Effect of sex hormones on the fate of methylmercury and on glutathione metabolism in mice

To investigate the mechanisms for the sex-related difference in the in vivo fate of methylmercury (MeHg), the effects of hormonal manipulation on the distribution and urinary excretion of the mercurial moiety (Hg) of injected MeHg and on hepato-renal metabolism of glutathione were studied in C57BL/6N mice. Twenty-four hours after oral administration of MeHg, urinary Hg levels were significantly higher in males than in females. Tissue Hg levels of males were higher in the kidney, but lower in the brain, liver and plasma than those of females. The fate of injected MeHg in castrated males was similar to that in normal females except for its brain levels. This feminization of the mercurial behavior in the castrated males was restored by treating with testosterone propionate (TP). When control mice were treated with TP, urinary excretion of Hg increased in both sexes, whereas renal Hg level increased only in females. Administration of estradiol benzoate (EB) to males decreased the renal accumulation and urinary excretion of Hg, whereas its hepatic levels increased. However, no significant change in the fate of MeHg was found in females pretreated with EB. Castration of females slightly decreased the urinary excretion of Hg. Thus, tissue distribution and urinary excretion of the administered MeHg seem to be subject to sex hormone control. Since MeHg has a high affinity for GSH, effects of hormonal manipulation on the metabolism of hepato-renal glutathione were also investigated. A significant sex-related difference in glutathione levels was found in plasma but not in the kidney, liver and erythrocytes. The half-lives of glutathione in the liver and kidney were significantly shorter in males than in females as determined by treatment with buthionine sulfoximine, a specific inhibitor of GSH synthesis. This difference was also modulated by the hormonal treatment. Since half-lives of GSH in the liver and kidney predominantly reflect the rate of its efflux from these tissues, the results suggest that GSH metabolism and/or secretory transport may be regulated by sex hormones. These and other observations suggest that the fate of MeHg may be modulated by way of regulating the inter-organ metabolism and transport of glutathione and its derivatives.     

Sex and strain differences of susceptibility to methylmercury toxicity in mice

Excretion and organ distribution of mercury and susceptibility to methylmercury (MeHg) toxicity were compared between strains and sexes after successive oral administration of MeHg chloride (5 mg/kg per day) using BALB/cA (C) and C57BL/6N (B6) mice. Every mouse died several days after initiation of toxic symptoms, and significant strain and sex differences were found with regard to length of survival. C mice of both sexes died earlier than B6 mice. B6 males survived much longer (greater than 6 weeks) than B6 females (3 weeks), whereas C males died earlier than C females. B6 male mice showed remarkably higher urinary Hg excretion and lower Hg levels in the brain, liver, kidney and blood than the other 3 groups. With daily MeHg administration, the Hg levels in all tissues except the kidney showed linear increase until the manifestation of toxic symptoms. Mercury accumulation in the kidney, the tissue with the greatest uptake of Hg in the mice examined herein, was biphasic: accumulation was rapid for 7-10 days after which the rate of increase was greatly reduced until death. It is suggested that conditions resulting in saturation of the rate of kidney Hg uptake might cause inhibition of urinary Hg excretion via some disturbance of renal function. Subsequently, Hg accumulation would be accelerated in various tissues, including the brain, leading to manifestation of toxic symptoms.     

Role of testosterone in gamma-glutamyltranspeptidase-dependent renal methylmercury uptake in mice.

