Background: Highly reactive halogens such as bromine are more commonly utilized, leading to an increase in quantities that are stocked and transported, therefore increasing the risk of accidental or deliberate exposure. Here we describe progression and potential mechanisms of adverse effects of a single injurious insult on the heart caused by bromine inhalation. Our studies have shown that bromine inhalation causes acute myocardial ischemia-reperfusion-like injury mediated by cytosolic calcium overload and increased calpain activity due to inactivation of SERCA. However, the progression of this injury in survivors is unknown. Our working hypothesis is that the initial injury causes irreversible damage that leads to chronic left ventricular systolic and diastolic dysfunction.Methods: Sprague Dawley rats received bromine exposure of 600 ppm for 45' and the survivors were sacrificed at 14 or 28 days, with matching naïve groups at each time point. Echocardiography, hemodynamic analysis, histology, electron microscopy and biochemical analysis of cardiac tissue were performed to assess functional, structural and molecular effects.Results: At 14 and 28 days, hemodynamic and echocardiographic analysis revealed increases in RV and LV end-diastolic pressure and LV end-diastolic wall stress with increased LV fibrosis at 28 days. TEM images demonstrated myofibrillar loss, cytoskeletal breakdown and mitochondrial damage at both time points. The myofibrillar damage and increased LV wall stress was reflected by increases in cTnI and NT-proBNP at both time points. LV shortening decreased as a function of increasing LV end-systolic wall stress and was accompanied by increased SERCA modification and a striking dephosphorylation of phospholamban with a significant increase in protein phosphatase 1. There was an increased 4-hydroxynonenal content in the myocardium at 28 days suggesting increased oxidative stress. Conclusions:These results indicate that the initial insult of bromine inhalation initiates a continuous process with chronic myocardial damage and subsequent LV systolic and diastolic dysfunction and that oxidative stress and phospholamban dephosphorylation play a central role.

The risk of accidental bromine (Br2) exposure to the public has increased due to its enhanced industrial use. Inhaled Br2 damages the lungs and the heart; however, adverse effects on the brain are unknown. In this study, we examined the neurological effects of inhaled Br2 in Sprague Dawley rats. Rats were exposed to Br2 (600 ppm for 45 min) and transferred to room air and cage behavior, and levels of glial fibrillary acidic protein (GFAP) in plasma were examined at various time intervals. Bromine exposure resulted in abnormal cage behavior such as head hitting, biting and aggression, hypervigilance, and hyperactivity. An increase in plasma GFAP and brain 4-hydroxynonenal (4-HNE) content also was observed in the exposed animals. Acute and delayed sympathetic nervous system activation was also evaluated by assessing the expression of catecholamine biosynthesizing enzymes, tryptophan hydroxylase (TrpH1 and TrpH2), and tyrosine hydroxylase (TyrH), along with an assessment of catecholamines and their metabolites. TyrH was found to be increased in a time-dependent manner. TrpH1 and TrpH2 were significantly decreased upon Br2 exposure in the brainstem. The neurotransmitter content evaluation indicated an increase in 5-HT and dopamine at early timepoints after exposure; however, other metabolites were not significantly altered. Taken together, our results predict brain damage and autonomic dysfunction upon Br2 exposure.

The threat from deliberate or accidental exposure to halogen gases is increasing, as is their industrial applications and use as chemical warfare agents. Biomarkers that can identify halogen exposure, diagnose victims of exposure or predict injury severity, and enable appropriate treatment are lacking. We conducted these studies to determine and validate biomarkers of bromine (Br 2) toxicity and correlate the symptoms and the extent of cardiopulmonary injuries. Unanesthetized rats were exposed to Br 2 and monitored noninvasively for clinical scores and pulse oximetry. Animals were euthanized and grouped at various time intervals to assess brominated fatty acid (BFA) content in the plasma, lung, and heart using mass spectrometry. Bronchoalveolar lavage fluid (BALF) protein content was used to assess pulmonary injury. Cardiac troponin I (cTnI) was assessed in the plasma to evaluate cardiac injury. The blood, lung, and cardiac tissue BFA content significantly correlated with the clinical scores, tissue oxygenation, heart rate, and cardiopulmonary injury parameters. Total (free + esterified) bromostearic acid levels correlated with lung injury, as indicated by BALF protein content, and free bromostearic acid levels correlated with plasma cTnI levels. Thus, BFAs and cardiac injury biomarkers can identify Br 2 exposure and predict the severity of organ damage.

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Accidental occupational bromine (Br>2>) exposures are common, leading to significant morbidity and mortality; however, the specific effects of Br>2> inhalation in female victims are unclear. Our studies demonstrated that acute high-concentration Br>2> inhalation is fatal, and cardiac injury and dysfunction play an important role in Br>2> toxicity in males. In this study, we exposed female Sprague Dawley rats, age-matched to those males from previously studied, to 600 ppm Br>2> for 45 min and assessed their survival, cardiopulmonary injury and cardiac function after exposure. Br>2> exposure caused serious mortality in female rats (59%) 48 h after exposure. Rats had severe clinical distress, reduced heart rates and oxygen saturation after Br>2> inhalation as was previously reported with male animals. There was significant lung injury and edema when measured 24 h after exposure. Cardiac injury biomarkers were also significantly elevated 24 h after Br>2> inhalation. Echocardiography and hemodynamic studies were also performed and revealed that the mean arterial pressure was not significantly elevated in females. Other functional cardiac parameters were also altered. Aside from the lack of elevation of blood pressure, all other changes observed in female animals were also present in male animals as reported in our previous study. These studies are important to understand the toxicity mechanisms to generate therapies and better-equip first responders to deal with these specific scenarios after bromine spill disasters.>