We have previously reported that 14-3-3β mRNA was overexpressed as well as c-mycmRNA in aflatoxin B1 (AFB1)-induced rat hepatoma K1 and K2 cells as compared with that of the normal liver tissue. 14-3-3β protein is known to play an important role in cell growth and differentiation through the binding to signal transduction factors. Here we report that the protein level of 14-3-3β expression was also significantly increased in K1 and K2 cells. Southern blot analysis demonstrated that some genetic changes including point mutation were caused in 14-3-3β gene locus, because different hybridization patterns were observed among the normal rat liver, K1 and K2 DNAs, when digested with Eco RI, Bam HI or Pst I. The addition of antisense 14-3-3β oligodeoxynucleotides (ODNs) reduced the growth rate of K2 cells. PCR-single-strand conformation polymorphism (SSCP) analysis of ras family genes including H-, K-and N-ras revealed that any mutations leading to oncogenic activity were not detected in both cells. These results suggest that the mutational activation of 14-3-3β gene expression, but not ras family genes, plays an important role in AFB1 hepatocarcinogenesis together with the deregulated expression of c-rnyc gene.
Immunomodulatory activity-guided fractionation of the ethyl acetate extract of an Ascomycete, Sordaria gondaensis, afforded three dioxopiperazine-type constituents as the immunosuppressive features of this fungus. They were elucidated to be two known fungal metabolites, tryprostatin B and fumitremorgin B, and a new metabolite 13-oxofumitremorgin B by their physicochemical and spectral data and the chemical correlation. This is the first time that both tryprostatin B and fumitremorgin B have been isolated from this fungus.
We found a naturally occurring Pollinosis in Japanese monkeys and have been developing biomedical studies on Pollinosis and related allergy using monkey model. We have also been examining a mechanism for increasing the allergic diseases. In current paper I will show a new evidence associating with increase in antigen-specific IgE production and allergy. Our results suggest that both of Th1/Th2 imbalance and downregulation of IgE-mediated antigen/allergen presentation leads to allergic diseases in human in last a few decades.
Although zearalenone (ZEN) produced by Fusarium species lacks estrogen-like structure, this mycotoxin exhibits estrogen-like effects on domesticated animals, particularly swine, and may contribute to the overall load of environmental estrogens. To clarify the mode of action of ZEN, we investigated the interaction of ZEN with the estrogen receptor (ER) and its effect on nuclear RNA polymerase activities and protein synthesis in the rat uterus. The results showed that ZEN and its analogs could albeit poorly bind to the rat uterine and brain ERs in vivo and in vitro, and their binding ability was of following order: α-zearalanol (α- ZAL)>α-zearalenol (α-ZEL)>β-ZAL>ZEN>β-ZEL. RNA polymerase activities in the uterine nuclei isolated from ZEN-treated rats were enhanced 4-fold of the vehicle control. Furthermore, a 52-kDa protein was specifically induced immediately after the addition of ZEN and its derivatives such as α-ZEL and α-ZAL to the immature rat uteri in vivo and in vitro. On the other hand, the induction of 52-kDa protein was hardly detected in the presence of RNA polymerase inhibitors including α-amanitin and actinomycin D, suggesting that ZEN and its analogs-ER complexes might act as a transcriptional activating factor. These findings clearly indicate that ZEN and its analogs, despite their non-steroidal structure, exhibit an estrogenic activity toward target tissues in a similar manner to that of natural estrogens. In addition, the binding ability of ZEN to the rat brain ER could assume the possibility that ZEN affects the estrogen feedback system in the rat brain to result in the shrinkage of ovary and testis and participates in behavioral abnormalities.
Zearalenone (ZEN), an estrogenic mycotoxin produced by several species of Fusarium, is often detected in cereals such as wheat, barley and corn, and animal feeds based on these contaminated grains, cause infertility, absorption of the fetus, enlargement of the uteri, and vaginal prolapse in livestock. The mechanism of action of ZEN can be explained by the fact that ZEN binds to estrogenic receptor.Toxicological approaches demonstrated that ZEN is positive in Rec-assay with Bacillus subtilis (Ueno et al., 1976) but negative in Ame's test using Salmonella-microsomes and S-9 mix (Wehner et al., 1978), and it is teratogenic in rats (Ruddick et al., 1976). Ruddick has reported the incidence of delayed or absent skeleton ossification increased with increasing dosage; the rib, sternum, tarsal bones and the parietal bone were those commonly affected.In the present paper, the cytotoxity, the chromosome aberration and the teratogenecity of ZEN were examined in order to clarify the toxicological effect of ZEN.
The 5 major mycotoxins causing impairments in the growth and reproductive ability of livestock are aflatoxin, zearalenone, deoxynivalenol, ochratoxin, and ergot.1) The first reported case of zearalenone (ZEN) toxicity was by McNutt in 1928, who described a pig with the main symptom of vulvovaginitis due to moldy corn.2) Since then, there have been many similar reports in North America, Europe, Australia, and other places.3, 4) Today, ZEN is widely known as an estrogenic mycotoxin. However, the toxicity of ZEN is transient, and it only very rarely leads to death. ZEN is nowadays sold on the market and used in low doses as a growth promoter in the livestock industry with cattle, sheep, and young pigs raised for meat, where the focus is on these effects rather than the toxicosis it produces.We herein present findings demonstrating that the administration of ZEN can induce persistent anovular estrus and irreversible infertility. We also briefly discuss the toxicity of ZEN as an endocrine-disrupting chemical, which differs from its toxicoses reported to date.
Zearalenone is an estrogenic mycotoxin, and known to be produced by several Fusarium species. Among them, F. graminearum, F. culmorum, and F. crookwellense are major zearalenone producers in Japan and responsible for the contamination of wheat and barley with zearalenone. However, the intracellular activity of zearalenone in fungi is still unclear due to the limited number of studies. As a natural endocrine disrupting metabolite, zearalenone will be required to clarify its physiological effects in human in more details.