To elucidate the mechanisms responsible for sex and age differences in renal methylmercury uptake, effects of castration and testosterone treatment on mercury content and activity of renal gamma-glutamyltranspeptidase (gamma-GTP), which supposedly plays an important role in renal mercury uptake, were investigated in mice. Between 2 and 8 weeks of age, renal methylmercury uptake in male mice determined 4 hr after injection of a nontoxic dose of methylmercuric chloride (MMC, 1 mumol/kg, sc) increased about fivefold. At 4 weeks of age, a significant sex difference in renal mercury uptake first appeared. Renal mercury content in 4-week-old male mice was twofold higher than that of females and increased with age, but remained constant in females. Small but significant (p less than 0.05) differences in mercury content in other tissues were observed, which could not account for the marked sex- and age-related differences in renal mercury concentrations. Renal gamma-GTP activity gradually increased in males with maturation, and a sexual dimorphism of renal gamma-GTP was apparent after the fourth week. Seven days after castration of 4-week-old male mice, both renal mercury content and gamma-GTP activity were decreased to the levels in females. Activity of gamma-GTP was subsequently elevated to control male levels by sc injection of testosterone (5 mg/kg/day x 7 days). In female mice, both renal mercury content and gamma-GTP activity were increased to the level of males by testosterone treatment (5 mg/kg/day x 14 days). Thus, the renal mercury content was closely correlated with changes in renal gamma-GTP activity. These results suggest that sex and age differences in renal methylmercury accumulation may be due to a difference in renal gamma-GTP activity controlled at least in part by testosterone.     

Strain difference in mercury excretion in methylmercury-treated mice

The strain differences in mercury excretion and organ distribution after administration of methylmercuric chloride (5 mg/kg) were studied in male mice of four strains, C57BL/6N, BALB/cA, C3H/HeN and AKR. The urinary excretion rate of mercury for 5 days following administration was 3.9–4.7 times higher in the C57BL strain than in the other three strains, whereas the mercury level in feces was highest in the AKR strain. Although the blood mercury concentration in the C57BL strain was almost half that in the others up to the 5th day, the plasma levels did not vary so widely. C57BL showed the highest ratio of plasma to whole blood mercury level, which was thought to originate from the lower affinity of methylmercury for hemoglobin. The variation of the plasma/whole blood ratios was rather small throughout the experimental period in each strain examined. In the C57BL strain, the mercury levels in brain, liver, kidney and blood were significantly lower on and after the 5th day than in the other three strains, probably because of the rapid elimination of body mercury into urine, but the mercury uptake by the brain and kidney 5 min after administration was at a rather higher rate than in the other strains. On the other hand, the highest tissue levels were shown by the C3H strain in the brain and liver, and by the BALB/c strain in the kidney. It was suggested that in the C57BL strain, the higher mercury distribution in plasma and rapid uptake by the kidney might result in higher urinary excretion.     

An explanation for strain and sex differences in renal uptake of methylmercury in mice.

The present investigation was designed to elucidate the mechanism for strain and sex differences in renal methylmercury accumulation, in five mouse strains, viz. BALB/cA, C57BL/6N, CBA/JN, C3H/HeN and ICR. Strain and sex comparisons of factors which influence renal mercury accumulation were made. Strain and sex differences were observed in renal mercury accumulation 4 h after methylmercuric chloride (MMC) (1 mumol/kg, s.c.) injection. Glutathione (GSH) content in liver and kidney showed significant strain and sex differences. Pretreatment with 1,2-dichloro-4-nitrobenzene (DCNB), to deplete hepatic GSH without affecting renal non-protein thiol (NPSH) level, led to a dose-dependent decrease in hepatic and plasma GSH concentrations that correlated with decreased mercury levels in the kidney 10 min after MMC (1 mumol/kg, i.v.) injection. This indicates that hepatic and plasma GSH levels are related to mercury accumulation into the kidney. Renal gamma-glutamyltranspeptidase (gamma-GTP) activity significantly varied among the strains, and in BALB/cA and ICR, renal gamma-GTP activity in males was about 2-fold higher than that in females. Renal gamma-GTP activity was also correlated with the renal mercury content. These results suggest that strain and sex differences in renal accumulation of mercury are attributable to differences in tissue GSH content and possibly to differences in renal gamma-GTP activity.     

Toxicokinetics of mercuric chloride and methylmercuric chloride in mice.

