A major corn-related mycotoxin, fumonisin B1 (FB1), continues to attract attention of researchers as well as risk-assessors due to the diverse toxicological characteristics, including distinct target tissues in different animal species and opposite susceptibility in males and females in mice and rats. More than thirty years passed since the structure identification as a sphingoid-like chemical, but the causal mechanism of the toxicity remains obscure in spites of extensive studies. Considerable amounts of knowledge have been accumulated on the biochemical/toxicological actions of FB1, but the influence on lipid dynamics and mobilization in the body has not been focused well in relation to the FB1-mediated toxicity. Considerable influences of this toxin on mobilization of sphingolipids and phospholipids and also on adaptive changes in their compositions in tissues are implicated from recent studies on FB1-interacting ceramide synthases. Accumulated patho-physiological data also suggest a possible role of hepatic phospholipid on FB1-mediated toxicity. Thus, a mechanism of FB1-mediated toxicity is discussed in relation to the mobilization of phospholipids and sphingolipids in the body in this context.
Methoxyacetate (MAA), formed by the metabolisms of ethylene glycol monomethyl ether (2-methoxyethanol), di-(2-methoxyethyl) phthalate and 1,6-dimethoxyhexane, is known to be a teratogenic and testicular toxicant in experimental animals. MAA is known to inhibit histone deacetylase and is associated with lactate-carrying monocarboxylate transporter expressed in Sertoli and fetal cells. In cells of rapid division, nucleosomal histone exchanges occur through the methyl and acetyl modifications and rates of nucleic acid syntheses are elevated with consumption of cellular energy. These phenomena are considered to associate with MAA-mediated teratogenicity and phase-selective spermatocyte disorders, and also suggest a mutual adverse-outcome pathway in which MAA-mediated histone deacetylase inhibition is involved through p21 activation as the early events. In addition, a possible functional relationship of one-carbon transferring folate/S-adenosyl methionine cycle with testicular metabolisms of sarcosine and creatine is envisioned. Thus, the mechanisms underlying the MAA toxicities will be discussed in relation to the current understanding of the involvement of the epigenetic phenomena and cell-specific metabolisms.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment on acrylamide (AA) (CAS No. 79-06-1) in foods generated through heating, as a self-tasking risk assessment. In rodent toxicity studies, major adverse effects were observed on neurotoxicity and male reproductive toxicity. Statistically significant increases in incidences were observed in the carcinogenicity studies in Harderian gland, mammary gland, lung and forestomach in mice, and in mammary gland, thyroid and testis in rats. Positive results were also obtained from in vitro and in vivo genotoxicity studies of AA and glycidamide (GA). Therefore, FSCJ recognized AA as a genotoxic carcinogen. Judging from the dietary AA intake among Japanese people, the non-neoplastic risk is extremely low because of sufficient margins of exposure (MOEs). The neoplastic risk, however, could not be excluded due to the insufficient MOEs, although no clear evidence on human health effect have been provided from the epidemiological studies. It is important to note that no consistent relationships between AA exposure and cancer incidences have been observed even in the studies focusing on the highly exposed populations in occupational settings. FSCJ thus concluded that continual efforts are necessary to reduce dietary AA intakes in accordance with the principle of ALARA (as low as reasonably achievable) from the viewpoint of public health.
Genotoxicity is a critical endpoint of toxicity to regulate environmental chemicals. Genotoxic chemicals are believed to have no thresholds for the action and impose genotoxic risk to humans even at very low doses. Therefore, genotoxic carcinogens, which induce tumors via genotoxic mechanisms, are regulated more strictly than non-genotoxic carcinogens, which induce tumors through non-genotoxic mechanisms such as hormonal effects, cell proliferation and cell toxicity. Although Ames bacterial mutagenicity assay is the gold standard to identify genotoxicity of chemicals, the genotoxicity should be further examined in rodents because Ames positive chemicals are not necessarily genotoxic in vivo. To better evaluate the genotoxicity of chemicals in a whole body system, gene mutation assays with gpt delta transgenic mice and rats have been developed. A feature of the assays is to detect point mutations and deletions by two distinct selection methods, ie, gpt and Spi− assays, respectively. The Spi− assay is unique in that it allows analyses of deletions and complex DNA rearrangements induced by double-strand breaks in DNA. Here, I describe the concept of gpt delta gene mutation assays and the application in food safety research, and discuss future perspectives of genotoxicity assays in vivo.
An unidentified foodborne disease associated with the consumption of raw fresh fish was noticed from 1999 in the West of Japan. In 2010, a novel multivalvulid parasite, Kudoa septempunctata (Myxozoa: Myxosporea) was discovered as being the causative agent of this disease and the Ministry of Health, Labour and Welfare of Japan (MHLW) named this disease “Kudoa food poisoning”. Kudoa septempunctata is a myxosporean with 6–7 polar capsules and shell valves in a spore. The life-cycle of K. septempunctata has not been elucidated yet. However, it probably involves an alternative invertebrate host such as polychaetes without direct transmission between fish. An epidemiological study elucidated that the main symptoms of “Kudoa food poisoning” are transient vomiting, diarrhea, abdominal pain and vomiting due to gastrointestinal mucosal disruption, most of which could be recovered within 24 h. The threshold for the onset of symptoms is estimated at about 7.2 × 107K. septempunctata spores per person based on an epidemiological calculation of a large-scale outbreak that occurred at Ehime prefecture. In a toxicological study, oral administration of 1 × 107 spore/g live K. septempunctata induced the acute accumulation of fluid in the gut of suckling mice and vomiting in house musk shrews (Suncus murinus). K. septempunctata decreased transepithelial resistance in a cultured human intestinal cell monolayer, resulting in a rapid increase of permeability. These pathogenic actions of viable Kudoa spores elicit symptoms in human patients. Regarding analytical methods, PCR amplification of species-specific genes and microscopic observation of characteristic spores are the best methods of choice for characterizing this parasite. To prevent the disease, heating at 95 °C for 10 min or freezing at −80 °C overnight is effective while a recent study demonstrated that liquid freezing is a more practical method. Fundamentally, the biological study of K. septempunctata including its life-cycle, alternative and invertebrate hosts is necessary for eradicating them. Realistically, monitoring of domestic flounder in farm and imported one in the quarantine should be useful. From the available literature, K. septempunctata appears to be a unique parasitic agent that induces foodborne diseases by invading the human intestinal mucosa but does not persist long enough in the tissue for further growth, eliciting a temporal increase in mucosal permeability. Further investigations are needed to elucidate the interactions between this myxosporean parasite and human tissue.