Neurotoxicity following acute inhalation of aerosols generated during resistance spot weld-bonding of carbon steel

Abstract Welding generates complex metal aerosols, inhalation of which is linked to adverse health effects among welders. An important health concern of welding fume (WF) exposure is neurological dysfunction akin to Parkinson's disease (PD). Some applications in manufacturing industry employ a variant welding technology known as “weld-bonding” that utilizes resistance spot welding, in combination with adhesives, for metal-to-metal welding. The presence of adhesives raises additional concerns about worker exposure to potentially toxic components like Methyl Methacrylate, Bisphenol A and volatile organic compounds (VOCs). Here, we investigated the potential neurotoxicological effects of exposure to welding aerosols generated during weld-bonding. Male Sprague–Dawley rats were exposed (25 mg/m3 targeted concentration; 4 h/day × 13 days) by whole-body inhalation to filtered air or aerosols generated by either weld-bonding with sparking (high metal, low VOCs; HM) or without sparking (low metal; high VOCs; LM). Fumes generated under these conditions exhibited complex aerosols that contained both metal oxide particulates and VOCs. LM aerosols contained a greater fraction of VOCs than HM, which comprised largely metal particulates of ultrafine morphology. Short-term exposure to LM aerosols caused distinct changes in the levels of the neurotransmitters, dopamine (DA) and serotonin (5-HT), in various brain areas examined. LM aerosols also specifically decreased the mRNA expression of the olfactory marker protein (Omp) and tyrosine hydroxylase (Th) in the olfactory bulb. Consistent with the decrease in Th, LM also reduced the expression of dopamine transporter (Slc6a3; Dat), as well as, dopamine D2 receptor (Drd2) in the olfactory bulb. In contrast, HM aerosols induced the expression of Th and dopamine D5 receptor (Drd5) mRNAs, elicited neuroinflammation and blood–brain barrier-related changes in the olfactory bulb, but did not alter the expression of Omp. Our findings divulge the differential effects of LM and HM aerosols in the brain and suggest that exposure to weld-bonding aerosols can potentially elicit neurotoxicity following a short-term exposure. However, further investigations are warranted to determine if the aerosols generated by weld-bonding can contribute to persistent long-term neurological deficits and/or neurodegeneration.

[1]  Omid Aminian,et al.  Pulmonary effects of spot welding in automobile assembly. , 2009, Occupational medicine.

[2]  T. Kosaka,et al.  Coexistence of immunoreactivities for glutamate decar☐ylase and tyrosine hydroxylase in some neurons in the periglomerular region of the rat main olfactory bulb: possible coexistence of gamma-aminobutyric acid (GABA) and dopamine , 1985, Brain Research.

[3]  T. Ikeda,et al.  Neurobehavioral effects of chronic occupational exposure to organic solvents among Japanese industrial painters. , 1993, Environmental research.

[4]  D. Grandy,et al.  Dopamine D2 receptors mediate two-odor discrimination and reversal learning in C57BL/6 mice , 2004, BMC Neuroscience.

[5]  G. Weissmann,et al.  Science fraud: from patchwork mouse to patchwork data , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  Sanae Nakagawa,et al.  Manganese exposure: neuropsychological and neurological symptoms and effects in welders. , 2006, Neurotoxicology.

[7]  B. Bjelke,et al.  Inhalation of Low Concentrations of Toluene Induces Persistent Effects on a Learning Retention Task, Beam-Walk Performance, and Cerebrocortical Size in the Rat , 2000, Experimental Neurology.

[8]  J. Chang,et al.  Manganese potentiates nitric oxide production by microglia. , 1999, Brain research. Molecular brain research.

[9]  A Wennberg,et al.  Manganese exposure in steel smelters a health hazard to the nervous system. , 1991, Scandinavian journal of work, environment & health.

[10]  Robert Gelein,et al.  EXTRAPULMONARY TRANSLOCATION OF ULTRAFINE CARBON PARTICLES FOLLOWING WHOLE-BODY INHALATION EXPOSURE OF RATS , 2002, Journal of toxicology and environmental health. Part A.

[11]  J. Finkelstein,et al.  Translocation of Inhaled Ultrafine Manganese Oxide Particles to the Central Nervous System , 2006, Environmental health perspectives.

[12]  Michael Jerrett,et al.  A study of the relationships between Parkinson's disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities. , 2007, Environmental research.