Future human exposure to inorganic mercury will probably lead to a few individuals occupationally exposed to high levels and much larger populations exposed to low or very low levels from dental fillings or from food items containing inorganic mercury; human exposure to methylmercury will be relatively low and depending on intake of marine food. Ideally, risk assessment is based on detailed knowledge of relations between external and internal dose, organ levels, and their relation to toxic symptoms. However, human data on these toxicokinetic parameters originate mainly from individuals or smaller populations accidentally exposed for shorter periods to relatively high mercury levels, but with unknown total body burden. Thus, assessment of risk associated with exposure to low levels of mercury will largely depend on data from animal experiments. Previous investigations of the toxicokinetics of mercuric compounds almost exclusively employed parenteral administration of relatively high doses of soluble mercuric salts. However, human exposure is primarily pulmonary or oral and at low doses. The present study validates an experimental model for investigating the toxicokinetics of orally administered mercuric chloride and methylmercuric chloride in mice. Major findings using this model are discussed in relation to previous knowledge. The toxicokinetics of inorganic mercury in mice depend on dose size, administration route, and sex, whereas the mouse strain used is less important. The "true absorption" of a single oral dose of HgCl2 was calculated to be about 20% at two different dose levels. Earlier studies that did not take into account the possible excretion of absorbed mercury and intestinal reabsorption during the experimental period report 7-10% intestinal uptake. The higher excretion rates observed after oral than after intraperitoneal administration of HgCl2 are most likely due to differences in disposition of systemically delivered and retained mercury. After methylmercury administration, mercury excretion followed first-order kinetics for 2 wk, independently of administration route, strain, or sex. However, during longer experimental periods, the increasing relative carcass retention (slower rate of excretion) caused the elimination to deviate from first-order kinetics. Extensive differences in the toxicokinetics of methylmercury with respect to excretion rates, organ deposition, and blood levels were observed between males and females.(ABSTRACT TRUNCATED AT 400 WORDS)     

Dose- and sex-dependent alterations in mercury distribution in fetal mice following methylmercury exposure

Methylmercuric chloride was orally given to inbred C57BL/6N mice on d 13 of pregnancy at doses of 2.5, 5, 10, and 20 mg/kg. Animals were sacrificed on each of d 14-18 of pregnancy, and mercury levels in the brain, liver, and kidney of both the fetus and dam were determined. The dose effect on the time course of mercury accumulation in the brain was observed both in the fetus and dam; after the higher doses administered, the brain mercury reached the highest concentration later than it did after the lower doses. In addition, the mercury concentration in the fetal brain was disproportionately higher after a dose of 20 mg/kg, which was toxic in the fetus since the weight of the brain was reduced. The concentration in the fetal brain was 1.6-4.9 times higher than in the maternal brain. The sex difference of fetuses in mercury levels was observed in the brain after a dose of 2.5 mg/kg, in which mercury concentration was higher in females than in males. This corresponded to the previously reported difference in adult mice and rats. However, the sex difference was not seen after doses of 5, 10, or 20 mg/kg.     

Comparative study of the sensitivity of male and female rats to methylmercury

Male and female rats were dosed daily by gastric gavage four or five times with 8.0 mg/kg Hg as methylmercury. Treatment lowered the body weight in relation to the body weight of untreated rats to the same extent in male and female rats but when body weight was related to the initial body weight, the effect of methylmercury was more pronounced in females than in males. The importance of differences in growth or loss of body weight is that in spite of the similar whole body clearance mercury concentrations were higher in females than in males. After identical doses the brains of females always contained more mercury than those of males and in both sexes the brain concentration of mercury showed a disproportionate elevation when the number of doses was increased from four to five. However, weight change alone does not explain the sex related difference in the brain concentration of mercury as this was evident even 72 h after a single dose. In agreement with the brain concentration of mercury, female rats developed more intensive co-ordination disorders and after five doses they had more extensive damage in the granular layer of the cerebellum than males.     

