Teresa Coccini
Research interests
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InterestsBiochemical markers, nanomaterial safety, environmental and occupational pollutants, Neurotoxicology, lung toxicity
Publications
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Application of Neurochemical Markers for Assessing Health Effects after Developmental Methylmercury and PCB Coexposure.
Journal of toxicology. 01/2012; 2012:216032.
Cholinergic muscarinic receptors (MRs) and monoamine oxidase activity (MAO-B), expressed both in brain and blood cells, were investigated in animals and exposed subjects to assess (i) MeHg (0.5-1 mg/kg/day GD7-PD7) and/or PCB153 (20 mg/kg/day GD10-GD16) effects on cerebellar MAO-B and MRs, and lymph... [more] Cholinergic muscarinic receptors (MRs) and monoamine oxidase activity (MAO-B), expressed both in brain and blood cells, were investigated in animals and exposed subjects to assess (i) MeHg (0.5-1 mg/kg/day GD7-PD7) and/or PCB153 (20 mg/kg/day GD10-GD16) effects on cerebellar MAO-B and MRs, and lymphocyte MRs, in dams and offspring 21 days postpartum; (ii) MAO-B in platelets and MRs in lymphocytes of a Faroese 7-year-old children cohort, prenatally exposed to MeHg/PCBs. Animal Data. MAO-B was altered in male cerebellum by MeHg, PCB153, and their combination (35%, 45%, and 25% decrease, resp.). Cerebellar MRs were enhanced by MeHg alone in dams (87%) and male pups (27%). PCB153 alone and in mixture did not modify cerebellar MRs. Similarly to brain, lymphocyte MRs were enhanced in both dams and offspring by MeHg alone. All changes were caused by 1 MeHg mg/kg/day, the lower dose was ineffective. Human Data. Both biomarkers showed homogeneous distributions within the cohort (MRs, range 0.1-36.78 fmol/million cells; MAO-B, 0.95-14.95 nmol/mg protein/h). No correlation was found between the two biomarkers and neurotoxicant concentrations in blood (pre- and postnatally).
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2.40Impact points
Comparative pulmonary toxicity assessment of pristine and functionalized multi-walled carbon nanotubes intratracheally instilled in rats: morphohistochemical evaluations.
Histology and histopathology. 03/2011; 26(3):357-67.
Increasing interest in safety evaluation of carbon nanotubes (CNTs) has risen in relation to their wide applications, together with the evidence of their cytotoxic effects. It has been shown that chemical functionalization extends the applications of CNTs, conferring them new functions that cannot o... [more] Increasing interest in safety evaluation of carbon nanotubes (CNTs) has risen in relation to their wide applications, together with the evidence of their cytotoxic effects. It has been shown that chemical functionalization extends the applications of CNTs, conferring them new functions that cannot otherwise be acquired by pristine CNTs, but also impacts on biological response to CNTs, modifying their toxicological profile. We assessed the onset of pulmonary toxic effects caused by pristine MW-CNTs and functionalized MW-NH₂ or MW-COOH, 16 days after intratracheal instillation (1 mg/kg b.w.); major endpoints tested included (i) histopathology of lung (Haematoxylin/Eosin Staining), (ii) apoptotic/proliferating features examined by TUNEL and PCNA immunostaining, and (iii) presence/distribution of (1) Transforming Growth Factor-beta1 (TGFß1), (2) Interleukin-6 (IL-6) and (3) Collagen (Type I) investigated by immunochemical methods, as markers of lung toxicity, inflammation, and fibrosis, respectively. Lung histopathology from exposed animals showed dark, particulate-laden macrophages, reflecting carbon nanomaterial engulfing, both at alveolar and bronchiolar levels, after treatment with all the tested CNTs. Alteration of lung architecture was also observed in several areas showing collapsed thick-walled alveoli and the presence of micro-haemorrhagic foci. TUNEL and PCNA, indicative of apoptosis and cell proliferation respectively, showed a significant increase of immunopositive cells at bronchiolar, alveolar and macrophagic levels, as expression of an improved cellular turnover. Increased immunoreactivity for pulmonary TGFß1 and IL-6 was observed in treated rats, particularly in bronchiolar areas, collapsed alveoli and at stromal level, while evident changes for collagen were not detected. Taken together these findings demonstrated the general pulmonary toxicity coupled with inflammatory response after in vivo exposure to CNTs, without overt signs of fibrosis and granuloma formation, irrespectively of nanotube functionalization.
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3.31Impact points
Developmental exposure to methylmercury and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) affects cerebral dopamine D1-like and D2-like receptors of weanling and pubertal rats.
Archives of toxicology. 02/2011; 85(10):1281-94.
