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Developmental toxicity evaluation of monoisoamyl meso-2,3-dimercaptosuccinate in mice
M A Bosque1, J L Domingo, J Corbella
1Laboratory of Toxicology and Biochemistry, School of Medicine, Rovira i Virgili University, Reus, Spain.
Abstract:
Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), a new dimercaptosuccinic acid (DMSA) analog with enhanced lipophilic properties, was evaluated for potential developmental toxicity. Intraperitoneal injections of Mi-ADMS were given to female Swiss mice (0, 47.5, 95, and 190 mg/kg) on gestational d 6-15. The maternal clinical status was monitored daily during treatment. At termination (gestational d 18), dams were evaluated for clinical status and gestational outcome. Each live fetus was weighed and examined for external, visceral, and skeletal abnormalities. Although no maternal mortality was observed, treatment with 95 and 190 mg/kg resulted in maternal toxicity, manifested as reduced body weight gain during treatment and increased relative liver weight. Embryo/fetal toxicity, consisting of a significant increase in the number of late resorptions as well as in the percentage of postimplantation loss, reduced (nonsignificant) fetal body weight, and an increase in the incidence of skeletal defects, was also observed at 190 mg/kg/d. However, no treatment-related external or soft-tissue malformations or developmental variations were found in any group. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was 47.5 mg/kg/d, whereas the NOAEL for developmental toxicity was 95 mg/kg/d. These results indicate that Mi-ADMS did not produce developmental toxicity in mice in the absence of maternal toxicity.
Insights
Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), a DMSA analog, showed no developmental toxicity in mice without maternal toxicity. Higher doses caused maternal and embryo/fetal toxicity, including skeletal defects.
Area of Science:
- Toxicology
- Developmental Biology
- Pharmacology
Background:
- Dimercaptosuccinic acid (DMSA) analogs are investigated for therapeutic applications.
- Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) is a novel DMSA analog with increased lipophilicity.
- Assessing the developmental toxicity of new chemical entities is crucial.
Purpose of the Study:
- To evaluate the potential developmental toxicity of Mi-ADMS in a murine model.
- To determine the no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity.
Main Methods:
- Pregnant Swiss mice received intraperitoneal injections of Mi-ADMS at varying doses (0, 47.5, 95, 190 mg/kg) during critical gestation periods (d 6-15).
- Maternal clinical status, body weight, and liver weight were monitored.
- Fetal outcomes were assessed, including examination for external, visceral, and skeletal abnormalities.
Main Results:
- Maternal toxicity (reduced body weight gain, increased liver weight) occurred at 95 and 190 mg/kg Mi-ADMS.
- Embryo/fetal toxicity, including increased resorptions, postimplantation loss, and skeletal defects, was observed at 190 mg/kg.
- The NOAEL for maternal toxicity was 47.5 mg/kg, and for developmental toxicity was 95 mg/kg.
Conclusions:
- Mi-ADMS did not induce developmental toxicity in the absence of maternal toxicity.
- The study establishes dose-dependent effects of Mi-ADMS on maternal and fetal health.
- Further research may explore the therapeutic window for Mi-ADMS, considering its lipophilic properties.