Strain independent elevation of hepatic mono-oxygenase enzymes in female mice

1. Hepatic microsomal drug metabolizing activity was compared in male and female AL/N, Balb/c, Balb/cJ, CD-1, C57BL/6J, C57BL/10J, DBA/2, and DBA/2J mice. 2. Cytochrome P-450-dependent hexobarbital hydroxylase and aminopyrine N-demethylase activities were sexually dimorphic with apparent maximal velocities consistently higher in females. Hexobarbital-induced sleeping times were greater in males, corresponding to their lower hepatic mono-oxygenase enzyme activities measured in vitro. 3. No murine sex differences were observed for the hydroxylation of aniline, while UDP-glucuronyltransferase activity was strain dependent with either no sexual dimorphism or higher activities in males. 4. Testectomy resulted in an elevation of hepatic hexobarbital metabolism to female levels in all strains examined. Thus, decreased hepatic cytochrome P-450-dependent xenobiotic metabolism in adult male mice results from the suppressive effects of gonadal androgens. 5. Sexually dimorphic patterns of hepatic hexobarbital and aminopyrine metabolism in adult mice are opposite in orientation and lower in magnitude than the well established relationship in rats in which these same substrates are metabolized at a rate 3 to 5 fold higher in intact males as compared to females or gonadectomized males.     

Effect of testosterone on the eosinophil response of C57BL/6 mice to infection with Brugia pahangi.

The kinetics of peripheral and bone marrow eosinophil responses of C57BL/6 mice against Brugia pahangi infection were compared between both sexes, and the effects of testosterone on these eosinophil responses were examined. At the early phase of infection (7 to 10 days), female mice showed significantly higher peripheral eosinophil response than did males, and on day 5, 7 and 10 postinfection bone marrow eosinophil responses were also high in females. Live infective larvae but not dead ones could induce these differential responses of eosinophils between sexes. Castration of male mice increased the peripheral and bone marrow eosinophil responses to the levels of female mice, whereas castration of female mice did not affect these responses. Furthermore, testosterone treatment at a pharmacological dose in female mice suppressed peripheral and bone marrow eosinophil responses at the early phase of infection. These results suggest that the male sex hormone, testosterone, but not the female sex hormone has a role in the down-regulation of the systemic eosinophil responses of C57BL/6 mice to infection with B. pahangi.     

Fate of hexachlorobenzene in C57BL/10 mice with iron overload

The distribution of radioactivity in male C57BL/10 mice dosed with [14C]hexachlorobenzene (HCB) was followed over 21 days and found to be high in adipose tissue and adrenals, moderate in thymus whereas liver was relatively poorly labelled. A predose of iron (500 mg/kg), which greatly promotes the porphyrogenic action of HCB in this strain, had only a small effect on the distribution of radioactivity in tissues and excreta. Iron induced excretion of urinary metabolites from HCB by C57BL/10 mice but not by the insensitive DBA/2 strain. However, there was no such difference in faecal metabolites, total metabolism was only slightly increased and there was no correlation between liver porphyrin levels and urinary excretion of metabolites by individual mice. At the end of 4 weeks exposure of iron-treated C57BL/10 mice to HCB urinary metabolites fell while porphyrin excretion continued to rise. Thus the considerable sensitisation of the C57BL/10 strain after iron overload to the induction of porphyria by HCB cannot be ascribed simply to enhancement of total metabolism but must be caused either by the formation of a specific undetected metabolite or induction of some other toxic process.     

Strain independent elevation of hepatic mono-oxygenase enzymes in female mice

1. Hepatic microsomal drug metabolizing activity was compared in male and female AL/N, Balb c, Balb/cJ, CD-1, C57BL/6J, C57BL/10J, DBA/2, and DBA/2J mice.

2. Cytochrome P-450-dependent hexobarbital hydroxylase and aminopyrine N-demethylase activities were sexually dimorphic with apparent maximal velocities consistently higher in females. Hexobarbital-induced sleeping times were greater in males, corresponding to their lower hepatic mono-oxygenase enzyme activities measured in vitro.