MeHg (0.5 mg/kg/day) and/or PCB153 (5 mg/kg/day) effects, administered orally to rat dams (GD7-PND21), were explored in PND21 and PND36 offspring brain in terms of density (Bmax) and affinity (Kd) of dopamine D1-like (D1-Rs) and D2-like receptors (D2-Rs), by saturation binding studies. D1-Rs decreas... [more] MeHg (0.5 mg/kg/day) and/or PCB153 (5 mg/kg/day) effects, administered orally to rat dams (GD7-PND21), were explored in PND21 and PND36 offspring brain in terms of density (Bmax) and affinity (Kd) of dopamine D1-like (D1-Rs) and D2-like receptors (D2-Rs), by saturation binding studies. D1-Rs decreased density in both cortex and striatum (15-30%) by MeHg and PCB153, either alone or combined, without additivity in PND21 males. Changes disappeared by PND36. In females, only MeHg caused a 15% Bmax decrease in striatum. D2-Rs enhanced density (23-50%) and reduced affinity in cortex to a similar extent by all treatments in both weanling and pubertal males. Affinity was also decreased in females by all types of exposure at both ages, while density was enhanced by PCB153 only in a delayed manner (PND36). No changes were detected in striatum. In MeHg and MeHg + PCB153 pup cortex, Hg concentrations ranged, on PND21, between 0.25 and 0.89 and 0.94-1.40 μg/g tissue, respectively, and were 5- to sixfold lower 2 weeks later. PCB153 levels, in PCB153 ± MeHg treated rats, were about 15 μg/g tissue (PND21) and 4-8 μg/g tissue (PND36). In striatum, the Hg and PCB153 concentrations were similar to those in cortex. Brain kinetics trend also applied to blood PCB153 or Hg levels. Perinatal exposure to MeHg and/or PCB153 affects D1- and D2-Rs in a gender-, time-, and brain area-dependent manner. Combined treatment does not exacerbate the neurochemical effects of the individual compounds.
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3.24Impact points
Effects of water-soluble functionalized multi-walled carbon nanotubes examined by different cytotoxicity methods in human astrocyte D384 and lung A549 cells.
Toxicology. 02/2010; 269(1):41-53.
The widespread projected use of functionalized carbon nanotubes (CNTs) makes it important to understand their potential harmful effects. Two cell culture systems, human A549 pneumocytes and D384 astrocytoma cells, were used to assess cytotoxicity of multi-walled CNTs (MWCNTs) with varying degrees of... [more] The widespread projected use of functionalized carbon nanotubes (CNTs) makes it important to understand their potential harmful effects. Two cell culture systems, human A549 pneumocytes and D384 astrocytoma cells, were used to assess cytotoxicity of multi-walled CNTs (MWCNTs) with varying degrees of functionalization. Laboratory-made highly functionalized hf-MW-NH(2) and less functionalized CNTs (MW-COOH and MW-NH(2)) were tested in comparison with pristine MWCNTs, carbon black (CB) and silica (SiO(2)) by MTT assay and calcein/propidium iodide (PI) staining. Purity and physicochemical properties of the test nanomaterials were also determined. In both MTT and calcein/PI assays, highly functionalized CNTs (hf-MW-NH(2)) caused moderate loss of cell viability at doses >or=100 microg/ml being apparently less cytotoxic than SiO(2). In preparations treated with CB or the other nanotube types (pristine MWCNTs, MW-COOH and the less functionalized amino-substituted MW-NH(2)) the calcein/PI test indicated no loss of cell viability, whereas MTT assay apparently showed apparent cytotoxic response, occurring not dose-dependently at exceedingly low CNT concentrations (1 microg/ml). The latter nanomaterials were difficult to disperse showing higher aggregate ranges and tendency to agglomerate in bundle-like form in cell cultures. In contrast, hf-MW-NH(2) were water soluble and easily dispersible in medium; they presented lower aggregate size range as well as considerably lower length to diameter ratios and low tendency to form aggregates compared to the other CNTs tested. The MTT data may reflect a false positive cytotoxicity signal possibly due to non-specific CNT interaction with cell culture components. Thus, these properties obtained by chemical functionalization, such as water solubility, high dispersibility and low agglomeration tendency were relevant factors in modulating cytotoxicity. This study indicates that properties obtained by chemical functionalization, such as water solubility, high dispersibility and low agglomeration tendency are relevant factors in modulating cytotoxicity of CNTs.
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1.61Impact points
Reduced platelet monoamine oxidase type B activity and lymphocyte muscarinic receptor binding in unmedicated children with attention deficit hyperactivity disorder.
Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals. 11/2009; 14(7):513-22.
