Takayuki Koga

Maternal Exposure to Dioxin Disrupts Gonadotropin Production in Fetal Rats and Imprints Defects in Sexual Behavior

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related substances are a class of environmental pollutants with suspected toxic effects on reproductive and developmental processes. This study investigated a hypothesis that maternal exposure to TCDD damages gonadotropin-regulated steroidogenesis in fetal gonads to imprint defects in sexual behavior as well as the maturation of gonadal tissues. Oral administration of 1 μg/kg TCDD to pregnant Wistar rats at gestational day (GD) 15 attenuated the expression of luteinizing hormone (LH), a regulator of gonadal steroidogenesis, in the pituitaries of male and female fetuses at GD20. TCDD treatment also reduced the fetal expression of testicular and ovarian steroidogenic proteins, including steroidogenic acute-regulatory protein. These changes in pituitary and gonadal proteins were fetus-specific, and this seems not to be because of the greater delivery of TCDD to the brain of fetuses than adults. This is because a reduction in LH production was not reproduced even although TCDD was administered intraventricularly to adult rats. Direct supplementation of equine chorionic gonadotropin (eCG), an LH-mimicking hormone, to TCDD-exposed fetuses at GD17 restored the reduced expression of gonadal steroidogenic proteins. Maternal exposure to TCDD delayed the development of gonadal tissues in male and female pups and impaired their sexual behavior. However, eCG treatment at the fetal stage again restored not only tissue maturation but also many of the behavioral defects that occurred at adulthood. These results demonstrate that TCDD disrupts steroidogenesis in fetuses by targeting pituitary gonadotropin production and imprints demasculinization in males and defeminization in females in terms of their copulatory behavior.

Restoration of Dioxin-Induced Damage to Fetal Steroidogenesis and Gonadotropin Formation by Maternal Co-Treatment with α-Lipoic Acid

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an endocrine disruptor, causes reproductive and developmental toxic effects in pups following maternal exposure in a number of animal models. Our previous studies have demonstrated that TCDD imprints sexual immaturity by suppressing the expression of fetal pituitary gonadotropins, the regulators of gonadal steroidogenesis. In the present study, we discovered that all TCDD-produced damage to fetal production of pituitary gonadotropins as well as testicular steroidogenesis can be repaired by co-treating pregnant rats with α-lipoic acid (LA), an obligate co-factor for intermediary metabolism including energy production. While LA also acts as an anti-oxidant, other anti-oxidants; i.e., ascorbic acid, butylated hydroxyanisole and edaravone, failed to exhibit any beneficial effects. Neither wasting syndrome nor CYP1A1 induction in the fetal brain caused through the activation of aryl hydrocarbon receptor (AhR) could be attenuated by LA. These lines of evidence suggest that oxidative stress makes only a minor contribution to the TCDD-induced disorder of fetal steroidogenesis, and LA has a restorative effect by targeting on mechanism(s) other than AhR activation. Following a metabolomic analysis, it was found that TCDD caused a more marked change in the hypothalamus, a pituitary regulator, than in the pituitary itself. Although the components of the tricarboxylic acid cycle and the ATP content of the fetal hypothalamus were significantly changed by TCDD, all these changes were again rectified by exogenous LA. We also provided evidence that the fetal hypothalamic content of endogenous LA is significantly reduced following maternal exposure to TCDD. Thus, the data obtained strongly suggest that TCDD reduces the expression of fetal pituitary gonadotropins to imprint sexual immaturity or disturb development by suppressing the level of LA, one of the key players serving energy production.

In vitro release of intederon-γ by peripheral blood mononuclear cells of patients with dermalophytosis in response to stimulation with trichophytin

1 Ognibene A]. Agranulocytosis due to dapsone. Ann Intern Med 1970: 72; 521-4. 2 Hornsten P, Keisu M. Wiholm B-E. The incidence of agranulocytosis during treatment of dermatitis herpetiformis with dapsone as reported in Sweden, 1972 through 1988. Arch Dermatol 1990:126: 919-22. 3 Duhra P. Charles-Holmes R. Linear IgA disease with haemorrhagic pompholyx and dapsone-induced neutropenia. Br J Dermatol 1991: 125:

Expression of phosphorylated Stat3, cyclin D1 and Bcl-xL in extramammary Paget disease

Background  Stat3 (Signal transducer and activator of transcription‐3) is an oncogene that plays a critical role in regulating fundamental processes associated with malignant transformation and cell survival. It participates in oncogenesis through upregulation of genes encoding apoptosis inhibitors (Bcl‐xL) and cell cycle regulators (cyclin D1). The expression of Stat3, Bcl‐xL and cyclin D1 protein has not been investigated in extramammary Paget disease (EMPD).

