title: Changes in rat urinary porphyrin profiles predict the magnitude of the neurotoxic effects induced by a mixture of lead, arsenic and manganese.
abstract: The neurotoxic metals lead (Pb), arsenic (As) and manganese (Mn) are ubiquitous contaminants occurring as mixtures in environmental settings. The three metals may interfere with enzymes of the heme bioshyntetic pathway, leading to excessive porphyrin accumulation, which per se may trigger neurotoxicity. Given the multi-mechanisms associated with metal toxicity, we posited that a single biomarker is unlikely to predict neurotoxicity that is induced by a mixture of metals. Our objective was to evaluate the ability of a combination of urinary porphyrins to predict the magnitude of motor activity impairment induced by a mixture of Pb/As/Mn. Five groups of Wistar rats were treated for 8 days with Pb (5mg/kg), As (60 mg/L) or Mn (10mg/kg), and the 3-metal mixture (same doses as the single metals) along with a control group. Motor activity was evaluated after the administration of the last dose and 24-hour (h) urine was also collected after the treatments. Porphyrin profiles were determined both in the urine and brain. Rats treated with the metal-mixture showed a significant decrease in motor parameters compared with controls and the single metal-treated groups. Both brain and urinary porphyrin levels, when combined and analyzed by multiple linear regressions, were predictable of motor activity (p<0.05). The magnitude of change in urinary porphyrin profiles was consistent with the greatest impairments in motor activity as determined by receiver operating characteristic (ROC) curves, with a sensitivity of 88% and a specificity of 96%. Our work strongly suggests that the use of a linear combination of urinary prophyrin levels accurately predicts the magnitude of motor impairments in rats that is induced by a mixture of Pb, As and Mn.
authors.affiliation: Instituto de Investigação do Medicamento, iMed.UL, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
authors.forename: Vanda
authors.initials: V
authors.lastname: Andrade
authors.affiliation: Instituto de Investigação do Medicamento, iMed.UL, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
authors.forename: M Luísa
authors.initials: ML
authors.lastname: Mateus
authors.affiliation: Instituto de Investigação do Medicamento, iMed.UL, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
authors.forename: M Camila
authors.initials: MC
authors.lastname: Batoréu
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.affiliation: Instituto de Investigação do Medicamento, iMed.UL, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal. Electronic address: apsantos@ff.ul.pt.
authors.forename: A P
authors.initials: AP
authors.lastname: Marreilha dos Santos
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D015415:Biomarkers / Q000652:urine; D001923:Brain Chemistry; D000075322:Heavy Metal Poisoning; D007854:Lead / Q000633:toxicity*; D008297:Male; D008345:Manganese / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000175:diagnosis; D011041:Poisoning / Q000175:diagnosis*; D011166:Porphyrins / Q000652:urine*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015415:Biomarkers; D011166:Porphyrins; D007854:Lead; D008345:Manganese; D001151:Arsenic
keywords: Lead, arsenic and manganese metal mixture; Neurotoxicity; Urinary porphyrin profiles