Several lines of evidence support the role of monoaminergic and cholinergic dysregulation in attention deficit hyperactivity disorder (ADHD) and the concept that peripheral blood neurotransmission indices may represent valuable surrogate CNS markers. We determined platelet MAO-B activity (p-MAO-B) a... [more] Several lines of evidence support the role of monoaminergic and cholinergic dysregulation in attention deficit hyperactivity disorder (ADHD) and the concept that peripheral blood neurotransmission indices may represent valuable surrogate CNS markers. We determined platelet MAO-B activity (p-MAO-B) and lymphocyte muscarinic cholinergic receptor binding (l-MR) in 44 unmedicated ADHD children (aged 9.1 +/- 2.87 years) and in 26 age-matched controls for comparison. Lower levels of p-MAO-B (approximately 35%) and l-MR (approximately 55%) in ADHD were observed compared with controls. Differences were gender-dependent: p-MAO-B was reduced in males only (5.20 +/- 2.99 vs 8.46 +/- 5.1 nmol mg(-1) protein h(-1) in ADHD and controls, respectively) and l-MR in females only (ADHD vs control: 6.63 +/- 1.75 and 15.30 +/- 8.35 fmol 10(-6) cells). The clinical significance was corroborated by the correlation between these markers and severity of specific symptoms: lower p-MAO-B associated with increased inattention scores (Conners' teacher-rating scale); lower l-MR associated with increased score for oppositional-defiant disorder (ODD) (SNAP-IV); and trend towards correlation between increased inattention (SNAP-IV) and lower l-MR.
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2.06Impact points
Comparative in vitro and ex-vivo myelotoxicity of aflatoxins B1 and M1 on haematopoietic progenitors (BFU-E, CFU-E, and CFU-GM): Species-related susceptibility.
Toxicology in vitro : an international journal published in association with BIBRA. 09/2009;
Haemato- and myelotoxicity are adverse effect caused by mycotoxins. Due to the relevance of aflatoxins to human health, the present study, employing CFU-GM-, BFU-E- and CFU-E-clonogenic assays, aimed at (i) comparing, in vitro, the sensitivity of human vs. murine haematopoietic progenitors to AFB1 a... [more] Haemato- and myelotoxicity are adverse effect caused by mycotoxins. Due to the relevance of aflatoxins to human health, the present study, employing CFU-GM-, BFU-E- and CFU-E-clonogenic assays, aimed at (i) comparing, in vitro, the sensitivity of human vs. murine haematopoietic progenitors to AFB1 and AFM1 (0.001-50mug/ml), (ii) assessing whether a single AFB1 in vivo treatment (0.3-3mg/kgb.w.) alters the ability of murine bone marrow cells to form myeloid and erythroid colonies, and (iii) comparing the in vitro with the in vitro ex-vivo data. We demonstrated (i) species-related sensitivity to AFB1, showing higher susceptibility of human myeloid and erythroid progenitors (IC(50) values: about 4 times lower in human than in murine cells), (ii) higher sensitivity of CFU-GM and BFU-E colonies, both more markedly affected, particularly by AFB1 (IC(50): 2.45+/-1.08 and 1.82+/-0.8muM for humans, and 11.08+/-2.92 and 1.81+/-0.20muM for mice, respectively), than the mature CFU-E (AFB1 IC(50): 12.58+/-5.4 and 40.27+/-6.05muM), irrespectively of animal species, (iii) regarding AFM1, a species- and lineage-related susceptibility similar to that observed for AFB1 and (iv) lack of effects after AFB1 in vivo treatment on the proliferation of haematopoietic colonies.
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1.61Impact points
No changes in lymphocyte muscarinic receptors and platelet monoamine oxidase-B examined as surrogate central nervous system biomarkers in a Faroese children cohort prenatally exposed to methylmercury and polychlorinated biphenyls.
Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals. 04/2009; 14(2):67-76.
Experimental evidence suggests that monoamine oxidase B (MAO-B) and muscarinic cholinergic receptors (mAChRs) are involved in the pathogenesis of neurotoxicity caused by methylmercury and polychlorinated biphenyls (PCBs). Blood samples from 7-year-old exposed children were analyzed for platelet MAO-... [more] Experimental evidence suggests that monoamine oxidase B (MAO-B) and muscarinic cholinergic receptors (mAChRs) are involved in the pathogenesis of neurotoxicity caused by methylmercury and polychlorinated biphenyls (PCBs). Blood samples from 7-year-old exposed children were analyzed for platelet MAO-B and lymphocyte mAChRs as potential markers of exposure to these neurotoxicants. The blood neurotoxicity biomarkers were compared with prenatal and current exposures and with neuropsychological test results. Both biomarkers showed homogeneous distributions within this cohort (mAChR, range 0.04-36.78 fmol/million cells; MAO-B, 0.95-14.95 nmol mg(-1) protein h(-1)). No correlation was found between the two biomarkers and either blood neurotoxicant concentrations or clinical findings. MAO-B and mAChR sensitivity may not be sufficiently high to assess early, subclinical responses to low/moderate methylmercury and/or PCB exposure, whereas these markers are significantly altered in sustained exposure scenarios, as shown by clinical studies in drug addicts or patients treated with psychopharmacological agents.