[13]  Dawn N. Wilson,et al.  The D2 antagonist spiperone mimics the effects of olfactory deprivation on mitral/tufted cell odor response patterns , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  H. Berendse,et al.  Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell , 2001, Annals of neurology.

[15]  B. Undem,et al.  Identification and substance P content of vagal afferent neurons innervating the epithelium of the guinea pig trachea. , 1999, American journal of respiratory and critical care medicine.

[16]  R. Egleton,et al.  Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier , 2001, Trends in Neurosciences.

[17]  G. Miller,et al.  Olfactory discrimination deficits in mice lacking the dopamine transporter or the D2 dopamine receptor , 2006, Behavioural Brain Research.

[18]  J. O'Callaghan,et al.  Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor‐α , 2006, Journal of neurochemistry.

[19]  D. Miller,et al.  Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: Implications for Parkinson's disease , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  M. Héry,et al.  Neurobehavioral disturbances arising from occupational toluene exposure. , 2002, American journal of industrial medicine.

[21]  K. Audus,et al.  Nitric oxide and blood-brain barrier integrity. , 2001, Antioxidants & redox signaling.

[22]  M. Vatta,et al.  Short-term Effects of Endothelins on Tyrosine Hydroxylase Activity and Expression in the Olfactory Bulb of Normotensive Rats , 2009, Neurochemical Research.

[23]  T. Getchell,et al.  Human and rodent OMP genes: conservation of structural and regulatory motifs and cellular localization. , 1994, Genomics.

[24]  Li Zhang,et al.  Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. , 2007, Neurotoxicology.

[25]  R. Doty,et al.  NEUROTOXIC EXPOSURE AND OLFACTORY IMPAIRMENT , 2001 .

[26]  W. Kreyling,et al.  Translocation of Inhaled Ultrafine Particles to the Brain , 2004, Inhalation toxicology.

[27]  Maryse Bouchard,et al.  Sequelae of fume exposure in confined space welding: a neurological and neuropsychological case series. , 2007, Neurotoxicology.

[28]  D. Jennings,et al.  Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders , 2005, Neurology.

[29]  G. Langolf,et al.  Acute behavioural comparisons of toluene and ethanol in human subjects. , 1991, British journal of industrial medicine.

[30]  Pratim Biswas,et al.  Characterization of the aerosols resulting from arc welding processes , 2001 .

[31]  N. Yamanouchi,et al.  White matter changes caused by chronic solvent abuse. , 1995, AJNR. American journal of neuroradiology.

[32]  Tze Wai Wong,et al.  Occupational Exposure to Mixtures of Organic Solvents Increases the Risk of Neurological Symptoms Among Printing Workers in Hong Kong , 2004, Journal of occupational and environmental medicine.

[33]  E. Hirsch,et al.  The inflammatory response in the Parkinson brain , 2001, Clinical Neuroscience Research.

[34]  P. Riederer,et al.  Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. , 1994, Neuroscience letters.

[35]  L. Franzen,et al.  Regulation of c-Fos mRNA and fos protein expression in olfactory bulbs from unilaterally odor-deprived adult mice , 1996, International Journal of Developmental Neuroscience.

[36]  A. Ghio,et al.  Dopaminergic neurotoxicity following pulmonary exposure to manganese-containing welding fumes , 2010, Archives of Toxicology.

[37]  Minoru Harada,et al.  Tumor necrosis factor-α (TNF-α) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients , 1994, Neuroscience Letters.

[38]  Elisabetta Dejana,et al.  Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. , 2004, Physiological reviews.

[39]  P Apostoli,et al.  Long-term exposure to "low levels" of manganese oxides and neurofunctional changes in ferroalloy workers. , 1999, Neurotoxicology.

[40]  W. McKinney,et al.  Development and characterization of a resistance spot welding aerosol generator and inhalation exposure system , 2014, Inhalation toxicology.

[41]  B. Sharrack,et al.  Role of Caspases in Cytokine-Induced Barrier Breakdown in Human Brain Endothelial Cells , 2012, The Journal of Immunology.

[42]  P S Goldman-Rakic,et al.  Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Thomas W. Eagar,et al.  Particle size distribution of gas metal and flux cored arc welding fumes , 2005 .

[44]  S. Tsukita,et al.  Size-selective loosening of the blood-brain barrier in claudin-5–deficient mice , 2003, The Journal of cell biology.

