Kunio Doi

Among many mycotoxins, T-2 toxin, macrocyclic trichothecenes, fumonisin B₁ (FB₁) and ochratochin A (OTA) are known to have the potential to induce neurotoxicity in rodent models. T-2 toxin induces neuronal cell apoptosis in the fetal and adult brain. Macrocyclic trichothecenes bring about neuronal cell apoptosis and inflammation in the olfactory epithelium and olfactory bulb. FB₁ induces neuronal degeneration in the cerebral cortex, concurrent with disruption of de novo ceramide synthesis. OTA causes acute depletion of striatal dopamine and its metabolites, accompanying evidence of neuronal cell apoptosis in the substantia nigra, striatum and hippocampus. This paper reviews the mechanisms of neurotoxicity induced by these mycotoxins especially from the viewpoint of oxidative stress-associated pathways.

It is not widely known how the developing brain responds to extrinsic damage, although the developing brain is considered to be sensitive to diverse environmental factors including DNA-damaging agents. This paper reviews the mechanisms of neurotoxicity induced in the developing brain of mice and rats by six chemicals (ethylnitrosourea, hydroxyurea, 5-azacytidine, cytosine arabinoside, 6-mercaptopurine and etoposide), which cause DNA damage in different ways, especially from the viewpoints of apoptosis and cell cycle arrest in neural progenitor cells. In addition, this paper also reviews the repair process following damage in the developing brain.

Jcl:WistarTGN(ARGHGEN)1Nts rat (Mini rat) is a growth hormone (GH)-deficient transgenic rat. The hair cycle in the dorsal skin of male Mini rats enters a long-lasting telogen phase after eights weeks of age, but depilation can induce a transient hair cycle again. In this study, a time-course profiling of genes expression was done on the dorsal skin of male Mini rats along the progression of depilation-induced hair cycle using DNA microarray analysis. As a result, 1,215 probe sets including 1,171 hair cycle-related ones showed more than 3-fold changes in expression compared with that in before-depilation telogen phase. The present data will contribute to elucidating the mechanisms of hair cycle regulation and should lead to the identification of novel molecular targets for hair growth and/or depilation agents.

Certain disease conditions can modify drug-induced toxicities, which, in turn, may cause a medication-related health crisis. Therefore, preclinical investigations into the alterations in drug-induced toxicities using appropriate disease animal models are very important. This paper reviews the reported data related to the effects of diabetes and hypertriglyceridemia, common lifestyle-related diseases in a modern society, on acetaminophen (APAP)-induced hepatotoxicity and nephrotoxicity in rats and mice. It has generally been reported that diabetes protects rats and mice from APAP-induced hepatotoxicity and there are several reports that help to speculate on the effects of diabetes on APAP-induced nephrotoxicity. In fructose-induced hypertriglyceridemic rats, hepatotoxicity of APAP becomes apparently less severe, whereas nephrotoxicity of APAP becomes significantly more severe. The mechanisms of alteration of APAP-induced hepatorenal toxicity under diabetic and hypertriglyceridemic conditions are also discussed in this paper.

T-2 toxin is a cytotoxic secondary fungal metabolite that belongs to the trichothecene mycotoxin family. This mycotoxin is a well known inhibitor of protein synthesis through its high binding affinity to peptidyl transferase, which is an integral part of the ribosomal 60s subunit, and it also inhibits the synthesis of DNA and RNA, probably secondary to the inhibition of protein synthesis. In addition, T-2 toxin is said to induce apoptosis in many types of cells bearing high proliferating activity. T-2 toxin readily passes the placenta and is distributed to embryo/fetal tissues, which include many component cells bearing high proliferating activity. This paper reviews the reported data related to T-2 toxin-induced maternal and fetal toxicities in pregnant mice and rats. The mechanisms of T-2 toxin-induced apoptosis in maternal and fetal tissues are also discussed in this paper.

1-β-D-Arabinofuranosylcytosine (Ara-C), a cytidine analogue, inhibits DNA synthesis and is used for the treatment of myelogenous leukemia. On the other hand, it is also known that Ara-C has a teratogenic effect. In the present study, pregnant rats were treated with 250 mg/kg of Ara-C on day 13 of gestation, and fetal tissues and placentae were collected from 3 to 48 hours after treatment to examine the sequential histopathological changes induced by prenatal Ara-C treatment. The weights of fetuses and placentae and the thickness of the placental labyrinth zone were significantly reduced at 48 hours after treatment. In the fetal tissues such as central nervous system and mesenchymes and in the placental labyrinth zone, the number of pyknotic cells stained positively by the TUNEL method increased markedly after treatment with Ara-C. In most fetal tissues, the number began to increase from 3 to 6 hours and peaked at 9 to 12 hours after treatment. In the placental labyrinth zone, the number peaked at 6 hours after treatment. Electron microscopical features of the pyknotic cells consisted with the ultrastructural characteristics of apoptotic cells. In various fetal organs and placentae, abnormal induction of apoptosis is suggested to induce growth inhibition and have a certain relation to the malformations. Moreover, abnormal induction of apoptosis would have a deep connection with the cytotoxic effect of Ara-C which may affect proliferative cells in fetuses and placentae developing rapidly.

The effects of exogenous growth hormone (GH)-treatment on the development and regeneration of CCl₄-induced acute hepatic injury were examined in GH-deficient Mini rats. Alanin aminotransferase (ALT) and asparate aminotransferase (AST) activities increased significantly at 24 and 48 hours (h) after CCl₄-administration in both GH-treated and non treated groups, and they tended to be suppressed by GH-treatment. The expression level of insulin-like growth factor (IGF)-1 mRNA was higher in GH (+) CCl₄ (+) group than in GH (-) CCl₄ (+) group, especially at 72 h, and that of hepatocyte growth factor (HGF) mRNA was also higher in some points in the former group. Histologically, degenerative changes of hepatocytes observed at 24 and 48 h was less severe in GH (+) CCl₄ (+) group than in GH (-) CCl₄ (+) group. At 72 h, depositions of reticular fibers and extracellular matrix materials were less severe and the number of desmin- or α-SMA-positive cells was larger in GH (-) CCl₄ (+) group than in GH (+) CCl₄ (+) group. Proliferating cell nuclear antigen (PCNA)-labeling index of centrilobular hepatocytes increased at 48 h in both GH (+) CCl₄ (+) and GH (-) CCl₄ (+) groups, and it returned to the control level at 72 h in the former group while that in the latter group showed still higher level at 72 h. In this study, it was shown that CCl₄-induced acute liver injury in Mini rats can be restored by exogenous GH-treatment, and upregulation of IGF-1 and HGF mRNAs may be involved in this phenomenon.

DNA damages and changes in proliferating activity of keratinocytes in rat dorsal skin exposed to a high-dose ultraviolet B (UVB) irradiation were examined immunohistochemically. The number of cells that express cyclobutane pyrimidine dimer (CPD), which represents UVB-induced DNA damage, started to increase at 1 h after irradiation, peaked at 3 h and thereafter decreased rapidly. Bromodeoxyuridine (BrdU)-labeling index (LI) was lower than that in control group from 1 to 24 h after irradiation, and it returned to the control level at 36 h. Topoisomerase II α (TIIα)-LI was significantly lower than that in control group from 1 to 12 h and showed the lowest value at 9 h. Thereafter, it increased and showed higher values than that in control group at 24, 36 and 72 h. These results suggest that DNA damages in survival basal keratinocytes may be repaired during 12 to 24 h and cell growth of keratinocytes may be arrested at least at 24 h.