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2.78Impact points
Single step determination of PCB 126 and 153 in rat tissues by using solid phase microextraction/gas chromatography-mass spectrometry: Comparison with solid phase extraction and liquid/liquid extraction.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. 03/2009;
A simple and reliable solid phase microextraction/gas chromatography-mass spectrometry (SPME/GC-MS) method was developed for the single-step determination of PCBs 126 and 153 in rat brain and serum, using liquid/liquid and solid phase extraction (SPE) as reference techniques. The multi-factor catego... [more] A simple and reliable solid phase microextraction/gas chromatography-mass spectrometry (SPME/GC-MS) method was developed for the single-step determination of PCBs 126 and 153 in rat brain and serum, using liquid/liquid and solid phase extraction (SPE) as reference techniques. The multi-factor categorical experimental design used to study simultaneously the main parameters and their interactions affecting the efficiency of the method, showed that the use of an 85mum PA exposed at 100 degrees C for 40min was the optimum sampling condition for both PCBs. SPME was then validated by studying its linear dynamic (over two orders of magnitude), limits of detection (brain: 2ng/g, serum: 0.2ng/g) and analytical precision that was within 9% for SPME in both brain and serum. Finally, the method was used to determine the brain and blood target dose in mothers and pups after oral exposure of the mothers.
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1.80Impact points
Neurodevelopmental toxicity of methylmercury: Laboratory animal data and their contribution to human risk assessment.
Regulatory toxicology and pharmacology : RTP. 08/2008; 51(2):215-29.
Methylmercury (MeHg) is one of the most significant public health hazards. The clinical findings in the victims of the Japanese and Iraqi outbreaks have disclosed the pronounced susceptibility of the developing brain to MeHg poisoning. This notion has triggered worldwide scientific attention toward ... [more] Methylmercury (MeHg) is one of the most significant public health hazards. The clinical findings in the victims of the Japanese and Iraqi outbreaks have disclosed the pronounced susceptibility of the developing brain to MeHg poisoning. This notion has triggered worldwide scientific attention toward the long-term consequences of prenatal exposure on child development in communities with chronic low level dietary exposure. MeHg neurodevelopmental effects have been extensively investigated in laboratory animals under well-controlled exposure conditions. This article provides an updated overview of the main neuromorphological and neurobehavioral changes reported in non-human primates and rodents following developmental exposure to MeHg. Different aspects of MeHg's effects on the immature organism are reported, with particular reference to the delayed onset of symptoms and the persistency of central nervous system (CNS) injury/dysfunction. Particular attention is paid to the comparative toxicity assessment across species, and to the degree of concordance/discordance between human and animal data. The contribution of animal studies to define the role of potential effect modifiers and variables on MeHg dose-response relationships is also addressed. The ultimate goal is to discuss the relevance of laboratory animal results, as a complementary tool to human data, with regard to the human risk assessment process.
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1.80Impact points
Human developmental neurotoxicity of methylmercury: Impact of variables and risk modifiers.
Regulatory toxicology and pharmacology : RTP. 08/2008; 51(2):201-14.
Methylmercury (MeHg) is a widespread environmental and food toxicant which has long been known to affect neurodevelopment in both humans and experimental animals. Risk assessment for MeHg is mainly based on human data coming from the massive episodes of poisoning in Japan and Iraq, as well as from l... [more] Methylmercury (MeHg) is a widespread environmental and food toxicant which has long been known to affect neurodevelopment in both humans and experimental animals. Risk assessment for MeHg is mainly based on human data coming from the massive episodes of poisoning in Japan and Iraq, as well as from large scale epidemiological studies concerning childhood development and neurotoxicity in relation to in utero exposure in various fish eating communities around the world. Despite the extensive literature and research, the threshold dose for MeHg neurotoxic effects is still unclear, in particular when it comes to subtle effects on neurobehaviour. In this article clinical and epidemiological findings concerning the neurodevelopmental toxicity of MeHg are reviewed. Much attention is focussed on the potential impact of factors, such as diet and nutrition, gender, pattern of exposure and co-exposure to other neurotoxic pollutants, which may modulate MeHg toxic effects. These factors, together with the notion that some symptoms may ensue or exacerbate with aging, contribute to the difficulties in the definition of safe levels for developmental exposure.
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1.80Impact points
Human developmental neurotoxicity of methylmercury and variables.
Regulatory toxicology and pharmacology : RTP. 07/2008;
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1.75Impact points
Cerebellum cholinergic muscarinic receptor (subtype-2 and -3) and cytoarchitecture after developmental exposure to methylmercury: an immunohistochemical study in rat.
Journal of chemical neuroanatomy. 06/2008; 35(3):285-94.
