As a main aim we want to point out the sources of oxidants as key factors in understanding the role oxidants play in the pathogenesis of brain vascular endothelial dysfunction. The question remains whether iron inversion and subsequent radical formation is a primary or secondary event in neurodegenerative disease.
Recent research suggest that iron inversion is an initial cause of neuronal cell death and axonal degeneration. Methemoglobin and their catabolic products, provoke adverse effects on vascular endothelium dysfunction, reduced regenerative capacity and increased rate of endothelial cell apoptosis.
The main diference between the hemoglobin and methemoglobin heme oxygenation is that the hemoglobin last degradation products are bilirubin-biliverdin, CO and Ferrous (Fe++) iron , but in the methemoglobin catabolism last products are bilirubin-biliverdin, CO and Ferric (Fe+++) iron, which in methemoglobinemia pathological condition have an important role having a redox-active and cytotoxic property, and as valuable biomarker.
biomarkers metheoglobin catabolism, brain blood barrier, brain ferric iron accumulation, neurodegenerative diseases
The objective is to direct attention about methemoglobin as a biomarker which has an important role in the detection of adverse effects of the oxidative stress, misbalanced production of ROS (Reactive Oxygen Species), RNS (Reactive Nitrogen Species) and RSS (Reactive Sulfur Species). According to our hypothesis, the people continuously inhaling environmental toxics as fuel burning products, methemoglobin as product of hemoglobin oxidation, takes on an important role, causing increased systemic oxidative stress of vital organs.
Strong exogenous oxidants such as NOx (Nitrogen Oxides: NO and NO2) reversibly oxidize oxyhemoglobin (Fe2+) to methemoglobin (Fe3+), and irreversible methemoglobinemia can arise because of the disruption of the oxidant/antioxidant balance, supported by the synergic SO2 metabolites degradation of antioxidant thiols. The formation of methemoglobin-ferric iron (Fe3+) from hemoglobin-ferrous iron (Fe2+) leads to the destruction of erythrocytes, so that free hemoglobin from hemolysis can be directly cytotoxic and can alter the state of endothelial cells and endothelial dysfunction. From the methemoglobin and heme catabolism there is released into the blood-stream the cytotoxic redox-active ferric iron, which contributes to endothelial injury and the development of neurovascular diseases.
Our results, obtainded in a large number of cases [1-3,6-8,16-20] point out the consequence of mother-fetal methemoglobinemia caused by environmental oxidants, causing oxyhemoglobin and methemoglobin hemolysis, hyperbilirubinemia and toxic brain damage with the view to the role of methemoglobin catabolism as the source of ferric(Fe(III)) form concentrated in various brain regions.
The role of methemoglobin on the structural and functional changes in the vascular endothelium
Methemoglobin and hemolysis both occur as a result of oxidative stress, but the prevalent difference between them is that methemoglobin is a reversible phenomenon (oxidant–antioxidant balance) whereas hemolysis, which occurs as a result of oxidative stress on the erythrocyte membrane, is an irreversible event. Methemoglobinemia can additionally exacerbate an existing anemia, stimulating hypoxia that may be additional dangerous. Own prospective study of methemoglobin in pregnancy, revealed a significant rise in the level of methemoglobin >1.5 g/L (r = 0.72, p < 0.01) in the air-polluted exposure period, which can be explained on the basis of an oxidant–antioxidant imbalance, resulting in methemoglobinemia . Methemoglobinemia and stillbirth recorded throughout exposure period are significantly higher than those recorded in the control period (p = 0.0205) and the frequencies of reproductive loss were significantly lower in the control than in the exposure period (p < 0.05) . In healthy women the methemoglobin participates with less than 1% of the haemoglobin level but its level rises in pathophysiological conditions when red blood cells are affected by genetic, xenobiotic, pharmaceutical, idiopathic or toxic agents from food and chemical compounds from the environment [3,4].
As I have found no evidence of the consequences of mother methemoglobinemia on the fetus, the second objective is to direct attention to methemoglobin as an early biomarker of the environmental toxic of oxidative stress effects, which puts pregnancy at risk and may later impair the health of newborns, children and adolescents. High concentrations of methemoglobin and its catabolites affect the function of the kidney, brain, and other vital organs, and are manifested as mother's preeclampsia and/or “fetal preeclampsia” . The increase of maternal methemoglobin could be a useful biomarker to determine when the health of pregnant women is threatened by toxic substances in the environment. The conversion of haemoglobin to methemoglobin (ferrous to ferric state) leads to haemolysis , and the consequences thereof.
In methemoglobinemia pathological conditions, methemoglobin catabolises into heme, and the activity of heme-oxygenase leads to products such as bilirubin-biliverdin, carbon monoxide, and Fe (III) with paramagnetic and toxic properties. Acting as oxidants, methemoglobin and heme affect the function of the capillary endothelium of blood-brain barrier, facilitating the passage on brain parenchyma the harmful substances as the methemoglobin, heme and/or the deposition of containing toxic Ferric (III) iron in the brain.
It is well known that ferrimethemoglobin (III) releases heme in the endothelial cells, inducing increased hem-oxygenase activity and Ferritin production. In fetal blood, Nitric oxide and Superoxide form Peroxinitrites (ONOO-) which converts oxyhaemoglobin into methemoglobin, and the methemoglobin-released hem induces endothelial cytolysis [7-11].
