Sequential analysis of testicular lesions and serum hormone levels in rats treated with a Psoralea corylifolia extract.

In order to clarify pathogenetic targets for the testicular toxicity of a extract of Psoralea corylifolia (P. corylifolia), F344 rats were fed diet containing 3% P. corylifolia extract for up to 12 weeks and subjected to hormone assays and histopathological examination on the testis and epididymis at weeks 1, 2, 4, 8 and 12 (Exp 1). Similar analyses were performed on 1, 3, 7 and 14 days after a single gavage administration of the P. corylifolia extract at a dose of 10 g/kg b.w. (Exp 2). In Exp 1, increase in the numbers of degenerated and exfoliated germ cells and loss of elongated spermatids beyond steps 7 or 8 were initially observed in the seminiferous tubules at week 1, followed by more pronounced degeneration of germ cells with depletion of post-meiotic populations from week 2. The tubular degeneration was associated with Leydig cell atrophy and persistent reduction of serum testosterone and FSH levels throughout the treatment period and a slight reduction of serum LH in later stages. In Exp 2, reduction of serum testosterone and FSH levels preceded degeneration of germ cells in stage VII and VIII tubules at 3 and 7 days after the administration. The results suggest that rapid androgen deprivation reflecting direct interference with Leydig cell function and simultaneous disturbance of the pituitary-testicular axis play pivotal roles in P. corylifolia extract-induced germ cell injury in seminiferous tubules.

Iron lactate induction of pancreatic and endometrial proliferative lesions and a lack of increased tumors in a 104-week carcinogenicity study in F344 rats.

Iron lactate has been used as a food additive for iron supplementation. The present study was conducted to determine whether it might have carcinogenic potential. A total of 150 male and 150 female Fischer 344 rats were divided into three groups and fed basal diet containing 0, 1 or 2% of iron lactate for 104 weeks. No iron lactate-induced tumors were observed in any groups, although the incidences of pancreatic acinar cell and endometrial gland hyperplasias were increased in males and females, respectively, in the 2% group. Thus our in vivo animal data indicate that iron lactate lacks carcinogenicity in male and female F344 rats. However, estrogenic effects might be concluded based on the data for endometrial lesions. In a second experiment, an estrogen responsive rat pituitary tumor cell line, MtT/Se, and a human breast cancer cell line, MCF-7, were therefore employed to examine the estrogenic potential of iron lactate with regard to receptor binding affinity and ERE-reporter gene activation. Results in both cases were negative. Further investigations are needed to elucidate the mechanisms of induction of pancreatic and endometrial proliferative lesions by iron lactate.

Studies on the carcinogenicity of potassium iodide in F344 rats.

A chronic toxicity and carcinogenicity study, in which male and female F344/DuCrj rats were given potassium iodide (KI) in the drinking water at concentrations of 0, 10, 100 or 1000 ppm for 104 weeks, and a two-stage carcinogenicity study of application at 0 or 1000 ppm for 83 weeks following a single injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN), were conducted. In the former, squamous cell carcinomas were induced in the salivary glands of the 1000 ppm group, but no tumors were observed in the thyroid. In the two-stage carcinogenicity study, thyroidal weights and the incidence of thyroid tumors derived from the follicular epithelium were significantly increased in the DHPN+KI as compared with the DHPN alone group. The results of our studies suggest that excess KI has a thyroid tumor-promoting effect, but KI per se does not induce thyroid tumors in rats. In the salivary gland, KI was suggested to have carcinogenic potential via an epigenetic mechanism, only active at a high dose.

[A 90-day repeated dose oral toxicity study of magnesium chloride in F344 rats].

In order to examine the toxicity of magnesium chloride hexahydrate, four groups of 10 male and 10 female F344 rats received the compound by dietary supplementation at 2.5, 0.5, 0.1 or 0% for 90 days. No treatment-related death was observed during the study. Transient soft stool and sustained increase in water consumption were observed both in males and females of the 2.5% group and slight reduction in body weight gain was noted in the high-dose males. There were no toxic changes in food consumption, organ weights, hematology and biochemistry, and histopathological examinations in any treated-groups. Based on these results, the no-observed-adverse-effect-level was estimated to be 0.5%, and 2.5% is considered to be appropriate as highest dose for a 2-year carcinogenicity study.

[A 13-week subchronic oral toxicity study of Perilla extracts in F344 rats].

A 13-week subchronic oral toxicity study of Perilla extracts in drinking water containing 0%, 2.5%, 5% and 10% extracts was performed in both sexes of F344 rats. Rats were randomly divided into 4 groups each consisting of 10 males and 10 females. No animals died during the period of administration. There were no treatment-related changes in body weight gain or in hematological or blood biochemistry values. Nor were any treatment-related histopathological changes observed in the highest dose group. These findings indicate that ingestion of 10% Perilla extracts in drinking water for 13-week does not cause any toxicological changes in rats.

Preventive effects of Shichimotsu-koka-to on renal lesions in stroke-prone spontaneously hypertensive rats.

Shichimotsu-koka-to (SKT) has been prescribed to treat patients with essential and renal hypertension. We investigated the effects of SKT on renal lesions in stroke-prone spontaneously hypertensive rats (SHRSPs). SHRSPs were given an extract of SKT by mixing it with drinking water, from 8 through 29 weeks of age, so that the average intake of SKT extract was about 1.5 g/kg/d. At 29 weeks of age, the kidneys of SHRSPs exhibited proliferative arteritis characterized by the proliferation of smooth muscle cells in the interlobular arteries, dilation and degeneration of renal tubules, infiltration of inflammatory cells and hemorrhage, with partial swelling or necrotizing of glomeruli. In particular, arteritis and periarteritis were noted. The treatment of SHRSPs with SKT ameliorated this morphological damage in the kidney and significantly decreased urea nitrogen in the serum. Treatment with SKT also strongly decreased the xanthine oxidase (XOD) activity and significantly increased the superoxide dismutase (SOD) activity in the kidney of SHRSPs; consequently, these values became close to those in normotensive Wistar Kyoto rats (WKYs). These results indicate that treatment with SKT ameliorated the histopathological damage and change in activity of enzymes related to free radicals in the kidney of SHRSPs, which may be important mechanisms for SKT for protecting SHRSPs from renal dysfunction.

