Genotoxicity and carcinogenicity risk assessment of prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist.

Prucalopride, a high affinity, selective serotonin type 4 (5-HT4) receptor agonist, was associated with increased neoplasia incidence (in endocrine tissues and liver) in 2-year rodent bioassays, without evidence of a genotoxic mechanism of action. Proposed mechanisms of action involve prolactin and the constitutive androstane receptor (CAR). Epigenetic mechanisms and their relevance to humans are discussed. Data from in vitro and in vivo rodent studies demonstrated that prucalopride-related stimulation of prolactin secretion (via dopamine receptor D2 antagonism at high doses) is a rodent-specific, non-genotoxic mechanism for inducing hyperplasia and neoplasia in prolactin receptor-expressing endocrine tissues. Additional data demonstrated that CAR-mediated liver enzyme induction underlies the observed hepatocellular adenomas and thyroid follicular adenomas in rodents. A 12-month neonatal mouse carcinogenicity study confirmed the lack of a genotoxic mechanism of action. Furthermore, tumors were observed only at very high exposures (200 and 63 fold higher in mice and rats, respectively, than human exposure after a daily therapeutic dose of 2 mg). The studies indicate that non-genotoxic, rodent-specific, epigenetic mechanisms that are considered clinically irrelevant are responsible for the increased incidence of neoplasias associated with very high exposure to prucalopride in rodents, and that prucalopride does not pose a carcinogenic safety risk to humans.

Association of environmental chemicals & estrogen metabolites in children.

BACKGROUND: The prevalence of pediatric hormonal disorders and hormonally-sensitive cancers are rising. Chemicals including bisphenol A (BPA), phthalates, parabens, 4-nonylphenol (4NP) and triclosan have been linked to disruption of endocrine pathways and altered hormonal status in both animal and human studies. Additionally, changes in estrogen metabolism have been associated with pediatric endocrine disorders and linked to estrogen-dependent cancers. The main objective of the study was to measure the presence of these environmental chemicals in prepubescent children and assess the relationship between chemical metabolites and estrogen metabolism. METHODS: 50 subjects (25 male, 25 female) were recruited from the principal investigator's existing patient population at his pediatric primary care office. The first 5 boys and 5 girls in each age group (4 through 8 years old inclusive) who presented for annual examinations were included, as long as they were Tanner Stage I (prepubertal) on physical exam, without diagnosis of hormonally-related condition and/or cancer and able to give a urine sample. Urine samples were collected in glass containers for analysis of chemical and estrogen metabolites. Study kits and lab analysis were provided by Genova Diagnostics (Duluth, GA). Summary statistics for the concentrations of each chemical metabolite as well as estrogen metabolites were computed (minimum, maximum, median and inter-quartile range) for males only, for females only and for all subjects. Comparisons between groups (e.g. males v. females) were assessed using the nonparametric Wilcoxon test, since the data was skewed. The correlation between concentrations of chemical metabolites and estrogen metabolites in prepubescent children were examined by the Spearman's correlation coefficient (ρ). RESULTS: 100 % of subjects had detectable levels of at least five chemicals [corrected] in their urine, and 74 % had detectable levels of eight or more chemicals. 28 % of subjects had measurable levels of 4NP. No associations were found between the urine levels of chemicals and estrogen metabolites. CONCLUSIONS: Endocrine disrupting environmental chemicals were detected in all children in the study, with measurable levels of 4NP in nearly 1/3 of subjects. This is the first known published study of 4NP levels in American children. No associations were found between the urine levels of chemicals tested and estrogen metabolites. The presence of multiple chemicals in a majority of children's urine coupled with increasing prevalence of pediatric hormonal disorders warrants further research to elucidate potential causal mechanisms in pre- and post-pubertal children.

[Relationship between toxic effects of potassium bromate and endocrine glands]. / Powiazania pomiedzy toksycznymi efektami bromianu potasowego a gruczolami wydzielania wewnetrznego.