The developing central nervous system (CNS) is a target of the environmental toxicant methylmercury (MeHg), and the cerebellum seems the most susceptible tissue in response to this neurotoxicant. The cholinergic system is essential for brain development, acting as a modulator of neuronal proliferati... [more] The developing central nervous system (CNS) is a target of the environmental toxicant methylmercury (MeHg), and the cerebellum seems the most susceptible tissue in response to this neurotoxicant. The cholinergic system is essential for brain development, acting as a modulator of neuronal proliferation, migration and differentiation processes; its muscarinic receptors (MRs) play pivotal roles in regulating important basic physiologic functions. By immunohistochemistry, we investigated the effects of perinatal (GD7-PD21) MeHg (0.5 mg/kg bw/day in drinking water) administration on cerebellum of mature (PD36) and immature (PD21) rats, evaluating the: (i) M2- and M3-MR expression; (ii) presence of gliosis; (iii) cytoarchitecture alterations. Regarding to M2-MRs, we showed that: at PD21, MeHg-treated animals did not display any differences compared to controls, while, at PD36 there was a significant increase of M2-immunopositive Bergmann cells in the molecular layer (ML), suggesting a MeHg-related cytotoxic effect. Similarly to M2-MRs, at PD21 the M3-MRs were not affected by MeHg, while, at PD36 a lacking immunoreactivity of the granular layer (IGL) was observed after MeHg treatment. In MeHg-treated rats, at both developmental points, we showed reactive gliosis, e.g. a significant increase in Bergmann glia of the ML and astrocytes of the IGL, identified by their expression of glial fibrillar acidic protein. No MeHg-related effects on Purkinje cells were detected neither at weaning nor at puberty. These findings suggest: (i) a delayed MeHg exposure-related effect on M2- and M3-MRs, (ii) an overt MeHg-related cytotoxic effect on cerebellar oligodendroglia, e.g. reactive gliosis, (iii) a selective vulnerability of granule cells and Purkinje neurons to MeHg, with the latter that remain unharmed.
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3.24Impact points
Perinatal co-exposure to methylmercury and PCB153 or PCB126 in rats alters the cerebral cholinergic muscarinic receptors at weaning and puberty.
Toxicology. 09/2007; 238(1):34-48.
In the last few decades, combined exposure to methylmercury (MeHg) and polychlorinated biphenyls (PCBs) from fish and seafood, and their potentially interactive effects on neurodevelopment, have been giving increasing cause for concern. We examined the combined effects of MeHg and either a non-dioxi... [more] In the last few decades, combined exposure to methylmercury (MeHg) and polychlorinated biphenyls (PCBs) from fish and seafood, and their potentially interactive effects on neurodevelopment, have been giving increasing cause for concern. We examined the combined effects of MeHg and either a non-dioxin PCB (PCB153) or a dioxin-like PCB (PCB126) congener on the developing brain cholinergic muscarinic receptors (MRs). These receptors are known to play a major role in many central functions including higher cognitive processes and the modulation of extrapyramidal motor activity. MRs in pup rat brains diminished following prenatal and lactational exposure, from gestational day [GD]7 to postnatal day [PND]21, to MeHg (0.5mg/kgbodyweight[bw]/day), PCB153 (5mg/kgbw/day), and PCB126 (100ng/kg/day), alone or in combination. Total MR density, as well as M1, M2, and M3 receptor subtypes of the weanling and pubertal rats, were affected in a brain-area-, gender-, time- and compound-dependent fashion. MeHg decreased (by 15-20%) the total MR density in a delayed (PND36) manner in the cerebral cortex of both genders, and early (at weaning) in the cerebellum of both genders, with the effect lasting until puberty (in males only). MeHg decreased the ACh M1- and M3-immunopositive neurons in the cerebral cortex and also increased the M2-immunopositive Bergmann glia in the cerebellum. PCB153 also induced a delayed (PND36) decrease (of 20%) in total MR number in the cerebellum of the male offspring and in the cerebral cortex of both genders. The latter effect was coupled with a decrease in ACh M1- and ACh M3-immunopositive neuron populations. PCB126 decreased (by 30-40%) total MR density in a gender-dependent manner, males being more sensitive than females. The effect was evident early (at PND21) and lasted until puberty in the cerebellum, while it was observed later (at PND36) in the cerebral cortex. The M1 and M3 receptors were similarly affected by PCB126. Co-exposure to MeHg and either PCB153 or PCB126 had the same effect on the cerebral MRs as exposure to each compound alone. The results rule out additive or synergistic interactions between MeHg and PCB153 or PCB126 on MRs in the brain areas examined. Some early-onset changes persisted until puberty, while other modifications became manifest only at the advanced time point (PND36), when the brain levels of total Hg, PCB153, and PCB126 had declined. These data support the ability of MeHg and PCBs to induce delayed neurotoxicity after developmental exposure.
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3.24Impact points
Methylmercury interaction with lymphocyte cholinergic muscarinic receptors in developing rats.
Environmental research. 03/2007; 103(2):229-37.