3. No murine sex differences were observed for the hydroxylation of aniline, while UDP-glucuronyltransferase activity was strain dependent with either no sexual dimorphism or higher activities in males.

4. Testectomy resulted in an elevation of hepatic hexobarbital metabolism to female levels in all strains examined. Thus, decreased hepatic cytochrome P-450-dependent xenobiotic metabolism in adult male mice results from the suppressive effects of gonadal androgens.

5. Sexually dimorphic patterns of hepatic hexobarbital and aminopyrine metabolism in adult mice are opposite in orientation and lower in magnitude than the well established relationship in rats in which these same substrates are metabolized at a rate 3 to 5 fold higher in intact males as compared to females or gonadectomized males.     

Male and female C57BL/6 mice respond differently to diazepam challenge in avoidance learning tasks

Benzodiazepines (BZ) impair learning and memory performance of animals. The goal of this study was to examine sex differences in the effects of diazepam on learning and memory of C57BL/6 mice in avoidance paradigms. Male and female C57BL/6 mice were tested in the one-way active avoidance, step-down passive avoidance, and foot-shock pain threshold tasks, following administration of vehicle or diazepam (1 mg/kg). No substantial sex or drug effects on the threshold of the pain response to shock were found. There were no significant differences in avoidance performance between vehicle-treated male and female mice while 1 mg/kg of diazepam produced opposite effects on performance of males and females in both tasks. Diazepam-treated females learned faster in the active avoidance task and showed stronger retention in the passive avoidance task. In contrast, diazepam impaired learning of males in the active avoidance task and had no effect on their performance in the passive avoidance task. Diazepam-induced impairment in males was not due to higher sensitivity to the sedative effect of diazepam as females were more sedated than males on the first trial of the passive avoidance task. Our data showed that sedative and amnesic effects of BZs are not tightly linked. This study also suggests that cognitive effects of BZs in rodents could be sex dependent and highlight the importance of using both sexes in studies on behavioral effects of psychoactive drugs.     

The role of age and sex hormones on the urinary excretion of zenarestat in rats.

1. Age-dependent changes in urinary excretion of zenarestat and the effect of gonadectomy and androgen treatment were investigated in Sprague-Dawley rats. 2. Urinary excretion of zenarestat scarcely differed between 3-week-old male and female rats; it decreased in males from 4 weeks of age, but in females urinary excretion of the drug was essentially constant during ageing. 3. Castration of male rats at 22 days of age abolished the adult sex difference in urinary excretion of zenarestat, while castration at 5 weeks of age produced urinary excretion of the drug about half that in females. 4. Ovariectomy of females at 22 days or 5 weeks of age had no effect on the urinary excretion of zenarestat. 5. Treatment of male and female gonadectomized rats with testosterone resulted in the urinary excretion of zenarestat characteristic of intact adult male rats.     

Possible role of hepatic glutathione in transport of methylmercury into mouse kidney

The mechanism of the renal uptake of methylmercury was studied in mice. Preadministration of 1,2-dichloro-4-nitrobenzene (DCNB), which is a reagent that depletes hepatic glutathione (GSH) without affecting the renal GSH level, 30 min before injection of methylmercury significantly decreased the renal accumulation of mercury. The renal accumulation of mercury in mice receiving methylmercury-GSH intravenously was significantly higher than that in mice receiving methylmercuric chloride. These results suggest the possibility that hepatic GSH, as a source of extracellular GSH, plays an important role in the renal accumulation of methylmercury. No significant difference in renal mercury accumulation between bile duct-cannulated mice and normal mice was observed, indicating that the enterohepatic circulation of methylmercury is not an important factor in the renal accumulation of methylmercury in mice. Pretreatment of mice with acivicin, a potent inhibitor of gamma-glutamyl transpeptidase (gamma-GTP), significantly depressed the renal uptake of methylmercury and increased the urinary excretion of GSH and methylmercury. In in vitro reactions, methylmercury-GSH was degraded into methylmercury-cysteinylglycine by gamma-GTP, and this product was then converted to methylmercury-cysteine by dipeptidase. These results suggest that methylmercury is transported into the kidney as a complex with GSH, and then incorporated into the renal cells after degradation of the GSH moiety by gamma-GTP and dipeptidase, although the methylmercury bound to extracellular GSH can be reversibly transferred to plasma proteins in the bloodstream.     

