Developmental Effects of Methylated Arsenic Metabolites in Mice

Hood, Ronald D.

doi:10.1007/s001289900753

Cited by 16 publications

(6 citation statements)

References 13 publications

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“…In experimental species, maternal exposure to inorganic arsenic (iAs) resulted in fetal exposure to iAs and its metabolites, methyl arsenic (MAs) and dimethyl arsenic (DMAs) (Tanaka, 1976;Lindgren et al, 1982;Hood et al, 1987Hood et al, ,1988. Exposure to MAs or DMAs produced maternal and fetal toxicity and teratogenesis in rodents (Rogers et al, 1981;Hood, 1998), suggesting that these arsenicals or their metabolites are the active forms. In women chronically consuming iAs-contaminated drinking water during pregnancy, DMAs was the predominant arsenical in either maternal or cord plasma (Concha et al, 1998); thus, iAs or its metabolites must cross human placenta.…”

Section: Introductionmentioning

confidence: 99%

Arsenicals in maternal and fetal mouse tissues after gestational exposure to arsenite

et al. 2006

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Exposure of pregnant C3H/HeNCR mice to 42.5-or 85-ppm of arsenic as sodium arsenite in drinking water between days 8 and 18 of gestation markedly increases tumor incidence in their offspring. In the work reported here, distribution of inorganic arsenic and its metabolites, methyl arsenic and dimethyl arsenic, were determined in maternal and fetal tissues collected on gestational day 18 of these exposure regimens. Tissues were collected from three females and from associated fetuses exposed to each dosage level. Concentrations of total speciated arsenic (sum of inorganic, methyl, and dimethyl arsenic) were higher in maternal tissues than in placenta and fetal tissues; total speciated arsenic concentration in placenta exceeded those in fetal tissues. Significant dosage-dependent (42.5 ppm versus 85 ppm of arsenite in drinking water) differences were found in total speciated arsenic concentrations in maternal lung (p < 0.01) and liver (p < 0.001). Total speciated arsenic concentrations did not differ significantly between dosage levels for maternal blood or for fetal lung, liver, and blood, or for placenta. Percentages of inorganic, methyl, or dimethyl arsenic in maternal or fetal tissues were not dosage-dependent. Over the range of total speciated arsenic concentrations in most maternal and fetal tissues, dimethyl arsenic was the most abundant arsenical. However, in maternal liver at the highest total speciated arsenic concentration, inorganic arsenic was the most abundant arsenical, suggesting that a high tissue burden of arsenic affected formation or retention of methylated species in this organ. Tissue concentration-dependent processes could affect kinetics of transfer of inorganic arsenic or its metabolites from mother to fetus.

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Section: Introductionmentioning

confidence: 99%

Arsenicals in maternal and fetal mouse tissues after gestational exposure to arsenite

et al. 2006

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“…Cranioschisis occulta with encephalocele was observed in 2 of 122 fetuses born to dams receiving the highest doses (50 mg/kg and 100 mg/kg) of DMA V . A later study (Hood, 1998a) tested DSMA and SDMA in pregnant CD-1 mice with single i.p. doses on specific days of gestation.…”

Section: Discussionmentioning

confidence: 99%

“…Lower doses were not evaluated. The studies summarized above (Willhite, 1981;Hood et al, 1982;Hood, 1998a) cannot support assessments of the risks of developmental effects in humans because they lack numerous study design and other elements needed to produce results appropriate for this purpose (DeSesso et al, 1998;Jacobson et al, 1999;Holson et al, 2000). First, the parenteral exposure routes used in these studies are not relevant to plausible human exposure scenarios.…”

Section: Discussionmentioning

confidence: 99%

Monomethylarsonic acid and dimethylarsinic acid: developmental toxicity studies with risk assessment