Iron is essential for the normal cell function, but it also generates toxic ROS that adversely affects vascular endothelium and the blood-brain barrier . Astrocytes distribute iron in the brain and possess transporters for transferrin-bound, haemin-bound, and non-transferrin-bound iron . In the brain, non-heme-bound iron is mostly found in ferritin. Nowadays, non-heme-bound Fe (III) is quantified using Magnetic Resonance Imaging (MRI), thanks to its paramagnetic properties . It is believed that most non-heme-bound iron is deposited in the form of ferritin, haemosiderin, or methemoglobin catabolic products , whereas transferrin-bound iron concentration is always low and cannot be detected by MRI.
Vascular endothelial cells are direct targets for free hemoglobin and for its oxidative derivative methemoglobin which readily release heme, an abundant source of redox-active Ferric iron which impact on brain vascular endothelial dysfunction and apoptosis performing Ferric- iron brain accumulation on the endothelium and cause brain capillary defects, and gradually manifest brain harmful effects from the mother-fetal pregnancy complication, manifest in new-born hyperbilirubinemia, children and adults mild disorders as dyslexia or learn and memory deficiency to the age process, and to the hard neurodegenerative disorders as Alzheimer, Parkinson and Multiple Sclerosis diseases.
- Mohorovic L (2003) The level of maternal methemoglobin during pregnancy in air-polluted environment. Environ Health Perspect 111: 1902-1905. [Crossref]
- Mohorovic L (2008) Impacts of Environmental Toxics and Meteorological Condition on Reproductive Loss and Stillbirth. Gynecologia et Perinatologia 17: 133-137.
- Mohorovic L, Petrovic O, Haller H (2008) Detection of Pregnancy Methemoglobinemia with a fast, noninvasive, continuous and inexpensive method using Masimo Pulse Co-Oximeter Rainbow RAD57-The result of the pilot study. 7th Congress of the Hungarian Perinatal Society-1st International Post-Congress Meeting of UENPS, Budapest.
- Kinoshita A, Nakayama Y, Kitayama T, Tomita M (2007) Simulation study of methemoglobin reduction in erythrocytes. Differential contributions of two pathways to tolerance to oxidative stress. FEBS J 274: 1449-1458. [Crossref]
- Mohorovic L, Petrovic O, Haller H, Micovic V (2010) Pregnancy loss and maternal methemoglobin levels: an indirect explanation of the association of environmental toxics and their adverse effects on the mother and the fetus. Int J Environ Res Public Health 7: 4203-4212. [Crossref]
- Mohorovic L, Materljan E, Brumini G (2008) Are neonatal jaundice, heart murmur, dyslalia and learning/memory impairments consequences of mother exposure to environmental oxidants? XXIV International Congress „Fetus as a patients“, Frankfurt.
- Mohorovic L, Matturri L (2008) Methemoglobin as The Biomarker Of Environmental Oxidants And Precursor Of Adverse Effcts Of Oxidative Stress On Mother And Fetus- Reasons For Its Early Detection And Therapy. Ehrlich II-2nd World Conference on Magic Bullets. Nurnberg, Abstract Book, A-216.
- Mohorovic L (2007) The role of methemoglobinemia in early and late complicated pregnancy. Med Hypotheses 68: 1114-1119. [Crossref]
- Starodubtseva MN, Ignatenko VA, Cherenkevich SN (1999) [Damage to erythrocytes caused by the interaction of nitrite-ions with hemoglobin]. Biofizika 44: 1068-1072. [Crossref]
- Balla J, Jacob HS, Balla G, Nath K, Eaton JW, et al. (1993) Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage. Proc Natl Acad Sci U S A 90: 9285-9289. [Crossref]
- Denicola A, Souza JM, Radi R (1998) Diffusion of peroxynitrite across erythrocyte membranes. Proc Natl Acad Sci U S A 95: 3566-3571. [Crossref]
- Li DJ, Luo H, Wang LL, Zou GL (2004) Potential of peroxynitrite to promote the conversion of oxyhemoglobin to methemoglobin. Acta Biochim Biophys Sin (Shanghai) 36: 87-92. [Crossref]
- Umbreit J (2007) Methemoglobin.it's not just blue: a concise review. Am J Hematol 82: 134-144. [Crossref]
- Jeney V, Balla J, Yachie A, Varga Z, Vercellotti GM, et al. (2002) Pro-oxidant and cytotoxic effects of circulating heme. Blood 100: 879-887. [Crossref]
- Rouault TA, Cooperman S (2006) Brain iron metabolism. Semin Pediatr Neurol 13: 142-148. [Crossref]
- Mohorovic L, Materljan E, Brumini G (2010) Consequences of methemoglobinemia in pregnancy in newborns, children, and adults: issues raised by new findings on methemoglobin catabolism. J Matern Fetal Neonatal Med 23: 956-959. [Crossref]
- Mohorovic L, Petrovic O, Haller H, Micovic V (2010) Pregnancy loss and maternal methemoglobin levels; an indirect explanation of the association of environmental toxics and their adverse effects on mother and the fetus. Int J Environ Res Public Health 7: 4203-4212. [Crossref]
- Mohorovic L (2004) First two months of pregnancy-critical time for preterm delivery and low birthweight caused by adverse effects of coal combustion toxics. Early Hum Dev 80: 115-123. [Crossref]
- Lavezzi AM, Mohorovic L, Alfonsi G, Corna MF, Matturri L (2011) Brain iron accumulation in unexplained fetal and infant death victims with smoker mothers-the possible involvement of maternalmethemoglobinemia. BMC pediatrics 11: 62. [Crossref]
- Mohorovic L (2015) Ferric Iron Brain Deposition as the Cause, Source and Originator of Chronic Neurodegenerative Disease. J Environ Anal Chemi 2-6.