Strain, sex and developmental profiles of cocaine metabolizing enzymes in mice

Cocaine is a potent hepatotoxin in laboratory mice, although the cocaine-induced hepatotoxicity (CIH) is due to the action of a metabolite of cocaine. Cocaine can be hydrolyzed by serum cholinesterase (ChE) to inactive products, or be oxidized by hepatic cytochrome P-450 and FAD-containing monooxygenase (FADM). The oxidative pathway is thought to be responsible for production of the hepatotoxic metabolite of cocaine, presumably norcocaine nitroxide. Female mice are much more resistant to CIH than males of the same strain. We have found that immature male mice are as resistant as females to the development of CIH. Males did not show any CIH until the onset of puberty (30 days of age), indicating that the development of CIH in males was under hormonal control. To determine if the major cocaine-metabolizing enzymes were responsible for the regulation of CIH, we measured the activities of ChE, cocaine N-demethylation (CND) and FADM as a function of sex in C57BL/6Ibg and DBA/2Ibg mice 20-21, 30 +/- 1 and 65 +/- 5 days of age. There was a significant sex difference in ChE activity (females higher than males) but no effect of age. Cocaine N-demethylation increased in both males and females with age, but there was no consistent sex difference. Activity of FADM declined in males as a function of age, but remained constant in females. The lack of a consistent correlation between enzyme activities and sex-, strain-, and age-dependent differences in susceptibility to CIH, do not support a regulatory role for ChE, CND or FADM in mediating the hepatotoxic response.     

Comparison of neurobehavioral changes in three inbred strains of mice prenatally exposed to methylmercury

Pregnant mice of three inbred strains (BALB/c, C57BL/6J, C57BL/6Cr) were orally given methylmercury (MMC; 3 x 3 mg/kg body weight) or the equivalent volume of phosphate-buffered saline during days 12-14 of gestation and allowed to deliver. The behaviors of their male offspring were evaluated in an open field and their home cage and in a Morris water maze. In the open field test, the BALB/c and C57BL/6Cr MMC groups exhibited less total locomotor activity than did their respective control groups. However, there was no significant difference observed between the MMC and control C57BL/6J strain. In the BALB/c strain, the MMC group exhibited significantly more central locomotion and significantly less peripheral locomotion than did the control group. These results indicated that the prenatal exposure to MMC caused decreases in open-field activity in the C57BL/6Cr and BALB/c strains, concomitantly with a change in emotional status in BALB/c strain. For spontaneous activity in their home cage, all groups moved more actively in the dark phase than in the light phase except BALB/c MMC group. The BALB/c MMC group moved in the light phase as much as in the dark phase, indicating a disturbance of nocturnal rhythm of spontaneous activity. In the Morris water maze, the C57BL/6Cr and C57BL/6J control groups perform very well over the 5 consecutive days. The prenatal exposure to MMC caused significantly prolonged latency in the C57BL/6Cr and C57BL/6J, but not in BALB/c strain. This result indicated that the prenatal exposure to MMC impaired the performance in the Morris water maze differently among the strains. This study provides a basis for evaluating strain-specific neurobehavioral changes when the widely used three inbred strains of mice are chronically exposed to MMC.     

The role of age and sex hormones on the urinary excretion of zenarestat in rats

1. Age-dependent changes in urinary excretion of zenarestat and the effect of gonadectomy and androgen treatment were investigated in Sprague—Dawley rats.