Potassium bromate (KBrO(3)) is a compound belonging to Group 2B of carcinogens (a possible human carcinogen). This agent was used as a food additive in flour treatment, as a component of cold-wave hair lotions, and is still used in barley processing. Additionally, KBrO(3) is formed as an oxyhalide by-product during water ozonation. KBrO(3) induces oxidative stress and may contribute to neoplasia in endocrine glands. It has been demonstrated that KBrO(3) triggers thyroid follicular cell tumors in rats. It has been revealed in our in vivo and in vitro studies that KBrO(3) significantly increases lipid peroxidation in rat and porcine thyroid. KBrO(3) also induces mesotheliomas which may secrete hormones or similar substances, such as parathyroid hormone related protein, phosphatonins or melanocyte stimulating hormone. In our experimental studies we demonstrated that antioxidants, such as pineal hormone - melatonin, indole-3-propionic acid (IPA) (a compound chemically and physically similar to melatonin) and antythyroid drug - propylthiouracil (PTU), produce distinct protective effects against lipid peroxidation due to KBrO(3) in the thyroid in vivo. KBrO(3) is a prooxidant which may induce neoplasia in endocrine glands and cause hormonal disturbances, however its damaging effects may be neutralized by hormones, mainly melatonin.

Chronic feeding study of pyrilamine in Fischer 344 rats.

The antihistamine, pyrilamine maleate, was fed for up to 2 years to groups of 57 Fischer 344 (F344) rats of each sex at dietary levels of 0, 300, 1500, or 3000 ppm (free base). Eight or nine of these rats per sex and dose group were killed at 65 weeks to analyze hematology and clinical chemistry in all groups and histopathology of control and high-dose animals. Histopathology also was performed on all dead or moribund rats and on all that survived for 2 years. Average daily exposures were 11 to 150 mg/kg pyrilamine compared to human dosages up to 3 mg/kg. Pyrilamine treatment did not reduce survival. Final body weights were reduced relative to controls (mid-dose males, 93%, females, 82%: high-dose males, 82%, females, 70%). The incidences of inflammation of the nasolacrimal duct (chronic in females; suppurative in males), liver cytoplasmic vacuolization (males), and the combination of animals with either liver basophilic or clear cell foci (males) tended to significantly increase with dose. Adrenal pheochromocytomas, mammary gland fibroadenomas, and neoplasms of the clitoral gland, thyroid c-cell, and pituitary gland all tended to decrease with increasing dose in females. In males only preputial gland neoplasms exhibited a similar negative trend. While two ovarian granulosatheca cell benign tumors occurred in high-dose females, these were thought to be a random occurrence. There was no evidence for the carcinogenicity of pyrilamine in F344 rats in the current study.

Rapid induction of enterochromaffinlike cell tumors by histamine2-receptor blockade.

The effect of acid inhibition on gastric endocrine cells was investigated in Praomys (Mastomys) natalensis. Long-term treatment (1 to 32 weeks) with an irreversible histamine 2-receptor blocker (loxtidine) caused a sustained increase in plasma gastrin levels, which was accompanied by a gradual increase in histamine and histidine decarboxylase activity of the gastric oxyntic mucosa. The density of endocrine cells in the oxyntic mucosa increased gradually, doubled by 8 weeks, and was three times that of controls after 24 weeks of treatment. Hyperplastic changes in the endocrine cell population were evident after 2 to 8 weeks in all animals, whereas dysplastic or neoplastic lesions were observed in half the animals after 16, 24, and 32 weeks of treatment. Gross tumors in the oxyntic mucosa were observed in 1/4 of the animals treated for 24 or 32 weeks. Proliferating cells were identified as enterochromaffinlike cells because they were argyrophilic and immunopositive for chromogranin A and histamine. The results demonstrate that histamine 2-receptor blockade initiated by loxtidine promotes a rapid development of enterochromaffinlike cell tumors in Mastomys and suggest a critical role for gastrin in the formation of these tumors. However, the rate and frequency by which carcinoid tumors appeared in Mastomys after acid inhibition was much greater than that reported in other species, indicating that several factors, including hormonal and genetic factors, are important in the development of gastric endocrine tumors.