Cerebral cholinergic muscarinic receptors (MR) have been suggested as one of the sensitive biochemical endpoints of the central nervous system altered by developmental exposure to the widespread seafood contaminant methylmercury (MeHg). In adult rats, MeHg has been shown to alter MR binding both in ... [more] Cerebral cholinergic muscarinic receptors (MR) have been suggested as one of the sensitive biochemical endpoints of the central nervous system altered by developmental exposure to the widespread seafood contaminant methylmercury (MeHg). In adult rats, MeHg has been shown to alter MR binding both in the brain and lymphocytes, supporting the use of MR in blood cells as a surrogate marker of CNS changes. The effects of MeHg have been evaluated on rat lymphocyte MR binding (using [3H]QNB as specific muscarinic ligand) in vivo (after perinatal exposure) and in vitro. For comparison, in vitro studies were also performed on human lymphocytes. Exposure to 1 mg MeHg/kg/day during pregnancy and lactation (from GD7 to PND7) significantly enhanced lymphocyte MR density in both adult and young rats 21 days after delivery, with a more pronounced effect in the mothers (B(max) increase of 139%) than in the male offspring (+49%) and female offspring (+73%) as compared with their respective controls (33+/-4, 41+/-8, and 37+/-4 fmol/million cells), in accordance with the higher Hg levels detected in the adult blood (11.3+/-2.2 microg/mL) than in pups (1.3+/-0.4 microg/L in both genders). A lower MeHg dose (0.5 mg/kg/day) was without any effect on lymphocyte MRs. In in vitro studies, MeHg was an almost equipotent inhibitor of (3)H-QNB binding to rat and human lymphocyte MRs (IC50 values were 4.1+/-0.29, 5.2+/-0.51, and 5.0+/-0.9 microM for total rat lymphocytes, rat T lymphocytes, and total human lymphocytes, respectively). Notably, the IC50 values for MeHg to lymphocyte MRs were comparable to the Hg levels reached in blood (5-50 microM) of the PND21 rats exposed to MeHg. The finding that the MR binding is a target for the effects of MeHg in peripheral blood cells is in accordance with our previous data in brain [Coccini et al., 2006. Effects of developmental co-exposure to methylmercury and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) on cholinergic muscarinic receptors in rat brain. Neurotoxicology, in press], and supports the use of this peripheral endpoint as a biomarker of MeHg-induced cerebral muscarinic alterations. The similarity of MeHg IC50 binding data between human and rat in peripheral tissues suggests the possible application of such biomarker to humans exposed to environmental chemicals.
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2.46Impact points
Brain monoaminergic neurotransmission parameters in weanling rats after perinatal exposure to methylmercury and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153).
Brain research. 10/2006; 1112(1):91-8.
The individual and joint effects of methylmercury (MeHg; 1 mg/kg body weight/day, GD7-PND7) and PCB153 (20 mg/kg body weight/day, GD10-GD16), administered orally to rat dams, were explored in 21-day-old rat offspring brain in terms of monoamine oxidase B (MAO-B) activity and regional content of dopa... [more] The individual and joint effects of methylmercury (MeHg; 1 mg/kg body weight/day, GD7-PND7) and PCB153 (20 mg/kg body weight/day, GD10-GD16), administered orally to rat dams, were explored in 21-day-old rat offspring brain in terms of monoamine oxidase B (MAO-B) activity and regional content of dopamine (DA), serotonin (5-HT), 5-hydroxy-indole-3-acetic acid (5-HIAA) and homovanillic acid (HVA). Neither treatment altered MAO-B in striatum, hippocampus, cerebellum and cerebral cortex of female pups. In males the cerebellum displayed a significantly reduced enzyme activity (25-45%) following all treatments. Concerning biogenic amines, 5-HT levels were decreased by 30-50% in the cerebral cortex of males and females by PCB153 alone and combined with MeHg, without changes in 5-HIAA and dopaminergic endpoints. In cerebellum of all pups, MeHg enhanced 5-HIAA levels, whereas PCB153, either alone or combined with MeHg, did not affect this endpoint. In striatum, PCB153 reduced the content of DA, HVA and 5-HIAA (respective control values: 2-3; 60-80; 8-10 ng/mg protein) to a similar extent when administered alone or together with MeHg (20-40%). Perinatal exposure to MeHg and/or PCB153 results in regionally and/or gender-specific alterations in the central dopaminergic and serotonergic systems at weaning. The combined treatment with MeHg and PCB153 does not exacerbate the neurochemical effects of the individual compounds.
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2.92Impact points
Effects of developmental co-exposure to methylmercury and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) on cholinergic muscarinic receptors in rat brain.
Neurotoxicology. 08/2006; 27(4):468-77.
