title: 2,5-hexanedione and carbendazim coexposure synergistically disrupts rat spermatogenesis despite opposing molecular effects on microtubules.
abstract: 2,5-Hexanedione (2,5-HD), a taxol-like promoter of microtubule assembly, and carbendazim (CBZ), a colchicine-like inhibitor of microtubule assembly, are two environmental testicular toxicants that target and disrupt microtubule function in Sertoli cells. At the molecular level, these two toxicants have opposite effects on microtubule assembly, yet they share the common physiologic effect of inhibiting microtubule-dependent functions of Sertoli cells. By studying a combined exposure to 2,5-HD and CBZ, we sought to determine whether CBZ would antagonize or exacerbate the effects of an initial 2,5-HD exposure. In vitro, 2,5-HD-treated tubulin had a decreased lag time and an increased maximal velocity of microtubule assembly. These 2,5-HD-induced in vitro alterations in microtubule assembly were normalized by CBZ exposure. In vivo, adult male rats were exposed to a 1% solution of 2,5-HD in the drinking water for 2.5 weeks. CBZ was administered by gavage (200 mg/kg body weight) at the same time as unilateral surgical ligation of the efferent ducts, 24 h before evaluation of the testis. Measures of testicular effect (testis weight, histopathologic changes [sloughing and vacuolization], and seminiferous tubule diameters) were all significantly altered with combined exposure. The testicular effects in the combined exposure group were either different (seminiferous tubule diameters), additive (% vacuolization), or greater than additive (% sloughing) compared to the effects of the individual toxicant exposure groups referenced to the controls. Therefore, CBZ coexposure does not antagonize the effects of an initial 2,5-HD exposure, as might be expected if their molecular effects on microtubule assembly were solely responsible for their combined toxicity; instead, 2,5-HD and CBZ act together to exacerbate the testicular injury.
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, 175 Meeting Street, Providence, Rhode Island 02912, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Markelewicz
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hall
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
mesh_terms: D000818:Animals; D000988:Antispermatogenic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002219:Carbamates / Q000008:administration & dosage / Q000633:toxicity*; D004357:Drug Synergism; D006588:Hexanones / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D008870:Microtubules / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012671:Seminiferous Tubules / Q000187:drug effects / Q000473:pathology; D012708:Sertoli Cells / Q000187:drug effects / Q000648:ultrastructure; D013091:Spermatogenesis / Q000187:drug effects*; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
chemical_list: D000988:Antispermatogenic Agents; D001562:Benzimidazoles; D002219:Carbamates; D006588:Hexanones; C011269:2,5-hexanedione; C006698:carbendazim