , Female , Humans , Male , Middle Aged , Pancreatic Neoplasms/chemically induced , Rats , Rats, Wistar , SerbiaABSTRACT
We present a 42-year-old male with strictured bilioenteric anastomosis after bile duct injury repair. The patient improved after percutaneous biliary drainage and balloon dilation of the stricture. Persistent bile reflux around the catheter insertion site prompted a cholangiogram that suggested an error in the enteric limb. Surgical exploration revealed that a torsed ileal loop was used for bilioenteric anastomosis. This error was repaired surgically. The patient had immediate and long-term resolution of symptoms.
Subject(s)
Bile Duct Diseases/surgery , Bile Ducts/injuries , Bile Ducts/surgery , Cholangiography , Cholecystectomy, Laparoscopic/adverse effects , Adult , Anastomosis, Surgical , Constriction, Pathologic , Drainage , Humans , MaleABSTRACT
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]. [...].
ABSTRACT
As the use of nanotechnology has expanded, an increased number of metallic oxides have been manufactured, yet toxicology testing has lagged significantly. Metals used in nano-products include titanium, silicon, aluminum, silver, zinc, cadmium, cobalt, antimony, gold, etc. Even the noble metals, platinum and cerium, have been used as a treatment for cancer, but the toxicity of these metals is still unknown. Significant advances have been made in our understanding and treatment of breast cancer, yet millions of women will experience invasive breast cancer in their lifetime. The pathogenesis of breast cancer can involve multiple factors; (1) genetic; (2) environmental; and (3) lifestyle-related factors. This review focuses on exposure to highly toxic metals, ("metalloestrogens" or "endocrine disruptors") that are used as the metallic foundation for nanoparticle production and are found in a variety of consumer products such as cosmetics, household items, and processed foods, etc. The linkage between well-understood metalloestrogens such as cadmium, the use of these metals in the production of nanoparticles, and the relationship between their potential estrogenic effects and the development of breast cancer will be explored. This will underscore the need for additional testing of materials used in nano-products. Clearly, a significant amount of work needs to be done to further our understanding of these metals and their potential role in the pathogenesis of breast cancer.
ABSTRACT
We examined the effects of chronic metals ingestion on social behavior in the normally highly social prairie vole to test the hypothesis that metals may interact with central dopamine systems to produce the social withdrawal characteristic of autism. Relative to water-treated controls, 10 weeks of chronic ingestion of either Hg(++) or Cd(++) via drinking water significantly reduced social contact by male voles when they were given a choice between isolation or contact with an unfamiliar same-sex conspecific. The effects of metals ingestion were specific to males: no effects of metals exposure were seen in females. Metals ingestion did not alter behavior of males allowed to choose between isolation or their familiar cage-mates, rather than strangers. We also examined the possibility that metals ingestion affects central dopamine functioning by testing the voles' locomotor responses to peripheral administration of amphetamine. As with the social behavior, we found a sex-specific effect of metals on amphetamine responses. Males that consumed Hg(++) did not increase their locomotor activity in response to amphetamine, whereas similarly treated females and males that ingested only water significantly increased their locomotor activities. Thus, an ecologically relevant stimulus, metals ingestion, produced two of the hallmark characteristics of autism - social avoidance and a male-oriented bias. These results suggest that metals exposure may contribute to the development of autism, possibly by interacting with central dopamine function, and support the use of prairie voles as a model organism in which to study autism.
