title: Neurotoxicity of Penicillium crustosum secondary metabolites: tremorgenic activity of orally administered penitrem A and thomitrem A and E in mice.
abstract: Several cases of neurological disease in dogs after poisoning by food- and feed-borne Penicillium toxins in Norway during the last years have uncovered a lack of knowledge regarding the toxicity and mechanism of action of neuroactive mycotoxins. In the present study, the lowest tremor-inducing dose after single oral administration of penitrem A to mice was 0.50 mg/kg bw. The estimated half maximal effective dose (ED(50)) in respect to the visual tremor scale was 2.74 mg/kg bw. Mice receiving the maximum penitrem A dose (8 mg/kg bw) suffered severe spontaneous tremors and even convulsions. Thomitrem A and E are penitrem analogues lacking the C-16-C-18 ether linkage and possessing an olefin at C-18-C-19. Compared with penitrem A, the lowest tremor-inducing dose of thomitrem A was 16-times higher (8 mg/kg bw) and thomitrem E was found to be non-tremorgenic at the highest dose tested (16 mg/kg bw). During a recovery phase of two weeks post administration animals appeared restored and no changes in feeding and other biological processes were observed. An initial dose-related weight reduction was observed 2 days after penitrem A administration. Penitrem A was absorbed and distributed to gastrointestinal tract, liver, kidneys and brain in the mice. Elimination of penitrem A appeared to be mainly hepatic and the highest concentration levels were found 1 h post administration for all investigated organs. The relationship between liver and gastrointestinal tract concentration levels showed time-dependent linear correlation and a doubling within 1.5 h.
authors.affiliation: Unilab Analyse AS, High-North Research Center on Climate and the Environment, Tromsø, Norway.
authors.forename: Angel
authors.initials: A
authors.lastname: Moldes-Anaya
authors.forename: Thomas
authors.initials: T
authors.lastname: Rundberget
authors.forename: Christiane K
authors.initials: CK
authors.lastname: Fæste
authors.forename: Gunnar S
authors.initials: GS
authors.lastname: Eriksen
authors.forename: Aksel
authors.initials: A
authors.lastname: Bernhoft
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D007211:Indoles / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009183:Mycotoxins / Q000008:administration & dosage / Q000633:toxicity*; D010407:Penicillium / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D014202:Tremor / Q000139:chemically induced*
chemical_list: D007211:Indoles; D009183:Mycotoxins; C473721:thomitrem A; C473720:thomitrem E; C003626:tremortin