Bisphenol A (BPA) is known to be an endocrine disruptor that affects the development of reproductive system. The aim of the present study was to investigate a group of testicular genes dysregulated by prenatal exposure to BPA. Pregnant ICR mice were treated with BPA by subcutaneous administration on days 7 and 14 of pregnancy. Tissue and blood samples were collected from 6-week-old male offspring. Testes were subjected to gene expression analysis using a testis-specific microarray (Testis2), consisting of 2,482 mouse cDNA clones annotated with Medical Subject Headings (MeSH) terms indicative of testicular components and functions. To interpret the microarray data, we used the MeSH terms significantly associated with the altered genes. As a result, MeSH terms related to androgens and Sertoli cells were extracted in BPA-treated groups. Among the genes related to Sertoli cells, downregulation of Msi1h, Ncoa1, Nid1, Hspb2, and Gata6 were detected in the testis of mice treated with BPA (twice administered 50 mg/kg). The MeSH terms associated with this group of genes may provide useful means to interpret the testicular toxicity of BPA. This article concludes that prenatal BPA exposure downregulates expression of genes associated with Sertoli cell function and affects the reproductive function of male offspring. Additionally, a method using MeSH to extract a group of genes was useful for predicting the testicular and reproductive toxicity of prenatal BPA exposure.

Toxicity of chemical substances to male reproductive system has been focused since the effects of a pesticide, dibromochloropropane (DBCP), on human spermatogenesis were discovered (Whorton et al., 1977). Because the damages on reproductive system may cause infertility and endanger the survival of the species, it is necessary to establish a simple way to evaluate the mechanism of reproductive toxicity of chemical substances for controlling and preventing their adverse effects. Testicular toxicity, a major male reproductive toxicity (Nishikawa et al., 2010) ABSTRACT -Testicular toxicity of chemical substances has been generally assessed by sperm properties and histology. However, the methods can provide only a few information of the mechanism of the toxicity. The aim of this study is to show a method that can evaluate an overview of testicular toxic mechanisms using a tissue-specific microarray and classification of genes using Medical Subject Headings (MeSH). Male ICR mice (6 weeks old) were treated with doxorubicin hydrochloride (0, 0.1, 0.3 mg/kg/ time, three times per week) by subcutaneous injection for 6 weeks (until 11 weeks old). Six weeks after the final administration, tissue and blood samples were obtained. Testes were subjected to gene expression analysis using quantitative RT-PCR and cDNA microarray (testis2). To interpret the microarray data, genes were classified using MeSH related to the functions of testis and sperm. Doxorubicin (both 0.1 and 0.3 mg/kg group) induced a decrease in sperm normal morphology and mortality, daily sperm production, and the number of Sertoli cells in the seminiferous tubules. Quantitative RT-PCR and microarray analysis showed dysregulation of mRNA expression levels of genes related to Sertoli cells, germ cells and spermatogenesis. Analysis of microarray data showed a significant enrichment of a total of ten MeSH categories including Spermatogenesis, Sertoli cells, Germ cells and Male infertility. This article concluded that analysis using testicular specific microarray combined with MeSH showed a more comprehensive overview of testicular toxic mechanisms than existing methods; i.e., examination of sperm properties and the histological examinations.

The objective of this study was to analyze the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) parameters of a single 2-g dose of extended-release formulation of azithromycin (AZM-SR) and its microbiological efficacy against gonococcal urethritis. Fifty male patients with gonococcal urethritis were enrolled in this study. In 36 patients, the plasma AZM concentrations were measured using liquid chromatography-tandem mass spectrometry, the AZM MIC values for the isolates were determined, and the microbiological outcomes were assessed. AZM-SR monotherapy eradicated in 30 (83%) of the 36 patients. AZM MICs ranged from 0.03 to 2 mg/liter. The mean value of the area under the concentration-time curve (AUC), estimated by population PK analysis using a two-compartment model, was 20.8 mg · h/liter. Logistic regression analysis showed that the PK/PD target value required to predict an eradication rate of ≥95% was a calculated AUC/MIC of ≥59.5. The AUC/MIC value was significantly higher in patients who achieved microbiological cure than in patients who achieved microbiological failure. Monte Carlo simulation using this MIC distribution revealed that the probability that AZM-SR monotherapy would produce an AUC/MIC exceeding the AUC/MIC target of 59.5 was 47%. Furthermore, the MIC distribution for strains isolated in this study was mostly consistent with that for strains currently circulating in Japan. In conclusion, in Japan, AZM-SR monotherapy may not be effective against gonococcal urethritis. Therefore, use of a single 2-g dose of AZM-SR either with or without other antibiotics could be an option to treat gonococcal urethritis if patients are allergic to ceftriaxone and spectinomycin or are diagnosed to be infected with an AZM-sensitive strain.