Irvine¹,

Boyer

DeSesso

2006

Birth Defects Research Pt B

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BACKGROUND:The toxicity of arsenic compounds is highly dependent on the valence and methylation state of the compound. Although there is extensive published literature on the potential developmental toxicity of inorganic arsenic compounds, little exists on organic arsenic compounds and, in particular, studies conducted in accordance with conventional regulatory guidelines appropriate for risk assessment are rare. The organic arsenic compounds, monomethylarsonic acid (MMA V ) and dimethylarsinic acid (DMA V , also called cacodylic acid), are the active ingredients in pesticide products that are used mainly for weed control. MMA V and DMA V are also metabolites of inorganic arsenic formed intracellularly by most living organisms (animals, plants and bacteria). In mammals, this occurs predominantly in liver cells. METHODS: Conventional developmental toxicity studies of orally administered MMA V and DMA V in the Sprague-Dawley rat and New Zealand White rabbit were conducted in commercial contract laboratories in the late 1980s for regulatory compliance. The results of these studies are summarized and presented to broaden the data available in the public domain. RESULTS: In both species, data shows an absence of dose-related effects at organic arsenic exposures that were not maternally toxic. MMA V doses of 0, 10, 100, and 500 mg/kg/day (rat) and 0, 1, 3, 7, and 12 mg/kg/day (rabbit) and DMA V doses of 0, 4, 12, and 36 mg/kg/day (rat) and 0, 3, 12, and 48 mg/kg/day (rabbit) were administered by oral gavage daily during organogenesis (Gestation Day [GD] 6-15, rat; GD 7-19, rabbit) and the litters examined at maternal sacrifice (GD 20, rat; GD 29, rabbit). After treatment with MMA V , maternal and fetal toxicity were observed at the highest doses of 500 mg/kg/day (rat) and 12 mg/kg/day (rabbit), but no treatment-related developmental toxicity at the lower doses, even in the presence of minimal maternal toxicity in the rat at 100 mg/kg/d. There was no evidence of teratogenicity associated with MMA V treatment. With DMA V , maternal and developmental toxicity were observed in the rat at 36 mg/kg/day, with a higher than spontaneous incidence of fetuses with diaphragmatic hernia. In the rabbit at 48 mg/kg/day, there was marked maternal toxicity, culminating for most females in abortion and with no surviving fetuses for evaluation. There was no treatment-related maternal or developmental toxicity in the rat or rabbit at 12 mg/kg/day. Based on pregnancy outcome, the developmental toxicity no observed adverse effect level (NOAEL) for orally administered MMA V were 100 and 7 mg/kg/day in the rat and rabbit, respectively, and for DMA V were 12 mg/kg/day in both species. CONCLUSIONS: Margins of exposure estimated based on conservative estimates of daily intakes of arsenic in all of its forms indicate that exposure to MMA V or DMA V at environmentally relevant exposure levels, by the oral route (the environmentally relevant route of exposure) is unlikely to pose a risk to pregnant women and their offspring. Birth Defects Res (Par...

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“…Such trivalent metabolites have been found to be considerably more toxic than the pentavalent methylated end products (MMA V and DMA V ), and thus arsenic methylation has been implicated as a potential major factor in arsenic toxicity, including carcinogenicity (Aposhian et al, 2000;Thomas et al, 2001). Hood (1998) reported that although those end products, DMA V and MMA V , can be teratogenic and embryotoxic when injected intraperitoneally into pregnant mice, the effective doses were considerably higher (as much as 100-fold) than the required doses of similarly injected arsenite (Hood, 1972) or arsenate (Hood and Bishop, 1972). When Lammon et al (2003) inhibited arsenic methylation by pretreatment of pregnant mice with periodate-oxidized adenosine (PAD), however, the adverse effects of both arsenate and arsenite on the mouse conceptus were enhanced.…”

Section: Introductionmentioning

confidence: 99%

Effects of protein deficient diets on the developmental toxicity of inorganic arsenic in mice

Lammon

Hood

2004

Birth Defects Research Pt B

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Developmental Effects of Methylated Arsenic Metabolites in Mice

Cited by 16 publications

References 13 publications

Arsenicals in maternal and fetal mouse tissues after gestational exposure to arsenite

Arsenicals in maternal and fetal mouse tissues after gestational exposure to arsenite

Monomethylarsonic acid and dimethylarsinic acid: developmental toxicity studies with risk assessment

Effects of protein deficient diets on the developmental toxicity of inorganic arsenic in mice

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