Basal Cell Carcinomas in Association with Basaloid Follicular Hamartoma

We describe a unique case of various types of basal cell carcinoma (BCC) associated with basaloid follicular hamartoma (BFH) in a 56-year-old female patient. The lesion consisted of a dark brown and elastic soft nodule and papules within the area of a birthmark on the neck. The lesion was surgically excised. Histological examination of the nodular region revealed aggregations of neoplastic basaloid cells. We diagnosed the nodule as BCC with a racemiform or reticular pattern. In addition, a specimen taken from brownish black papules within the birthmark was found to be composed of anastomosing cords of basaloid cells accompanied by infundibular cystic structures. These features were consistent with an infundibulocystic BCC. In contrast, specimens from a hamartomatous plaque showed distinctive branching strands of basaloid cells that are suggestive of BFH. Therefore, our findings indicate that several types of BCC may develop within a BFH.

Expression of insulin-like growth factor-1 receptor, p-AKT and p-ERK1/2 protein in extramammary Paget's disease.

Background  The insulin‐like growth factor‐1 (IGF‐1) receptor (R)‐induced phosphatidylinositol 3‐kinase (PI3K)/AKT and mitogen‐activated protein kinase (MAPK)/ERK signal transduction cascade, which have critical roles in prevention of apoptosis and regulation of cell cycle progression, plays an important role in tumorigenesis. The expression of IGF‐1R, AKT and ERK1/2 has been described in some human malignancies, but not in extramammary Pagets disease (EMPD).

Interferon-γ and interleukin-2 production by peripheral blood mononuclear cells from a paiient with gold contact allergy

resolution of 512 x SI 2 image dots and 2Sf> intensity levels. The use of the fluorescence technique allows a picture of maximal contrast to be obtained: the iiuurescent ulcerated and reference surfaces appear white, whereas the surrounding non-fluorescent healthy skin is presented as black (Fig. 3). This enables the image processing software (Optimas. Bioscan, U.S.A.) to determine independently the borders ofthe ulcer and

Spontaneous regression of multiple seborrheic keratoses associated with nasal carcinoma

Seborrheic keratoses are very common epidermal neoplasms. We describe a patient with seborrheic keratoses presenting multifocal spontaneous regression. The patient had a concurrent nasal adenoid cystic carcinoma. The simultaneous regression of seborrheic keratoses ceased after total resection of the nasal carcinoma. Histological examination revealed marked infiltration of mononuclear cells, including CD4+, CD8+, CD68+ and cutaneous lymphocyte‐associated antigen‐positive cells, with profound accumulation of CD1a+ dendritic cells. Although apoptotic keratinocytes were not found in the lesional epidermis by histology, the majority of keratinocytes in the regressing seborrheic keratosis were positively stained by the TUNEL method. We postulate that the internal malignancy may induce spontaneous regression of seborrheic keratoses.

A subchronic (180-day) oral toxicity study of ethyl tertiary-butyl ether, a bioethanol, in rats

Abstract A subchronic (180-day) toxicity study was conducted to evaluate the effects of ethyl tertiary-butyl ether (ETBE), a biomass fuel, in male and female rats. ETBE was administered at dose levels of 0, 5, 25, 100 and 400 mg/kg/body weight (b.w.)/day by gavage. No treatment-related adverse effects were observed at 5, 25 or 100 mg/kg. Centrilobular hypertrophy of hepatocytes was observed in males and females and their relative liver weights were increased, suggesting enhanced metabolic activity. From these results, we concluded that the no observed adverse effect level of ETBE was 100 mg/kg b.w./day under the conditions tested.

Dioxin-induced increase in leukotriene B4 biosynthesis through the aryl hydrocarbon receptor and its relevance to hepatotoxicity owing to neutrophil infiltration

Dioxin and related chemicals alter the expression of a number of genes by activating the aryl hydrocarbon receptors (AHR) to produce a variety of disorders including hepatotoxicity. However, it remains largely unknown how these changes in gene expression are linked to toxicity. To address this issue, we initially examined the effect of 2,3,7,8-tetrachrolodibenzo-p-dioxin (TCDD), a most toxic dioxin, on the hepatic and serum metabolome in male pubertal rats and found that TCDD causes many changes in the level of fatty acids, bile acids, amino acids, and their metabolites. Among these findings was the discovery that TCDD increases the content of leukotriene B4 (LTB4), an inducer of inflammation due to the activation of leukocytes, in the liver of rats and mice. Further analyses suggested that an increase in LTB4 comes from a dual mechanism consisting of an induction of arachidonate lipoxygenase-5, a rate-limiting enzyme in LTB4 synthesis, and the down-regulation of LTC4 synthase, an enzyme that converts LTA4 to LTC4. The above changes required AHR activation, because the same was not observed in AHR knock-out rats. In agreement with LTB4 accumulation, TCDD caused the marked infiltration of neutrophils into the liver. However, deleting LTB4 receptors (BLT1) blocked this effect. A TCDD-produced increase in the mRNA expression of inflammatory markers, including tumor-necrosis factor and hepatic damage, was also suppressed in BLT1-null mice. The above observations focusing on metabolomic changes provide novel evidence that TCDD accumulates LTB4 in the liver by an AHR-dependent induction of LTB4 biosynthesis to cause hepatotoxicity through neutrophil activation.