Developmental toxicity of estrogenic chemicals on rodents and other species

ABSTRACT  Antenatal sex-hormone exposure induces lesions in mouse reproductive organs, which are similar to those in humans exposed in utero to a synthetic estrogen, diethylstilbestrol. The developing organisms including rodents, fish and amphibians are particularly sensitive to exposure to estrogenic chemicals during a critical window. Exposure to estrogens during the critical period induces long-term changes in reproductive as well as non-reproductive organs, including persistent molecular alterations. The antenatal mouse model can be utilized as an indicator of possible long-term consequences of exposure to exogenous estrogenic compounds including possible environmental endocrine disrupters. Many chemicals released into the environment potentially disrupt the endocrine system in wildlife and humans, some of which exhibit estrogenic activity by binding to the estrogen receptors. Estrogen responsive genes, therefore, need to be identified to understand the molecular basis of estrogenic actions. In order to understand molecular mechanisms of estrogenic chemicals on developing organisms, we are identifying estrogen responsive genes using cDNA microarray, quantitative RT-PCR, and differential display methods, and genes related to the estrogen-independent vaginal changes in mice induced by estrogens during the critical window. In this review, discussion of our own findings related to endocrine distuptor issue will be provided.     

Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma

h-warts/LATS1 is a human homolog of the Drosophila warts tumor suppressor gene, which functions as a component of the mitotic apparatus. LATS1-deficient (Lats1(-/-)) mice have been reported to develop ovarian stromal tumors and soft tissue sarcomas. We investigated the status of the h-warts/LATS1 in 50 human soft tissue sarcomas to address its potential function as a tumor suppressor in human sarcoma development. In our RT-PCR assay, 7 (14%) (3 of 4 myxoid liposarcomas, 3 of 7 leiomyosarcomas, 1 of 9 malignant fibrous histiocytomas) of 50 sarcomas examined had no or a reduced expression of the h-warts/LATS1, indicating down-regulated gene expression. We further analyzed alterations of the h-warts/LATS1 in these seven sarcomas. Using microsatellite markers for chromosome 6q23-25.1, to which the h-warts/LATS1 is localized, an allelic loss of this locus was detected in one leiomyosarcoma, in which a missense point mutation of the h-warts/LATS1 was detected by PCR single-strand conformation polymorphism. Clusters of CpG dinucleotides in a 5' putative promoter region were hypermethylated in the other six sarcomas. Our data suggest that the molecular alterations of the h-warts/LATS1 could be of pathologic importance in human sarcomagenesis.     

A case of pseudo-Bartter's syndrome induced by long-term ingestion of furosemide delivered orally through health tea

A 32-year-old woman with a three-year history of muscle weakness and hypokalemia, was admitted to our hospital because of hypokalemic periodic paralysis. Clinical and laboratory findings were consistent with Bartter's syndrome. Although she denied any ingestion of diuretics substantial quantities of furosemide were detected in her urine. She had been drinking health tea which contained about 90 mg of furosemide per teabag daily for five years. Four years after discontinuation of drinking the tea, the hypokalemia was completely ameliorated, but poor renal concentration ability is still present. We conclude that is a case of pseudo-Bartter's syndrome that was caused by long-term ingestion of the health tea supplemented illegally with furosemide, and suspect that such cases may be observed more frequently than currently thought.     

Successful treatment of nocturnal eating/drinking syndrome with selective serotonin reuptake inhibitors

Nocturnal eating/drinking disorder (NE/DS) is a rare syndrome that includes disorders of both eating and sleeping. It is characterized by awakening in the middle of the night, getting out of bed, and consuming large quantities of food quickly and uncontrollably, then returning to sleep. This may occur several times during the night. Some patients are fully conscious during their nocturnal eating, while some report total amnesia. The aetiology of NE/DS is still unclear, and there is no satisfactory treatment. Four patients with NE/DS are described. Treatment with a selective seroronin reuptake inhibitor (SSRI) was effective in controlling their episodes of nocturnal eating. To our knowledge, this is the first published case report of successful treatment with SSRIs in NE/DS.     

