Judy L. Aschner

Mercury neurotoxicity: Mechanisms of blood-brain barrier transport

Mercury exists in a wide variety of physical and chemical states, each of which has unique characteristics of target organ toxicity. The classic symptoms associated with exposure to elemental mercury vapor (Hg0) and methylmercury (CH3Hg+; MeHg) involve the central nervous system (CNS), while the kidney is the target organ for the mono- and divalent salts of mercury (Hg+ and Hg++, respectively). Physical properties and redox potentials determine the qualitative and quantitative differences in toxicity among inorganic mercury compounds, while the ability of MeHg to cross the blood-brain barrier accounts for its accumulation in the CNS and a clinical picture that is dominated by neurological disturbances. This review gives an up-to-date account of mercurys physical and chemical properties and its interaction with biologically active sites pertinent to transport across the blood-brain barrier, a major regulator of the CNS millieu.

Manganese neurotoxicity: cellular effects and blood-brain barrier transport.

The observations by Couper in 1837 are acknowledged as the earliest description of the toxic syndrome associated with chronic manganese (Mn) exposure. Since that time, many of the neurotoxic aspects of manganism have been described, yet, the primary basis for its neurotoxicity remains unknown. Recent evidence corroborates the original hypothesis by Maynard and Cotzias (82) which invokes the mitochondrion as the target organelle for Mn cytotoxicity which is primarily expressed as a perturbation in Ca2+ homeostasis. Despite recognition that excessive Mn exposure culminates in Mn accumulation in the CNS and a clinical picture dominated by neurological disturbances, the role of the blood-brain barrier in the CNS uptake of Mn has received little attention. Accordingly, the first part of this review summarizes the current understanding of the interaction of Mn with biologically active sites in the induction of Mn cytotoxicity. The second part of this review summarizes what is known about Mn transport across the blood-brain barrier, a major regulator of the CNS milieu, with the contention that the rate and extent of Mn transport across the blood-brain barrier modulates its neurotoxicity.

Mortality reduction by heart rate characteristic monitoring in very low birth weight neonates: A randomized trial

OBJECTIVE To test the hypothesis that heart rate characteristics (HRC) monitoring improves neonatal outcomes. STUDY DESIGN We conducted a two-group, parallel, individually randomized controlled clinical trial of 3003 very low birth weight infants in 9 neonatal intensive care units. In one group, HRC monitoring was displayed; in the other, it was masked. The primary outcome was number of days alive and ventilator-free in the 120 days after randomization. Secondary outcomes were mortality, number of ventilator days, neonatal intensive care unit stay, and antibiotic use. RESULTS The mortality rate was reduced in infants whose HRC monitoring was displayed, from 10.2% to 8.1% (hazard ratio, 0.78; 95% CI, 0.61-0.99; P = .04; number needed to monitor = 48), and there was a trend toward increased days alive and ventilator-free (95.9 of 120 days compared with 93.6 in control subjects, P = .08). The mortality benefit was concentrated in infants with a birth weight <1000 g (hazard ratio, 0.74; 95% CI, 0.57-0.95; P = .02; number needed to monitor = 23). There were no significant differences in the other outcomes. CONCLUSION HRC monitoring can reduce the mortality rate in very low birth weight infants.

Manganese transport across the blood-brain barrier: Relationship to iron homeostasis

The binding characteristics of manganese (Mn) to transferrin (Tf) were examined on G-75 Sephadex gel columns. When 54MnCl2 was combined with Tf and immediately fractionated on the Sephadex column, 49% of 54Mn was found to Tf. The fraction of 54Mn which was Tf-bound was dependent upon the incubation period, and increased in a time-dependent fashion. In vivo, 6 hr of intravenous administration of ferric-hydroxide dextran complex significantly inhibited (p less than 0.05) 54Mn brain uptake as compared to its uptake in iron-free dextran-treated rats. These results suggest that iron (Fe) homeostasis may play an important role in the regulation of Mn transport across the blood-brain barrier (BBB).

Manganese accumulates in iron-deficient rat brain regions in a heterogeneous fashion and is associated with neurochemical alterations

Previous studies have shown that iron deficiency (ID) increases brain manganese (Mn), but specific regional changes have not been addressed. Weanling rats were fed one of three semipurified diets: control (CN), iron deficient (ID), or iron deficient/manganese fortified (IDMn+). Seven brain regions were analyzed for Mn concentration and amino acid (glutamate, glutamine, taurine, γ-aminobutyric acid) concentrations. Both ID and IDMn+ diets caused significant (p<0.05) increases in Mn concentration across brain regions compared to CN. The hippocampus was the only brain region in which the IDMn+ group accumulated significantly more Mn than both the CN and ID groups. ID significantly decreased GABA concentration in hippocampus, caudate putamen, and globus pallidus compared to CN rats. Taurine was significantly increased in the substantia nigra of the IDMn+ group compared to both ID and CN. ID also altered glutamate and glutamine concentrations in cortex, caudate putamen, and thalamus compared to CN. In the substantia nigra, Mn concentration positively correlated with increased taurine concentration, whereas in caudate putamen, Mn concentration negatively correlated with decreased GABA. These data show that ID is a significant risk factor for central nervous system Mn accumulation and that some of the neurochemical alterations associated with ID are specifically attributable to Mn accumulation.

