Methylmercury distribution in the pregnant rat and embryo during early midbrain organogenesis.

BACKGROUND: The period of neurogenesis represents a window of susceptibility for in utero methylmercury (MeHg) exposure. This study examined the toxicokinetics of potentially neurotoxic doses of MeHg during neurogenesis in the developing rat to provide additional information in the areas of mercury speciation and inter-study variability. METHODS: Pregnant Sprague-Dawley rats were dosed s.c. with 5-22 mg/kg MeHg on Day 11 of gestation to target rapidly dividing cells of the developing midbrain. Maternal liver, kidney, skin, blood, placenta, and the embryonic body and brain were evaluated for total and inorganic mercury content at 24, 48, and 72 hr after dosing. Tissue Hg partitioning ratios derived from our data were then compared to those derived from previous studies. RESULTS: Mercury was present in all tissues examined by 24 hr after dosing, and levels remained relatively stable over the subsequent 2 days in most tissues. The exceptions were the maternal blood and kidney, in which total mercury decreased significantly over the three days after dosing. Inorganic mercury concentrations were similarly stable over time. At maternal MeHg doses above 12 mg/kg, non-linearities were observed in mercury accumulation in the embryo, placenta and maternal liver. The mercury tissue partitioning coefficients ranged from 0.09 for maternal blood:embryo to 1.97 for maternal blood:kidney. CONCLUSIONS: Our observations at the 5 mg/kg dose were consistent with those of previous studies that involved evaluations at slightly later gestational times. The estimates of tissue partitioning coefficients we derived using multiple studies provide valuable insight into the effects of inter-study variability.

Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on tissue and urine mercury levels following prolonged methylmercury exposure in rats.

Methylmercury, a potent neurotoxicant, accumulates in the brain as well as the kidney during chronic exposure. We evaluated the capacity of 2,3-dimercapto-1-propanesulfonic acid (DMPS), a tissue-permeable metal chelator, to reduce brain, kidney, and blood Hg levels and to promote Hg elimination in urine following exposure of F-344 rats to methylmercury hydroxide (MMH) (10 ppm) in drinking water for up to 9 weeks. Inorganic (Hg2+) and organic (CH3Hg+) mercury species in urine and tissues were assayed by cold vapor atomic fluorescence spectroscopy (CVAFS). Following MMH treatment for 9 weeks, Hg2+ and CH3Hg+ concentrations were 0.28 and 4.80 microg/g in the brain and 51.5 and 42.2 microg/g in the kidney, respectively. Twenty-four hours after ip administration of a single DMPS injection (100 mg/kg), kidney Hg2+ and CH3Hg+ declined 38% and 59%, whereas brain mercury levels were slightly increased, attributable entirely to the CH3Hg+ fraction. Concomitantly, Hg2+ and CH3Hg+ in urine increased by 7.2- and 28.3-fold, respectively, compared with prechelation values. A higher dose of DMPS (200 mg/kg) was no more effective than 100 mg/kg in promoting mercury excretion. In contrast, consecutive DMPS injections (100 mg/kg) given at 72-h intervals significantly decreased total mercury concentrations in kidney, brain, and blood. However, the decrease in brain and blood mercury content was restricted entirely to the CH3Hg+ fraction, consistent with the slow dealkylation rate of MMH in these tissues. Mass balance calculations showed that the total amount of mercury excreted in the urine following successive DMPS injections corresponds quantitatively to the total amount of mercury removed from the kidney, brain, and blood of MMH-exposed rats. These findings confirm the efficacy of consecutive DMPS treatments in decreasing mercury concentrations in target tissue and in reducing overall mercury body burden. They demonstrate further that the capacity of DMPS to deplete tissue Hg2+ is highly tissue-specific and reflects the relative capacity of the tissue for methylmercury dealkylation. In light of this observation, the inability of DMPS to reduce Hg2+ levels in brain or blood may explain the inefficacy of DMPS and similar chelating agents in the remediation of neurotoxicity associated with prolonged MMH exposure.

Quantitative evaluation of urinary porphyrins as a measure of kidney mercury content and mercury body burden during prolonged methylmercury exposure in rats.

Changes in urinary porphyrin excretion patterns (porphyrin profiles) during prolonged mercury exposure are attributable to mercury accumulation in the kidney and to consequent effects of Hg2+ on renal porphyrin metabolism. In the present study, we evaluated the quantitative relationship of urinary porphyrin concentrations to mobilizable renal mercury content, using the metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS) to modulate kidney mercury levels. Rats exposed to methylmercury hydroxide (MMH) at 10 ppm in drinking water for 6 weeks were treated with up to 3 consecutive doses of DMPS (100mg/kg, ip) at 72-h intervals. Consistent with previous findings, the concentrations of pentacarboxyl- (5-) and copro- (4-) porphyrins and of an atypical porphyrin specific to mercury exposure, precoproporphyrin, were significantly elevated in urine of MMH-exposed rats, compared with that of rats exposed to distilled water (dH2O) for the same period. Consecutive DMPS treatments of MMH-exposed rats significantly decreased kidney concentrations of total, as well as Hg2+ and CH3Hg+ species, and promoted increased urinary mercury excretion. Concomitantly, DMPS treatment decreased both kidney and urinary porphyrin concentrations, consistent with depletion of renal mercury levels. Regression analyses demonstrated a high correlation (r approximately 0.9) between prechelation urinary porphyrins and postchelation urinary mercury levels and also between prechelation urinary porphyrins and prechelation kidney mercury concentrations. These findings demonstrate that urinary porphyrin concentrations relate quantitatively to DMPS-mobilizable mercury in the kidney and, therefore, serve as a biochemical measure of renal mercury content.