Fundamental Toxicological Sciences

2020 - Vol. 7 No. 4

2020 - Vol. 7

Original Article
Retinoic acid dramatically enhances cytotoxicity of equol against human monoblastic U937 cells, but not against human peripheral neutrophils Vol.7, No.4, p.201-206
Hidehiko Kikuchi , Kaori Harata , Chikage Kawai , Harishkumar Madhyastha , Akira Yamauchi , Futoshi Kuribayashi
Released: May 27, 2020
Abstract Full Text PDF[1M]

Since phytoestrogens (e.g. biochanin A, coumestrol, daidzein, genistein and glycitein) are structurally similar to estrogen, they mimic estrogen function. Phytoestrogens consist in certain edible plants, especially in soybeans. Among them, interestingly, equol that has the greatest estrogenic activity is generated from daidzein by gut microbes. Therefore, the relationship between phytoestrogens and gut (including intestinal cells and bacteria) is being watched with strong interest. In this paper, we revealed that all-trans retinoic acid (RA) dramatically enhances cytotoxicity of several phytoestrogens against U937 cells. While β-estradiol and phytoestrogens tested showed no effect on the viability of U937 cells in the absence of RA, 10 μM coumestrol, (±)-equol and genistein brought about remarkably reduced viability of U937 cells at 24 h (to ~15%, ~7% and ~35%, respectively) in the presence of 1 μM RA. In particular, the cytotoxicity of (±)-equol was drastically enhanced in the presence of RA. Moreover, very interestingly, (±)-equol showed no effect on the viability of human peripheral neutrophils even in the presence of RA. As is well known, human monoblastic leukemia U937 cells have been used as an in vitro model for macrophage that exists in intestine and plays significant roles to maintain intestinal homeostasis. These data suggest that equol not only can serve as an effective modifier in therapy for leukemia in combination with RA but also may affect the maintenance of intestinal homeostasis.

Original Article
Postnatal wheel running mitigates endocrine disruption of mammary gland development in mice Vol.7, No.4, p.189-199
Emily E. Schmitt , Weston W. Porter , J. Timothy Lightfoot
Released: May 27, 2020
Abstract Full Text PDF[4M]

We investigated if access to a running wheel after in utero exposure to benzyl butyl phthalate (BBP) ameliorates the toxicological effects of BBP exposure. Our purpose was to determine if post-birth exercise after prenatal BBP exposure could reverse alterations in mammary gland development. Twenty-five female pups were exposed to 500 mg/kg of BBP on days 9-15 in utero and analyzed for mammary gland development and morphology. Mice either had access to a running wheel beginning at 8 weeks of age or were in a cage with a “locked” wheel to prevent running activity. Whole mount staining showed delayed mammary gland morphology development, regardless of wheel exposure in the treated groups. Additional histology staining revealed BBP exposed mice that were not allowed exercise, had larger ducts with multiple cell layers containing proliferative cells suggesting a favorable environment for tumor growth. In addition, there was a significant increase in progesterone status in the mouse mammary gland at 20 weeks but not 10 weeks, regardless of wheel exposure. BBP exposure led to abnormal mammary gland development in female mice and access to a running wheel helped ameliorate some, but not all, of the harmful effects due to BBP exposure at either 10 weeks or 20 weeks of age. Our results are significant because they indicate that exercise can reverse most of the BBP-initiated alterations in the mouse mammary gland, and physical activity has a positive impact on most developmental parameters in the mouse mammary gland.

