Synaptic Cysteine Sulfhydryl Groups as Targets of Electrophilic Neurotoxicants

ToxSci Advance Access originally published online on July 31, 2006
Toxicological Sciences 2006 94(2):240-255; doi:10.1093/toxsci/kfl066
© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Synaptic Cysteine Sulfhydryl Groups as Targets of Electrophilic Neurotoxicants

Richard M. LoPachin*,1 and David S. Barber
* Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467-2490 Center for Environmental and Human Toxicology, University of Florida, Gainesville, Florida 32611-0885
Received May 17, 2006; accepted June 26, 2006

Many structurally diverse chemicals (e.g., acrylamide, 2,4-dithiobiuret, methylmercury) are electrophiles and cause synaptic dysfunction by unknown mechanisms. The purpose of this Forum review is to discuss the possibility that highly nucleophilic cysteine thiolate groups within catalytic triads of synaptic proteins represent specific and necessary targets for electrophilic neurotoxicants. Most of these toxicants share the ability to adduct or otherwise modify nucleophilic sulfhydryl groups. It is also now recognized that synaptic activity is regulated by the redox state of certain cysteine sulfhydryl groups on proteins. Electrophilic neurotoxicants might, therefore, produce synaptic toxicity by modifying these thiols. Because most proteins contain cysteine residues, target specificity is an issue that significantly detracts from the mechanistic validity of this hypothesis. However, recent research indicates that these thiolates are receptors for the endogenous nitric oxide (NO) pathway and that subsequent reversible S-nitrosylation finely regulates a broad spectrum of synaptic activities. We hypothesize that electrophilic neurotoxicants selectively adduct/derivatize NO-receptor thiolates in catalytic triads and that the resulting loss of fine gain control impairs neurotransmission and produces neurotoxicity. This proposal has mechanistic implications for a large class of electrophilic chemicals used in the agricultural and industrial sectors. In addition, research based on this hypothesis could provide mechanistic insight into neurodegenerative conditions such as Parkinsonism and Alzheimer's disease that presumably involve endogenous production of neurotoxic electrophiles (e.g., acrolein, 4-hydroxy-2-nonenal). The proposed mechanism of electrophilic neurotoxicants represents a new and exciting experimental framework for mechanistic research in human neuropathological conditions associated with toxicant exposure or disease-based processes.

Key Words: neurotoxicity; nitric oxide; toxic neuropathy; protein adduct; redox signaling; S-nitrosylation.
http://toxsci.oxfordjournals.org/cgi/content/abstract/94/2/240

Immunosuppressive Effect of Subchronic Exposure to a Mixture of Eight Heavy Metals

Arch Environ Contam Toxicol. 2007 Jul 26; [Epub ahead of print]

Immunosuppressive Effect of Subchronic Exposure to a Mixture of Eight Heavy Metals, Found as Groundwater Contaminants in Different Areas of India, Through Drinking Water in Male Rats.

Jadhav SH, Sarkar SN, Ram GC, Tripathi HC.

Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122, Uttar Pradesh, India, snsarkar@ivri.up.nic.in.

Immunotoxicity is an important health hazard of heavy metal exposure. Because the risk of combined exposure in the population cannot be neglected, we examined whether subchronic exposure to a mixture of metals (arsenic, cadmium, lead, mercury, chromium, nickel, manganese, and iron) via drinking water at contemporary Indian groundwater contamination levels and at concentrations equivalent to the WHO maximum permissible limit (MPL) in drinking water can induce immunotoxicity in male rats. Data on groundwater contamination with metals in India were collected from literature and metals were selected on the basis of their frequency of occurrence and contamination level above the MPL. Male albino Wistar rats were exposed to the mixture at 0, 1, 10, and 100 times the mode concentrations (the most frequently occurring concentration) of the individual metals in drinking water for 90 days. In addition, one group was exposed to the mixture at a concentration equal to the MPL of the individual metal and another group was used as positive control for immune response studies. The end points assessed were weights of organs, hematological indices, humoral and cell-mediated immune responses, and histopathology of skin and spleen. The MPL and 1x doses did not significantly affect any of the parameters and none of the doses induced any significant changes after 30 days of exposure. The mixture at 10x and 100x doses increased the relative weight of the spleen, but that of thymus, adrenals, and popliteal lymphnodes were increased with the 100x dose. After 90 days, 10x and 100x doses decreased serum protein and globulin contents and increased the albumin:globulin ratio; the albumin level was decreased only with the 100x dose. After 60 days, the total erythrocyte count (TEC), hemoglobin (Hb) level, and packed cell volume (PCV) were decreased with the 100x dose, whereas after 90 days, 10x and 100x doses reduced the TEC, total leukocyte count, Hb level, PCV, mean corpuscular volume, and mean corpuscular hemoglobin. With the 100x dose, the lymphocyte count was decreased after 60 and 90 days, but the neutrophil number was increased after 90 days. Antibody titer was decreased after 75 days with the 100x dose, but after 90 days, it was decreased with both the 10x and 100x doses. In delayed-type hypersensitivity response, these two doses decreased ear thickness after 24 and 48 h and skin biopsies showed a dose-dependent decrease in inflammatory changes. Histologically, the spleen revealed depletion of lymphoid cells and atrophic follicles with reduced follicular activity with higher doses. The findings suggest that hematopoietic and immune systems are toxicologically sensitive to the mixture, which could lead to anemia and suppression of humoral and cell-mediated immune responses in male rats at 10 and 100 times the mode concentrations of the individual components in contaminated groundwater.

PMID: 17657459 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17657459&itool=iconabstr&itool=pubmed_DocSum

Excess dampness and mold growth in homes: an evidence-based review of the aeroirritant effect and its potential causes

Allergy Asthma Proc. 2007 May-Jun;28(3):262-70.

Excess dampness and mold growth in homes: an evidence-based review of the aeroirritant effect and its potential causes.

Hope AP, Simon RA.

Division of Allergy, Asthma and Immunology, Scripps Clinic, La Jolla, California 92037, USA. aph11@columbia.edu

Exposure to fungi produces respiratory disease in humans through both allergic and nonallergic mechanisms. Occupants of homes with excess dampness and mold growth often present to allergists with complaints of aeroirritant symptoms. This review describes the major epidemiological and biological studies evaluating the association of indoor dampness and mold growth with upper respiratory tract symptoms. The preponderance of epidemiological data supports a link between exposure to dampness and excess mold growth and the development of aeroirritant symptoms. In addition, biological and clinical studies evaluating potential causal substances for the aeroirritant effect, notably volatile organic compounds (VOCs), are examined in detail. These studies support the role of VOCs in contributing to the aeroirritant symptoms of occupants of damp and mold-contaminated homes.