Induction of squamous cell carcinomas in the salivary glands of rats by potassium iodide.

In a 2-year carcinogenicity study of potassium iodide (KI) in F344/DuCrj rats, squamous cell carcinomas (SCCs) were observed in the salivary glands of 4/40 males and 3/40 females receiving 1000 ppm KI in the drinking water. Ductular proliferation with lobular atrophy was observed at high incidence in the submandibular glands of the high-dose animals, and squamous metaplasia was frequently evident within the proliferative ductules and the larger interlobular ducts. A transition from metaplasia to SCC was apparent. The results suggest that squamous metaplasia in proliferative ductules, occurring secondarily to lobular impairment induced by KI, may develop into SCCs via a non-genotoxic, proliferation-dependent mechanism.

UDP-GT involvement in the enhancement of cell proliferation in thyroid follicular cell proliferative lesions in rats treated with thiourea and vitamin A.

The mechanisms underlying enhanced cell proliferation in thyroid proliferative lesions of rats simultaneously treated with large amounts of vitamin A (VA) and thiourea (TU) were investigated. Male F344 animals were initiated with N-bis(2-hydroxypropyl)nitrosamine (2800 mg/kg body weight, single s.c. injection). Starting 1 week later, groups received water containing 0.2% TU (TU group), diet containing 0.1% VA (VA group), both 0.2% TU and 0.1% VA (TU + VA group) or tap water/basal diet without supplement (control group) for 10 weeks. The serum levels of triiodothyronine (T3) and thyroxine (T4) were decreased and the thyroid stimulating hormone (TSH) levels were elevated in the TU and TU + VA groups, with the degree of change being significantly greater in the combined treatment group. The induction of P450 isoenzymes by TU was not enhanced by VA supplementation, but uridine diphosphate glucuronosyltransferase (UDP-GT) activity in the liver was significantly increased in the TU + VA group compared to the TU group. Thyroid weights were increased in both the TU and TU + VA groups, this being more pronounced with VA supplementation. Thyroid follicular cell hyperplasias and neoplasias were induced to similar extents in both TU treated groups, but their cell proliferation appeared to be increased by the VA supplementation. The results of the present study suggest that enhanced cell proliferation is due to increased TSH stimulation, resulting from the decrease in serum T3/T4 levels brought about by induction of liver UDP-GT activity with the combined action of TU + VA as well as inhibition by TU of thyroid hormone synthesis in the thyroid.

[A 13-week subacute oral toxicity study of pectin digests in rats].

A 13-week subacute oral toxicity study of pectin digests was performed in both sexes of F344 rats. Water containing 0, 0.15, 0.5, 1.5 or 5% pectin digests was fed to 10 males and 10 females per group to detect its toxicity. No animals died during the administration period. Body weight gain was suppressed in male of the 5% group compared with the 0% group. Serum biochemistry analysis revealed a significant increase in BUN in male group treated with 5% and increases in CRN in male group treated with 1.5% or more. The weight of liver was significantly increased in female groups treated with 1.5% or more. Histopathologically, no treatment-related damage was observed in any dosed groups. Based on these results, the NOEL of pectin digests for both sexes in F344 rats was considered to be 0.5% in drinking water (male 545, female 657 mg/kg/day).

Transient ipsilateral blood flow reduction in the thalamus and cerebral cortex after pontine infarction.

Remote cerebral hypoperfusion associated with pontine lesions is rare. We describe a patient who showed transient ipsilateral hypoperfusion in the thalamus and cerebral cortex after a pontine infarct. This resolved within 8 days after onset. Anatomical considerations strongly suggested involvement of the cerebellothalamocortical pathway in this case.

Effects of caffeine, nicotine, ethanol and sodium selenite on pancreatic carcinogenesis in hamsters after initiation with N-nitrosobis(2-oxopropyl)amine.

The modulating effects of caffeine, nicotine, ethanol and sodium selenite on development of N-nitrosobis(2-oxopropyl)-amine (BOP)-initiated pancreatic tumors were investigated. Female Syrian golden hamsters were given s.c. injections of BOP (10 mg/kg body weight) or saline alone once a week for 3 weeks and then administered 2000 p.p.m. caffeine, 25 p.p.m. nicotine, 20% ethanol or 4 p.p.m. sodium selenite in their drinking water for the next 37 weeks. Control animals were given tap water alone after BOP initiation. Only the BOP-treated groups developed pancreatic adenocarcinomas and dysplasias. The multiplicity of pancreatic carcinomas was significantly higher (P less than 0.05) in animals receiving caffeine than in the controls. In addition, caffeine treatment slightly increased the incidence of carcinomas. Nicotine and ethanol also showed tendencies to enhance pancreatic carcinogenesis, although there were statistically no significant differences regarding lesion development. In contrast, sodium selenite administration was associated with a tendency for a decrease in the number of carcinomas and dysplasias. Thus, among these chemicals of obvious significance to human life-style, caffeine enhanced the development of pancreatic tumors when administered during the post-initiation phase in this hamster model.