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Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Dec 03; Vol. 110 (49), pp. 19932-7. Date of Electronic Publication: 2013 Oct 28. - Publication Year :
- 2013
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Abstract
- The Indian subcontinent is the only region where arsenic contamination of drinking water coexists with widespread resistance to antimonial drugs that are used to treat the parasitic disease visceral leishmaniasis. We have previously proposed that selection for parasite resistance within visceral leishmaniasis patients who have been exposed to trivalent arsenic results in cross-resistance to the related metalloid antimony, present in the pentavalent state as a complex in drugs such as sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime). To test this hypothesis, Leishmania donovani was serially passaged in mice exposed to arsenic in drinking water at environmentally relevant levels (10 or 100 ppm). Arsenic accumulation in organs and other tissues was proportional to the level of exposure and similar to that previously reported in human liver biopsies. After five monthly passages in mice exposed to arsenic, isolated parasites were found to be completely refractory to 500 μg · mL(-1) Pentostam compared with the control passage group (38.5 μg · mL(-1)) cultured in vitro in mouse peritoneal macrophages. Reassessment of resistant parasites following further passage for 4 mo in mice without arsenic exposure showed that resistance was stable. Treatment of infected mice with Pentostam confirmed that resistance observed in vitro also occurred in vivo. We conclude that arsenic contamination may have played a significant role in the development of Leishmania antimonial resistance in Bihar because inadequate treatment with antimonial drugs is not exclusive to India, whereas widespread antimonial resistance is.
- Subjects :
- Animals
Antimony Sodium Gluconate
Cell Line
India
Macrophages drug effects
Mass Screening
Mass Spectrometry
Mice
Mice, Inbred BALB C
Antiprotozoal Agents metabolism
Arsenic toxicity
Drinking Water analysis
Drug Resistance drug effects
Environmental Exposure adverse effects
Leishmania drug effects
Leishmaniasis, Visceral drug therapy
Water Pollutants, Chemical toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 110
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 24167266
- Full Text :
- https://doi.org/10.1073/pnas.1311535110