2. Urinary excretion of zenarestat scarcely differed between 3-week-old male and female rats; it decreased in males from 4 weeks of age, but in females urinary excretion of the drug was essentially constant during ageing.

3. Castration of male rats at 22 days of age abolished the adult sex difference in urinary excretion of zenarestat, while castration at 5 weeks of age produced urinary excretion of the drug about half that in females.

4. Ovariectomy of females at 22 days or 5 weeks of age had no effect on the urinary excretion of zenarestat.

5. Treatment of male and female gonadectomized rats with testosterone resulted in the urinary excretion of zenarestat characteristic of intact adult male rats.     

Influence of dietary protein levels on the fate of methylmercury and glutathione metabolism in mice.

We investigated the influence of dietary protein levels on the fate of methylmercury (MeHg), the tissue glutathione (GSH) levels and the efflux rates of GSH in C57BL/6N male mice. One group of mice was fed a 7.5% protein diet (low protein diet, LPD) and the other was fed a 24.8% protein diet (normal protein diet, NPD). The cumulative amount of Hg in urine in LPD-fed mice was approximately 3.7-times lower than in NPD group during the 7 days after oral administration of MeHg (20 mumol/kg), although the fecal Hg levels were identical in the two groups. Hg concentration in kidney, liver and blood decreased time-dependently for 7 days after the administration in both groups of mice, whereas the brain levels continued to increase during this period. Tissue Hg levels in the LPD group were significantly higher than in the NPD group except for the liver. Although the hepatic GSH level in LPD-fed mice was significantly lower than in NPD-fed mice, the levels in the kidney, brain, blood and plasma were not different between the two groups. The efflux rate (mumol/g body weight per day) of hepatic GSH in LPD-fed mice was significantly lower than in the NPD group, whereas the efflux rates of renal GSH were identical in both groups. When MeHg (20 mumol/kg)-pretreated mice were injected with acivicin, a specific inhibitor of gamma-glutamyltranspeptidase, the urinary Hg levels increased by 60- and 36-fold in groups fed LPD and NPD, respectively. As a result, the difference in urinary Hg levels between the two groups disappeared with acivicin treatment. This result indicated that LPD feeding might decrease urinary Hg excretion by increasing the retention of MeHg metabolite(s) in renal cells. Thus, our present study suggested that the dietary protein status, which could modulate the metabolism of thiol compounds, played an important role in determining the fate of MeHg.     

Higher faecal excretion and lower tissue accumulation of mercury in Wistar rats from contaminated fish than from methylmercury chloride added to fish.

A short-term low level exposure experiment was conducted on rats in order to determine urinary and faecal excretion, accumulation, and biological responses to methylmercury from fish products. Male Wistar rats were fed fish-meal diets containing methylmercury contaminated fish (1.45 or 2.61 mgHg/kg as methylmercury), uncontaminated fish supplemented with methylmercury chloride (CH3HgCl) at similar levels (1.24 and 2.49 mgHg/kg, respectively) or uncontaminated fish as a control (0.052 mgHg/kg) for 4 weeks (n=6 rats per treatment). After 2 and 4 weeks of exposure, rats were placed in metabolic chambers for 48 h to assess overall faecal and urinary excretion of mercury. The overall faecal excretion in rats fed fish supplemented with CH3HgCl (12%) was significantly lower (P <0.05) than rats fed methylmercury in fish muscle (19%) or rats fed control diet (76%). Urinary excretion did not differ among the experimental groups. Rats fed the highest level of CH3HgCl had a significantly higher (P <0.05) blood, liver, kidney and brain mercury contamination compared to rats fed methylmercury contaminated fish or rats fed control diet. Metallothionein levels in kidney were significantly higher in CH3HgCl-fed rats compared to rats fed contaminated fish. The results indicate a higher faecal excretion and lower tissue accumulation, and metallothionein induction in rats following exposure to methylmercury naturally incorporated in fish compared to methylmercury chloride added to the same matrix.