Anesthetic management of two patients with hypertrophic obstructive cardiomyopathy for percutaneous transluminal septal myocardial ablation

We experienced anesthetic management of two patients with hypertrophic obstructive cardiomyopathy (HOCM) for percutaneous transluminal septal myocardial ablation (PTSMA). PTSMA had been performed more than a year earlier in both cases, and symptoms and exercise tolerance were improved after PTSMA. Laparotomy for suspected ovarian cancer in one patient and thoracotomy for metastatic lung cancer in the other patient were proposed. Preoperative echocardiography showed reduced left ventricular outflow tract pressure gradient (from 90 mmHg before PTSMA to 10 mmHg and from 81 mmHg to 17 mmHg, respectively) and decreased septal wall thickness. Systolic anterior movement of mitral valve apparatus had disappeared. General anesthesia in the former and general anesthesia combined with epidural anesthesia in the latter were employed. Anesthesia was induced with propofol and fentanyl. A laryngeal mask was used to minimize hemodynamic fluctuations during induction and emergence in the former. Anesthesia was maintained with propofol, sevoflurane and supplemental fentanyl. Epidural anesthesia was also used to maintain anesthesia in the latter. The postoperative course was uneventful in each case. PTSMA for HOCM might be useful to prevent perioperative cardiac events.     

Effect of moxibustion stimulation of various skin areas on cortical cerebral blood flow in anesthetized rats

The effect of moxibustion stimulation of various skin areas (cheek, forepaw, upper arm, chest, back, lower leg, hindpaw and perineum) on cerebral blood flow (CBF) of the parietal cortex was examined in anesthetized rats after eliminating emotional influences. Moxibustion stimulation was performed by burning a moxa cone of about 4 mg weight placed on the shaved skin. CBF of the parietal cortex was measured using a laser Doppler flowmeter. Stimulation of the cheek, forepaw, upper arm and hindpaw produced significant increases in CBF, but stimulation of the other areas did not produce significant responses. Moxibustion stimulation of the forepaw and hindpaw produced an increase in the mean arterial pressure (MAP), while stimulation of the other areas did not. After spinal transection at the 2nd thoracic level, the MAP response to stimulation of the forepaw was abolished, whereas the CBF response to stimulation of the forepaw remained. The CBF response in spinalized rats was not affected by cutting cervical sympathetic and facial parasympathetic nerves, while it was almost abolished by intravenous administration of muscarinic and nicotinic cholinergic blocking agents. The CBF response was abolished by crushing the brachial plexus ipsilateral to the stimulated side. It is suggested that the increase in CBF, independent of MAP and emotional responses, elicited by moxibustion stimulation is a reflex response whose afferent pathway is composed of somatic afferent nerves, and whose efferent pathway involves intracerebral cholinergic nerves. A contribution of endogenous opioids in the present CBF responses was neglected, because naloxone did not influence the CBF responses.     

Seco-prezizaane-type sesquiterpenes and an abietane-type diterpene from Illicium minwanense

A methanol extract of the pericarps of Illicium minwanense afforded seven new seco-prezizaane-type sesquiterpenes (2-8) and a new abietane-type diterpene (9), together with six previously known compounds (1 and 10-14). The structures of the new compounds, (1S)- and (1R)-minwanenone (2 and 3), 1alpha-hydroxy-6-deoxypseudoanisatin (4), (2S)-hydroxy-6-deoxypseudoanisatin (5), 3-oxopseudoanisatin (6), (3S,6R)-4,7-epoxy-6-deoxypseudoanisatin (7), 7-O-methylpseudomajucin (8), and (+)-8,11,13,15-abietatetraene (9), were elucidated by spectroscopic data analysis and chemical transformations. The absolute configurations of 1 and 5 were established by X-ray crystallographic analysis of their p-bromobenzoyl derivatives.