title: Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis.
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.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.
authors.forename: Meghan R
authors.initials: MR
authors.lastname: Perry
authors.forename: Susan
authors.initials: S
authors.lastname: Wyllie
authors.forename: Andrea
authors.initials: A
authors.lastname: Raab
authors.forename: Joerg
authors.initials: J
authors.lastname: Feldmann
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
mesh_terms: D000818:Animals; D000967:Antimony Sodium Gluconate; D000981:Antiprotozoal Agents / Q000378:metabolism*; D001151:Arsenic / Q000633:toxicity*; D002460:Cell Line; D060766:Drinking Water / Q000032:analysis*; D004351:Drug Resistance / Q000187:drug effects*; D004781:Environmental Exposure / Q000009:adverse effects*; D007194:India; D007891:Leishmania / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D008403:Mass Screening; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D000981:Antiprotozoal Agents; D060766:Drinking Water; D014874:Water Pollutants, Chemical; D001151:Arsenic; D000967:Antimony Sodium Gluconate
keywords: drug resistance; environmental pollution; sodium antimony gluconate; treatment failure