The developing nervous system is thought to be particularly sensitive to polychlorinated biphenyls (PCBs) present as food contaminants together with methylmercury (MeHg). Effects of perinatal co-exposure to PCB153 and MeHg on brain cholinergic muscarinic receptors (MRs) were investigated by saturati... [more] The developing nervous system is thought to be particularly sensitive to polychlorinated biphenyls (PCBs) present as food contaminants together with methylmercury (MeHg). Effects of perinatal co-exposure to PCB153 and MeHg on brain cholinergic muscarinic receptors (MRs) were investigated by saturation binding studies in mature and immature rats. MeHg alone (1mg/kg/day, GD7-PND7) enhanced cerebral MRs more in dams (87% and 60% in cerebellum and cerebral cortex, respectively) than in PND21 pups (0-50%) in accordance with the higher Hg levels detected in the adult brain (7-9 microg/g) than in the male and female offspring's brain (1.5-2.8 microg/g). Prenatal administration of PCB153 (20mg/kg/day, GD10-GD16), leading to higher contaminant levels in the offspring brain than in that of adults (25-66 microg/g versus 3 microg/g), induced cerebral MR changes of similar extent at both ages, namely decreased cerebellar (20-30%) and increased cortical MR density (40-50%). Co-exposure to PCB and MeHg had no more effect than exposure to either compound alone on cerebral cortex MRs, whereas, in the cerebellum, the combined treatment induced a PCB-like lowering of the MR density that masked the MeHg-induced receptor increase. None of the treatments affected the striatal and hippocampal MRs. A lower MeHg dose (0.5 mg/kg/day) was without any effect on cerebral MRs. These results show that MRs are one of the sensitive biochemical endpoints of the central nervous system altered by developmental exposure to MeHg and PCB153. Cerebral cortex and cerebellum were the most susceptible targets in the response to these neurotoxicants. MR changes were detected in both immature and adult animals and the interaction of MeHg and PCB153 at the level of these receptors occurred in a non-additive manner.
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2.56Impact points
Lymphocyte cytochrome c oxidase, cyclic GMP and cholinergic muscarinic receptors as peripheral indicators of carbon monoxide neurotoxicity after acute and repeated exposure in the rat.
Life sciences. 04/2006; 78(17):1915-24.
Changes in cerebral cytochrome oxidase (COX) activity, nitric oxide (NO)-cyclic GMP (cGMP) pathway and cholinergic muscarinic receptors (MRs) have been reported in rodents acutely exposed to carbon monoxide (CO). These endpoints measurable in lymphocytes may serve as peripheral markers of CO neuroto... [more] Changes in cerebral cytochrome oxidase (COX) activity, nitric oxide (NO)-cyclic GMP (cGMP) pathway and cholinergic muscarinic receptors (MRs) have been reported in rodents acutely exposed to carbon monoxide (CO). These endpoints measurable in lymphocytes may serve as peripheral markers of CO neurotoxicity. The early and delayed effects of repeated and acute in vivo CO inhalation were investigated on COX activity, cGMP formation and MR binding in rat brain and lymphocytes to assess whether each endpoint was similarly affected both centrally and peripherally. Male Wistar rats either inhaled 500 ppm CO, 6 h/day, 5 days/week, 4 weeks (repeated exposure) or 2,400 ppm, 1 h (single exposure). Neither treatment altered brain or lymphocyte COX activity 1 and 7 days post-treatment. Also ineffective were repeated and acute CO treatments towards (3)H-quinuclidinyl benzilate (QNB) binding to MRs in cerebral cortex, hippocampus, striatum, cerebellum (respective controls, mean+/-S.D.: 171 +/- 45, 245 +/- 53, 263 +/- 14 and 77 +/- 7 fmol/mg protein) and lymphocytes (24 +/- 10 fmol/million cells) at the same time points. In lymphocytes control cGMP levels averaged 1.98 +/- 0.99 pmol/mg protein under basal conditions, and 3.94 +/- 0.55 pmol/mg protein after NO-stimulation. One day after chronic treatment cessation, the CO-treated group displayed about a 50% decrease in both basal and NO-stimulated cGMP values, which persisted up to 7 days after, compared to air-exposed rats. Acutely, CO caused a delayed enhancement (+140%) of NO-induced activation of soluble guanylate cyclase. The finding that the NO-cGMP pathway is a target for the delayed effects of CO in peripheral blood cells is in accordance with our data in brain [Hernández-Viadel, M., Castoldi, A.F., Coccini, T., Manzo, L., Erceg, S., Felipo, V., 2004. In vivo exposure to carbon monoxide causes delayed impairment of activation of soluble guanylate cyclase by nitric oxide in rat brain cortex and cerebellum. Journal of Neurochemistry 89, 1,157-1,165], and supports the use of this peripheral endpoint as a biomarker of CO central effects.
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1.29Impact points
Lymphocyte muscarinic receptors and platelet monoamine oxidase-B as biomarkers of CNS function: effects of age and gender in healthy humans.
Environmental toxicology and pharmacology. 05/2005; 19(3):715-20.