Subject(s)
Arvicolinae , Autistic Disorder/chemically induced , Cadmium Chloride/toxicity , Mercuric Chloride/toxicity , Metals, Heavy/toxicity , Social Behavior , Animals , Autistic Disorder/metabolism , Behavior, Animal/drug effects , Brain/drug effects , Brain/metabolism , Cadmium/administration & dosage , Cadmium/metabolism , Cadmium/toxicity , Cadmium Chloride/administration & dosage , Disease Models, Animal , Female , Male , Mercuric Chloride/administration & dosage , Mercury/administration & dosage , Mercury/metabolism , Mercury/toxicity , Metals, Heavy/administration & dosage , Motor Activity/drug effects , Random Allocation , Recognition, Psychology , Sex Characteristics , Time FactorsABSTRACT
Human immunodeficiency virus (HIV)-1 Tat protein plays a key role in the pathogenesis of both HIV-1-associated cognitive-motor disorder and drug abuse. Dopamine (DA) transporter (DAT) function is strikingly altered in patients with HIV-1-associated dementia and a history of chronic drug abuse. This study is the first in vitro evaluation of potential mechanisms underlying the effects of Tat protein on DAT function. Rat striatal synaptosomes were incubated with recombinant Tat(1-86) protein, and [(3)H]DA uptake and the binding of [(3)H]2beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (WIN 35,428) and [(3)H]1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine (GBR 12935) were determined. Tat decreased [(3)H]DA uptake, [(3)H]WIN 35,428 binding, and [(3)H]GBR 12935 binding in a time-dependent manner. The potency of Tat for inhibiting [(3)H]DA uptake (K(i) = 1.2 microM) was the same as that for inhibiting [(3)H]GBR 12935 binding but 3-fold less than that for inhibiting [(3)H]WIN 35,428 binding. Mutant Tat proteins did not alter [(3)H]DA uptake. Kinetic analysis of [(3)H]DA uptake revealed that Tat (1 or 10 microM) decreased the V(max) value and increased the K(m) value in a dose-dependent manner. The V(max) value, decreased by Tat (1 microM), returned to the control level after washout of Tat, indicating that the inhibitory effect of Tat on DA uptake was reversible. Saturation studies revealed that Tat decreased the B(max) value and increased the K(d) value of [(3)H]WIN 35,428 binding, whereas Tat decreased the B(max) value of [(3)H]GBR 12935 binding, without a change in the K(d) value. These findings provide new insight into understanding the pharmacological mechanisms of Tat-induced dysfunction of the DAT in the dopaminergic system in HIV-infected patients.
Subject(s)
Cocaine/analogs & derivatives , Corpus Striatum/cytology , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine/metabolism , Synaptosomes/metabolism , tat Gene Products, Human Immunodeficiency Virus/metabolism , Animals , Binding Sites/physiology , Cocaine/metabolism , Dopamine Plasma Membrane Transport Proteins/drug effects , Dopamine Uptake Inhibitors/metabolism , In Vitro Techniques , Leucine/metabolism , Male , Piperazines/metabolism , Protein Binding/physiology , Rats , Rats, Sprague-Dawley , Surface Plasmon Resonance , Synaptosomes/drug effects , tat Gene Products, Human Immunodeficiency Virus/pharmacologyABSTRACT
Individuals suffering from human immunodeficiency virus type 1 (HIV-1) infection suffer from a wide range of neurological deficits. The most pronounced are the motor and cognitive deficits observed in many patients in the latter stages of HIV infection. Gross postmortem inspection shows cortical atrophy and widespread neuronal loss. One of the more debilitating of the HIV-related syndromes is AIDS-related dementia, or HAD. Complete understanding of HIV neurotoxicity has been elusive. Both direct and indirect toxic mechanisms have been implicated in the neurotoxicity of the HIV proteins, Tat and gp120. The glutamatergic system, nitric oxide, calcium, oxidative stress, apoptosis, and microglia have all been implicated in the pathogenesis of HIV-related neuronal degeneration. The aim of this review is to summarize the most recent work and provide an overview to the current theories of HIV-related neurotoxicity and potential avenues of therapeutic interventions to prevent the neuronal loss and motor/cognitive deficits previously described.
ABSTRACT
BACKGROUND: Prenatal cocaine exposure produces attentional deficits which to persist through early childhood. Given the role of norepinephrine (NE) in attentional processes, we examined the forebrain NE systems from prenatal cocaine exposed rats. Cocaine was administered during pregnancy via the clinically relevant intravenous route of administration. Specifically, we measured alpha2-adrenergic receptor (alpha2-AR) density in adolescent (35-days-old) rats, using [3H]RX821002 (5 nM). RESULTS: Sex-specific alterations of alpha2-AR were found in the hippocampus and amygdala of the cocaine-exposed animals, as well as an upregulation of alpha2-AR in parietal cortex. CONCLUSION: These data suggest that prenatal cocaine exposure results in a persistent alteration in forebrain NE systems as indicated by alterations in receptor density. These neurochemical changes may underlie behavioral abnormalities observed in offspring attentional processes following prenatal exposure to cocaine.