title: Disruption of spermatogenesis in the liver fluke, Fasciola hepatica by two artemisinin derivatives, artemether and artesunate.
abstract: An in vivo study in the laboratory rat model has been carried out to monitor changes to the spermatogenic cells in the testis tubules of adult Fasciola hepatica following treatment with the artemisinins, artemether and artesunate. Rats infected with the triclabendazole (TCBZ)-resistant Sligo isolate were dosed orally with artemether at a concentration of 200 mg/kg and flukes recovered at 24, 48 and 72 h post treatment (pt). Rats infected with the TCBZ-resistant Oberon isolate were dosed orally with artesunate at a concentration of 200 mg/kg and flukes recovered 24, 48, 72 and 96 h pt. The flukes were processed for histological and transmission electron microscope (TEM) examination. Changes to the spermatogenic cells were evident at 24 h pt with artemether. The spermatogonial and spermatocyte cells contained abnormal mitochondria, there were fewer spermatids and spermatozoa in the tubules than normal, and a number of cells showed signs of apoptosis. There was a further decline in cell numbers at 48 h pt and the organization of the spermatocyte and spermatid rosettes was atypical. Sperm formation had become abnormal and those spermatozoa present possessed only a single axoneme. By 72 h pt, the testis tubules were vacuolated and filled with abnormal cells and cell debris. Only spermatogonial cells could be identified and there was widespread evidence of apoptosis in the cells. Distinct cellular changes following artesunate treatment did not become apparent until 48 h pt. The changes seen were similar to those described for artemether, but were generally less severe at matching time-periods. The fine structural changes occurring in the spermatogenic cells were compared to those observed in other cell types and fluke tissues and the overall information was collated to identify the cellular targets for artemisinin action and to establish the time-line for drug action.
authors.affiliation: Parasite Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast,97 Lisburn Road,BelfastBT9 7BL,Northern Ireland,United Kingdom.
authors.forename: J F
authors.initials: JF
authors.lastname: O'Neill
authors.affiliation: Parasite Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast,97 Lisburn Road,BelfastBT9 7BL,Northern Ireland,United Kingdom.
authors.forename: R C
authors.initials: RC
authors.lastname: Johnston
authors.affiliation: Parasite Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast,97 Lisburn Road,BelfastBT9 7BL,Northern Ireland,United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Halferty
authors.affiliation: Veterinary Sciences Division, Agri-Food and Biosciences Institute (AFBI), Stormont,BelfastBT4 3SD,United Kingdom.
authors.forename: R E B
authors.initials: RE
authors.lastname: Hanna
authors.affiliation: Parasite Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast,97 Lisburn Road,BelfastBT9 7BL,Northern Ireland,United Kingdom.
authors.forename: G P
authors.initials: GP
authors.lastname: Brennan
authors.affiliation: Parasite Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast,97 Lisburn Road,BelfastBT9 7BL,Northern Ireland,United Kingdom.
authors.forename: I
authors.initials: I
authors.lastname: Fairweather
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage* / Q000494:pharmacology; D000077332:Artesunate; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005210:Fasciola hepatica / Q000187:drug effects* / Q000502:physiology; D005211:Fascioliasis / Q000188:drug therapy*; D006651:Histocytochemistry; D008297:Male; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D013091:Spermatogenesis / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D037621:Artemisinins; D000077332:Artesunate; D000077549:Artemether