Fasciola hepatica: disruption of spermatogenesis by the fasciolicide compound alpha

Abstract

Sheep infected with the triclabendazole-susceptible Cullompton isolate of Fasciola hepatica were dosed with 15 mg/kg of compound alpha at 12 weeks post-infection. Adult flukes were recovered from the bile ducts at 24, 48, and 72 h post-treatment (p.t.). Changes to the spermatogenic cells in the testis were examined by histology and transmission electron microscopy. Disruption to the testes became increasingly severe over time. The testis tubules shrank in size, became vacuolated, and contained fewer cells. Identification of cell types became difficult, and apoptotic eosinophilic bodies were the predominant feature at 72 h p.t. Changes to the spermatogonia were evident at 24 h p.t., the cells containing swollen and electron-lucent mitochondria. The proportion of tertiary spermatogonia increased at 48 h p.t., and they showed signs of autophagy. Multinucleate spermatogonia were a feature of drug treatment at this time point, and they contained autophagic vacuoles. By 72 h p.t., it was difficult to identify primary and secondary spermatogonia, and there were no recognisable clusters of tertiary spermatogonia. Most spermatogonial cells were multinucleate and in the process of breaking down. With regard to the primary spermatocytes, fragmentation of the cytophore was observed at 24 h p.t. Intact rosettes were rare after 48 h treatment; collections of cells were seen, but were not organised into clusters. By 72 h p.t., no spermatocyte cells could be recognised. The results indicate that spermatogenesis was severely affected by compound alpha.

Fasciola hepatica: time-dependent disruption of spermatogenesis following in vivo treatment with triclabendazole

“…The relatively greater sensitivity of the testis to TCBZ action is in line with previous data on other fasciolicides (Dawes 1966a(Dawes , b, 1967(Dawes , 1968Stammers 1975aStammers , 1976Hanna et al 2006;McConville et al 2010). In a sense, this is irrelevant for the Cullompton isolate, because it is triploid and parthenogenetic, being able to produce viable eggs without sperm (Fletcher et al 2004).…”

“…Much of the body of the fluke is dedicated to the production of the gametes, in an effort to maximise fecundity and ensure continuation of the life cycle. The consequent high rate of metabolic activity and cell division that occurs in the testis makes this tissue useful for studying anthelminticinduced effects (eg Dawes 1966aDawes , b, 1967Dawes , 1968Stammers 1975aStammers , b, 1976Hanna et al 2010;McConville et al 2010). This is of particular significance as triclabendazole (TCBZ), like other benzimidazole drugs, is believed to target the microtubule component of the cytoskeleton, thus blocking mitotic and meiotic cell division and the differentiation of spermatogenic and spermiogenic cells (Stitt and Fairweather 1992).…”

Disruption of egg formation by Fasciola hepatica following treatment in vivo with triclabendazole in the sheep host

“…The occurrence of the latter has been interpreted as representative of apoptosis (Hanna et al, 2010) and has been seen in other reproductive tissues such as the testis (Hanna et al, 2010;McConville et al, 2009b); this point will be discussed below. The decline in cell population could be interpreted as due to inhibition of cell division, which is consistent with an anti-microtubule action of a benzimidazole drug like TCBZ.…”

5-Chloro-2-methylsulfanyl-6-(naphthalen-1-yloxy)-1H-benzimidazole methanol monosolvate

“…For related literature on compound alpha, see: Rivera et al (2004); Vera-Montenegro et al (2003); Fairweather (2009); McConville et al (2010). For the synthesis of compound alpha, see: Herná ndez et al (2002).…”