Parenteral nutrition as an unexpected and preventable source of mercury exposure in preterm infants.

Perinatal mercury exposure has neurodevelopmental consequences, which may be worse in preterm infants. In our cohort (N = 60), maternal and infant prenatal exposures were low, but infant levels increased during hospitalization and correlated only with duration of parenteral nutrition. A non-negligible exposure resulted from the nutrition preparation on equipment shared with adult preparations.

Organic and inorganic mercury in neonatal rat brain after prenatal exposure to methylmercury and mercury vapor.

BACKGROUND: Many populations are exposed to multiple species of mercury (Hg), predominantly organic Hg as methylmercury (MeHg) from fish, and inorganic Hg as Hg vapor from dental amalgams. Most of our knowledge of the neurotoxicity of Hg is based on research devoted to studying only one form at a time, mostly MeHg. OBJECTIVES: In this study we investigated the effects of prenatal exposure to MeHg and Hg vapor on Hg concentrations in the brain of neonatal rats. METHODS: Female Long-Evans hooded rats were exposed to MeHg (0, 3, 6, or 9 ppm as drinking solution), Hg vapor (0, 300, or 1,000 microg/m3 for 2 hr/day), or the combination of both, from 30 days before breeding through gestational day 18. On postnatal day 4, whole brains were taken from one male and one female from each of four litters in each treatment group to assess organic and inorganic Hg in the brain by cold vapor atomic absorption spectrometry. RESULTS: Statistical analysis using linear mixed effects models showed that MeHg dose was the primary determinant of both organic and inorganic brain Hg levels. For both outcomes, we also found significant interactions between MeHg and Hg vapor exposure. These interactions were driven by the fact that among animals not exposed to MeHg, animals exposed to Hg vapor had significantly greater organic and inorganic brain Hg levels than did unexposed animals. CONCLUSION: This interaction, heretofore not reported, suggests that coexposure to MeHg and Hg vapor at levels relevant to human exposure might elevate neurotoxic risks.

Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells.

The heavy metal mercury (Hg) is known to have immunomodulatory properties affecting lymphocyte signal transduction, death receptor signaling and autoimmunity. In this study we tested the hypothesis that Hg exposure would attenuate T-cell activation and caspase 8 and 3 activity in response to antigenic stimuli. To test this hypothesis, BALB/cJ mice were exposed to 10 mg/l mercuric chloride (HgCl(2)) in their drinking water for 2 weeks followed by injection with 20 microg of the Staphylococcal aureus enterotoxin B (SEB) superantigen. Eighteen hours after SEB challenge, there was a statistically significant reduction in caspase 8 and caspase 3 enzyme activity in the SEB reactive Vbeta8+ T-cells. The attenuated caspase activity in Hg-exposed mice persisted for 48 h after exposure. Moreover, activation of caspase 8 and caspase 3 was reduced by more than 60% in CD95 deficient MRL/MpJ-Fas(lpr) mice demonstrating that caspase 8 and 3 activation in response to SEB is CD95 dependent. In addition to the effects of Hg on caspase activity, expression of the T-cell activation marker CD69 was also attenuated in SEB reactive Vbeta8 T-cells in Hg-exposed mice. Moreover, CD69 expression in MRL/MpJ-Fas(lpr) mice was also reduced. Taken together the caspase and CD69 data support a role for CD95 in promoting a proapoptotic and activated state in SEB responsive T-lymphocytes and this state is attenuated by the autoimmune potentiating environmental agent mercury.

Attenuation of CD95-induced apoptosis by inorganic mercury: caspase-3 is not a direct target of low levels of Hg2+.

Exposure to environmental mercury may be a factor that contributes to idiosyncratic autoimmune disease. Studies have demonstrated that inorganic, ionic mercury (i.e., Hg2+) modulates several lymphocyte signal transduction pathways, which may be a mechanism whereby Hg2+ dysregulates the immune response. The CD95/Fas apoptotic signaling pathway, which is of critical importance in regulating peripheral tolerance, is disrupted by low and environmentally relevant concentrations of Hg2+. Activation of the cysteine protease caspase-3 is a critical component of both CD95-mediated and TNF-alpha-induced apoptosis. The present work demonstrates that Hg2+ selectively disrupts death receptor mediated caspase-3 activation, where CD95-mediated caspase-3 activation is impaired in Hg2+ treated cells; whereas TNF-alpha-induced caspase-3 activation is not. Using the fluorogenic caspase-3 substrate, Ac-DEVD-7-amino-4-methyl coumarin, to measure caspase-3 enzyme activity as well as Western blotting to track processing of the caspase-3 proenzyme, we have considered the potential direct and indirect effects of Hg2+ on caspase-3. At relatively high concentrations and in a cell-free system, Hg2+ is capable of targeting the active site cysteinyl of caspase-3 resulting in enzyme inhibition. However, at more environmentally relevant exposures, Hg2+ does not gain access in appreciable quantities to the intracellular compartment where caspase-3 resides. Collectively, these data establish that Hg2+ impairs CD95-mediated apoptosis by targeting a plasma membrane proximal signaling event. By measuring the cellular Hg2+ content following various exposure conditions, we have determined that a cellular Hg2+ burden of approximately 50 ng/10(6) cells is sufficient to impair CD95-mediated caspase-3 activation. The present study furthers an understanding of the mechanism whereby relatively low and non-cytotoxic concentrations of Hg2+ may disrupt peripheral tolerance leading to sustained autoimmune disease.