Urinary delta-ALA: A potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese

Abstract

Lead (Pb), arsenic (As) and manganese (Mn) are neurotoxic elements that often occur in mixtures for which practically no information is available on biomarkers (BMs) for the evaluation of exposure/effects. Exposures to these metals may increase delta-aminolevulinic acid (delta-ALA), which in itself may potentiate neurotoxicity. The objective of this study was to investigate the utility of urinary delta-ALA (delta-ALA-U) levels as BM of exposure and/or neurotoxic effects induced by this mixture. Five groups of Wistar rats were treated for 8 days with Pb (5 mg/kg), As (60 mg/L), Mn (10 mg/kg), the 3-metal mixture (same doses of the single metals), and control group. Motor activity was evaluated and 24-h urine collected before and after the treatment. 24-hours (h) after the last dose, the rats were sacrificed and the brains removed for analyses. Delta-ALA and metal levels were determined in brain and urine. Co-treated rats showed a significant (p<0.05) correlation between increased Pb, As, Mn and delta-ALA levels in the brain and decreased motor activity. Delta-ALA-U concentrations were higher in the mixture-treated group than the sum of the delta-ALA-U levels in each single-treated groups and discriminated (p<0.05) between the mixture and untreated rats. Moreover, delta-ALA-U was correlated (p<0.05) with brain delta-ALA levels. These results establish that treatments with this metal mixture exacerbate behavioral dysfunction, increasing most prominently brain Pb levels. This study is the first to establish that delta-ALA-U levels represent a sensitive BM of exposure/neurotoxic effect to this metal mixture.

Changes in rat urinary porphyrin profiles predict the magnitude of the neurotoxic effects induced by a mixture of lead, arsenic and manganese

“…Moreover, once within neural cells, ALA cannot be released into the blood (García et al, 1998). Previous studies from our laboratory have also established that treatment with a metal-mixture containing Pb, As and Mn causes significant accumulation of ALA in the brain (Andrade et al, 2013), consistent with increased porphyrin levels in Mn-treated rats (Maines, 1980). The brain is normally well protected from changes in ALA plasma concentrations by the low blood-brain barrier permeability of this compound as well as by a saturable efflux mechanism that is present at the choroid plexus (Ennis et al, 2003).…”

“…A sub-acute assay was performed as previously described by Andrade et al (2013). Adult, male Wistar rats (165-206 g) were acclimated in the animal facility for 15 days.…”

“…Behavioral assays were performed as previously described by Andrade et al (2013). Motor activity was assessed in an open-field apparatus (Marreilha dos Santos et al, 2012) to evaluate impaired performance upon metal exposure.…”

Inorganic Arsenic Exposure and Children’s Neurodevelopment: A Review of the Evidence

“…The two chemicals that have been examined in this way are lead and manganese. The rationale for examining these metals is provided by studies in rodents indicating that, compared to animals exposed to one metal at a time, combined exposure to arsenic, lead, and manganese resulted in lower brain levels of monoamines [53] and reduced dopamine response to stimulation [54], greater brain levels of delta-amino levulinic acid [55], greater white matter damage [56], reduction in glial fibrillary acid protein expression and increased apoptosis of astrocytes [57]. In three epidemiological studies, all conducted in Mexico, no evidence supporting a significant interaction between arsenic and lead was found [29,36,41].…”

Acetylcholinesterase activity and oxidative stress indices in cerebellum, cortex and hippocampus of rats exposed to lead and manganese

“…Pb is one of the key environmental heavy metal pollutants and exposure to this metal occur from a variety of sources. Besides metal smelting operations, increased Pb levels in the environment are principally attributed to combustion of leaded gasoline, contaminated water supply by industrial waste, as well as, occupational settings (Jemiola-Rzeminska, 2007; Andrade et al 2013). After gastrointestinal absorption, Pb is predominantly deposited in the brain, kidney and blood, which can induce neurological, nephrotoxic and hematological effects respectively (ATSDR, 2007;Hodgson, 2010).…”