Letter
Repeated 28-day and 13-week dose toxicity studies of oils prepared from the internal organs of the Japanese giant scallop (Patinopecten yessoensis) in rats Vol.7, No.4, p.177-188
Koki Sugimoto , Eito Shimizu , Nozomi Hagihara , Ryota Hosomi , Kenji Fukunaga , Munehiro Yoshida , Takeya Yoshioka , Koretaro Takahashi
Released: May 27, 2020
Abstract Full Text PDF[959K]

The discarded internal organs of the Japanese giant scallop (Patinopecten yessoensis) are abundant resources rich in n-3 polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid and docosahexaenoic acid. However, they have not been utilized due to contamination with toxic substances such as cadmium (Cd) and the occurrence of diarrhetic shellfish toxins (DST). We have successfully prepared a high-quality scallop oil (SCO) from its internal organs with negligible contamination with Cd and DST. The scallop internal organs were obtained from two different scallop processing areas, Mutsu and Uchiura bays, Japan, and referred to as SCO-M and SCO-U, respectively. To evaluate the safeties of SCO-M and SCO-U as food ingredients and n-3 PUFA supplements, repeated 28-day and 13-week dose oral toxicity studies in rats were conducted. Rats were fed diets containing 1% and 5% of SCO-M and SCO-U, respectively, in the repeated 28-day dose oral toxicity study and 5% SCO-M or SCO-U in the repeated 13-week dose oral toxicity study (limit test). No adverse toxicological effects were observed when rats were fed diets containing SCO-M and/or SCO-U at up to 5% for 28 days and 13 weeks. These results suggest that SCO-M and SCO-U are safe products in terms of subacute toxicity under these experimental conditions.

Original Article
The aminoethyl group is a crucial structural moiety in metal-mediated oxidative DNA damage by catecholamines Vol.7, No.4, p.171-176
Koji Ueda , Yoshihiko Nishino , Yoshinori Okamoto , Nakao Kojima , Hideto Jinno
Released: May 19, 2020
Abstract Full Text PDF[1M]

Oxidative stress is involved in the development of many neurological diseases. The interactions between catecholamines and copper or iron generate reactive oxygen species that lead to oxidative DNA damage in vitro. Furthermore, catechol structure is essential for DNA damage. Here, we clarified the effect of aminoethyl side chains on DNA damage. Endogenous catecholamines (dopamine, noradrenaline, and adrenaline) were more effective than other catechols (catechol, 4-ethylcatechol, and 3,4-dihydroxybenzylamine) in strand break and base oxidation of calf thymus DNA. The presence of copper caused more DNA damage than iron. Furthermore, adrenaline oxidized to adrenochrome more rapidly by copper than iron. Leukoadrenochrome, an oxidation intermediate formed by the intramolecular cyclization of aminoethyl side chains, rapidly increased the formation of 8-hydroxy-2′-deoxyguanosine compared with adrenalin. These results show the effect of aminoethyl side chains in catecholamine-induced oxidative DNA damage. This mechanism may partly show the vulnerability of catecholaminergic neurons against oxidative stress.

Letter
Bacteriological evaluation of feasibility of food poisoning from long-term stored “pack-cooked” meals Vol.7, No.4, p.167-170
Toshihiro Kobayashi , Harumi Sakuda
Released: May 19, 2020
Abstract Full Text PDF[851K]

Recently, a “pack cooking” method, which uses heat-resistant plastic bags, has attracted attention for being simple and safe for emergencies such as natural disasters. One serving is filled in a pack. It uses less kitchenware and clean water, so “pack cooking” will particularly be a powerful tool for soup runs. However, its risk for food poisoning has not been given attention. It is important to consider the safety of “pack-cooked” meals, because medical shortage is as much a problem as food shortage during natural disasters. We conducted a bacteriological evaluation of curry and rice as typical “pack-cooked” meals, assuming that they were stored at room temperature for a long time. “Pack-cooked” meal samples were stored at 25°C and 4°C for 24 hr, and their homogenates were used as sample for bacteriological analysis. Obvious standard plate count bacteria were found in “pack-cooked” curry, which was stored at 25°C for 24 hr, whereas those stored at 4°C for 24 hr did not. Furthermore, there was a sample that was stored at 25°C for 24 hr in which coliform bacteria were detected. Since 25°C is equivalent to room temperature, our results demonstrate that the “pack-cooked” curry stored at room temperature for 24 hr could cause food poisoning. While “pack cooking” is a useful method, it is important to understand that prolonged storage at room temperature of “pack-cooked” meals should be avoided.