Lymphocyte cholinergic muscarinic receptors (MRs) and platelet monoamine oxidase-B (MAO-B) activity are considered surrogate markers of the same parameters in the central nervous system. Lymphocyte MR binding and platelet MAO-B activity were measured in a consistent number of healthy human adults an... [more] Lymphocyte cholinergic muscarinic receptors (MRs) and platelet monoamine oxidase-B (MAO-B) activity are considered surrogate markers of the same parameters in the central nervous system. Lymphocyte MR binding and platelet MAO-B activity were measured in a consistent number of healthy human adults and analysed according to gender and age. The mean value±S.D. of MR binding neither differed between males (12.2±10.0fmol/10(6)cells, range: 0.5-37.9, n=86) and females (10.7±9.7fmol/10(6)cells, range: 0.5-39.7, n=69) nor among age groups. MAO-B activity was significantly higher in women (geometric mean: 11.3nmol/mgprotein/h, with 65% of values from 7.3 to 17.6; n=43), than in men (7.7nmol/mgprotein/h, with 65% of values from 4.5 to 13; n=95). Males aged 56-66 years displayed a higher, though not statistically significant, basal enzyme activity than younger subjects. Altogether these data indicate gender-related differences in MAO activity, but not in MR binding, and inter-individual differences in the basal values of both peripheral blood markers in healthy subjects.
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4.00Impact points
In vivo exposure to carbon monoxide causes delayed impairment of activation of soluble guanylate cyclase by nitric oxide in rat brain cortex and cerebellum.
Journal of neurochemistry. 07/2004; 89(5):1157-65.
Carbon monoxide induces delayed neurological and neuropathological alterations, including memory loss and cognitive impairment. The bases for the delay remain unknown. Activation of soluble guanylate cyclase by nitric oxide modulates some forms of learning and memory. Carbon monoxide binds to solubl... [more] Carbon monoxide induces delayed neurological and neuropathological alterations, including memory loss and cognitive impairment. The bases for the delay remain unknown. Activation of soluble guanylate cyclase by nitric oxide modulates some forms of learning and memory. Carbon monoxide binds to soluble guanylate cyclase, activating it but interfering with its activation by nitric oxide. The aim of this work was to assess whether exposure of rats to carbon monoxide alters the activity of soluble guanylate cyclase or its modulation by nitric oxide in cerebellum or cerebral cortex. Rats exposed chronically or acutely to carbon monoxide were killed 24 h or 7 days later. Acute carbon monoxide exposure decreased cyclic guanosine monophosphate (cGMP) content and reduced activation of soluble guanylate cyclase by nitric oxide. Cortex was more sensitive than cerebellum to chronic exposure, which reduced activation of soluble guanylate cyclase by nitric oxide in cortex. In cerebellum, chronic exposure induced delayed impairment of soluble guanylate cyclase activation by nitric oxide. Acute exposure effects were also stronger at 7 days than at 24 h after exposure. This delayed impaired modulation of soluble guanylate cyclase by nitric oxide may contribute to delayed memory loss and cognitive impairment in humans exposed to carbon monoxide.
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Diagnostic accuracy of urinary amanitin in suspected mushroom poisoning: a pilot study.
Journal of toxicology. Clinical toxicology. 02/2004; 42(6):901-12.
BACKGROUND. Amatoxin-containing species are responsible for the most severe cases of mushroom poisoning, with high mortality rate. Therefore, this poisoning should be ruled out in all patients presenting gastrointestinal symptoms after wild mushroom ingestion. OBJECTIVE. To determine sensitivity, sp... [more] BACKGROUND. Amatoxin-containing species are responsible for the most severe cases of mushroom poisoning, with high mortality rate. Therefore, this poisoning should be ruled out in all patients presenting gastrointestinal symptoms after wild mushroom ingestion. OBJECTIVE. To determine sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic efficacy (DE) of urinary amanitin analysis in cases of suspected mushroom poisoning. METHODS. All cases of mushroom ingestion referred to a Poison Center during a one-month period were analyzed. Amanitin measurements were performed by ELISA method (functional least detectable dose 1.5 ng/ml; cut-off value not clearly established). Gastrointestinal symptoms latency and initial clinical assessment were considered alternative diagnostic tools. Definitive diagnosis was used as the reference standard. RESULTS. Among 61 patients included in the study, amatoxin poisoning was diagnosed in 10 cases. Urine samples were collected 5.5 to 92 hours after mushroom ingestion. Urinary amanitin DE was 91.8%, 93.4%, and 80.3%, based on the cut-off value considered (1.5, 5.0, and 10.0 ng/ml, respectively). Symptoms latency longer than 6 hours and initial clinical assessment DE were 70.5% and 67.2%, respectively. To identify amatoxin poisoning, initial clinical assessment resulted more sensitive and urinary amanitin analysis more specific. CONCLUSIONS. Urinary amanitin analysis is a valuable diagnostic tool and may significantly contribute to the management of suspected mushroom poisoning. At present, the best diagnostic accuracy can be obtained taking advantage of both the high sensitivity and negative predictive value of the clinical assessment performed by an experienced toxicologist, and the high specificity and positive predictive value that characterize urinary amanitin analysis.
Following (5)
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Sandra Ceccatelli
Karolinska Institutet -
Annabella Vitalone
Università degli Studi di Roma "La Sapienza" -
Graziella Bernocchi
Università degli studi di Pavia -
Giorgio Rossi
Ospedale Maggiore Policlinico Milano -
Vicente Felipo
Centro de Investigación Príncipe Felipe
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