[45]  P. Mcgeer,et al.  Inflammation and neurodegeneration in Parkinson's disease. , 2004, Parkinsonism & related disorders.

[46]  M. Leon,et al.  Synaptophysin-like immunoreactivity in the rat olfactory bulb during postnatal development and after restricted early olfactory experience. , 1996, Brain research. Developmental brain research.

[47]  S. J. Dong,et al.  A study of the role of adhesives in weld-bonded joints , 1999 .

[48]  Jenny R. Roberts,et al.  Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes. , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  R. Bakshi,et al.  MRI in chronic toluene abuse: low signal in the cerebral cortex on T2-weighted images , 1998, Neuroradiology.

[50]  A. Emara,et al.  Chronic manganese poisoning in the dry battery industry , 1971, British journal of industrial medicine.

[51]  R. Bowler,et al.  Dose–effect relationships between manganese exposure and neurological, neuropsychological and pulmonary function in confined space bridge welders , 2006, Occupational and Environmental Medicine.

[52]  R. Kream,et al.  Olfactory marker protein (OMP) gene deletion causes altered physiological activity of olfactory sensory neurons. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[53]  R. Balster Neural basis of inhalant abuse. , 1998, Drug and alcohol dependence.

[54]  D. Lawrence,et al.  Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[55]  J. D. Wang,et al.  Acute and chronic neurological symptoms among paint workers exposed to mixtures of organic solvents. , 1993, Environmental research.

[56]  M. Trenerry,et al.  Neurologic manifestations in welders with pallidal MRI T1 hyperintensity , 2005, Neurology.

[57]  Roberta F. White,et al.  Solvents and neurotoxicity , 1997, The Lancet.

[58]  W. Hanneman,et al.  Gene deletion of nos2 protects against manganese-induced neurological dysfunction in juvenile mice. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[59]  D. Deleu,et al.  Cerebellar Dysfunction in Chronic Toluene Abuse: Beneficial Response to Amantadine Hydrochloride , 2000, Journal of toxicology. Clinical toxicology.

[60]  M. Vatta,et al.  Calcium-dependent mechanisms involved in the modulation of tyrosine hydroxylase by endothelins in the olfactory bulb of normotensive rats , 2013, Neurochemistry International.

[61]  M. Ueno,et al.  Blood-brain barrier disruption in the hypothalamus of young adult spontaneously hypertensive rats , 2004, Histochemistry and Cell Biology.

[62]  J. Cavanagh Solvent neurotoxicity. , 1985, British journal of industrial medicine.

[63]  H. Wolburg,et al.  Tight Junctions of the Blood–Brain Barrier , 2000, Cellular and Molecular Neurobiology.

[64]  M. Pai,et al.  Central neurological abnormalities and multiple chemical sensitivity caused by chronic toluene exposure. , 2003, Occupational medicine.

[65]  K. Fuxe,et al.  Persistent effects of subchronic toluene exposure on spatial learning and memory, dopamine-mediated locomotor activity and dopamine D2 agonist binding in the rat. , 1993, Toxicology.

[66]  D Mergler,et al.  Early manifestations of manganese neurotoxicity in humans: an update. , 1997, Environmental research.

[67]  J RODIER,et al.  Manganese Poisoning in Moroccan Miners , 1955, British journal of industrial medicine.

[68]  P. Biberfeld,et al.  Transmitter histochemistry of the rat olfactory bulb. I. Immunohistochemical localization of monoamine synthesizing enzymes. Support for intrabulbar, periglomerular dopamine neurons , 1977, Brain Research.

[69]  J. Mink,et al.  Welding-related parkinsonism , 2001, Neurology.

[70]  Roberto G Lucchini,et al.  High prevalence of Parkinsonian disorders associated to manganese exposure in the vicinities of ferroalloy industries. , 2007, American journal of industrial medicine.

[71]  S Katharine Hammond,et al.  Respiratory Health Effects Related to Occupational Spray Painting and Welding , 2005, Journal of occupational and environmental medicine.

[72]  J. Luo,et al.  Pulmonary function abnormalities and airway irritation symptoms of metal fumes exposure on automobile spot welders. , 2006, American journal of industrial medicine.

[73]  J. Donaldson,et al.  The physiopathologic significance of manganese in brain: its relation to schizophrenia and neurodegenerative disorders. , 1987, Neurotoxicology.