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

The neurotoxicity of high levels of methylmercury (MeHg) is well established both in humans and experimental animals. Astrocytes accumulate MeHg and play a prominent role in mediating MeHg toxicity in the central nervous system (CNS). Although the precise mechanisms of MeHg neurotoxicity are ill-defined, oxidative stress and altered mitochondrial and cell membrane permeability appear to be critical factors in its pathogenesis. The present study examined the effects of MeHg treatment on oxidative injury, mitochondrial inner membrane potential, glutamine uptake and expression of glutamine transporters in primary astrocyte cultures. MeHg caused a significant increase in F(2)-isoprostanes (F(2)-IsoPs), lipid peroxidation biomarkers of oxidative damage, in astrocyte cultures treated with 5 or 10 microM MeHg for 1 or 6 h. Consistent with this observation, MeHg induced a concentration-dependant reduction in the inner mitochondrial membrane potential (DeltaPsi(m)), as assessed by the potentiometric dye, tetramethylrhodamine ethyl ester (TMRE). Our results demonstrate that DeltaPsi(m) is a very sensitive endpoint for MeHg toxicity, since significant reductions were observed after only 1 h exposure to concentrations of MeHg as low as 1 microM. MeHg pretreatment (1, 5 and 10 microM) for 30 min also inhibited the net uptake of glutamine ((3)H-glutamine) measured at 1 min and 5 min. Expression of the mRNA coding the glutamine transporters, SNAT3/SN1 and ASCT2, was inhibited only at the highest (10 microM) MeHg concentration, suggesting that the reduction in glutamine uptake observed after 30 min treatment with lower concentrations of MeHg (1 and 5 microM) was not due to inhibition of transcription. Taken together, these studies demonstrate that MeHg exposure is associated with increased mitochondrial membrane permeability, alterations in glutamine/glutamate cycling, increased ROS formation and consequent oxidative injury. Ultimately, MeHg initiates multiple additive or synergistic disruptive mechanisms that lead to cellular dysfunction and cell death.

Interactions between excessive manganese exposures and dietary iron-deficiency in neurodegeneration

For nearly a century, manganese has been recognized as an essential nutrient for proper bone formation, lipid, amino acid and carbohydrate metabolism. While manganese deficiency is characterized by symptoms ranging from stunted growth and poor bone remodeling to ataxia, it is manganese toxicity that is far more devastating from a public health standpoint. Most cases of manganese toxicity are the result of occupational exposure to high levels of the metal, and are characterized by specific neurological symptoms referred to as manganism. While manganism shares many common features with Parkinsons disease, there are distinct differences between the two disorders suggesting that manganism might indirectly affect nigrostriatal dopaminergic function. Recent studies from our laboratory show that dietary iron deficiency is a risk factor for brain manganese accumulation and that the striatum is particularly vulnerable. This review briefly discusses manganese from nutritional and toxicological aspects.

Requirement of argininosuccinate lyase for systemic nitric oxide production

Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases.

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Chronic exposure to excessive levels of Mn results in a movement disorder termed manganism, which resembles Parkinsons disease (PD). The pathogenic mechanisms underlying this disorder are not fully understood. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity. In the present study, we investigated the effects of Mn on mitochondrial function. Primary astrocyte cultures were prepared from cerebral cortices of one-day-old Sprague-Dawley rats. We have examined the cellular toxicity of Mn and its effects on the phosphorylation of extracellular signal-regulated kinase (ERK) and activation of the precursor protein of caspase-3. The potentiometric dye, tetramethyl rhodamine ethyl ester (TMRE), was used to assess the effect of Mn on astrocytic mitochondrial inner membrane potential (DeltaPsi(m)). Our studies show that, in a concentration-dependent manner, Mn induces significant (p<0.05) activation of astrocyte caspase-3 and phosphorylated extracellular signal-regulated kinase (p-ERK). Mn treatment (1 and 6 h) also significantly (p<0.01) dissipates the DeltaPsi(m) in astrocytes as evidenced by a decrease in mitochondrial TMRE fluorescence. These results suggest that activations of astrocytic caspase-3 and ERK are involved in Mn-induced neurotoxicity via mitochondrial-dependent pathways.

Spontaneous focal gastrointestinal perforation in very low birth weight infants

Spontaneous, focal gastrointestinal perforation occurred in six very low birth weight infants. The first recognized clinical sign of perforation in five of the six infants was striking blue-black discoloration of the abdominal wall. In all cases the clinical and radiographic presentations, as well as the histologic findings, were distinct from those associated with necrotizing enterocolitis. All 4 infants who underwent exploratory laparotomy and repair had excellent surgical outcomes.