Citrate ester substitutes for di-2-ethylhexyl phthalate: In vivo reproductive and in vitro cytotoxicity assessments.

Di-2-ethylhexyl phthalate (DEHP) is frequently used as a plasticizer for wrapping films, in toys, and in medical devices. Previous studies demonstrated that DEHP in mouse reduced testicular and epididymis weights, suppressed levels of serum testosterone, luteinizing hormone, and follicle-stimulating hormone, and decreased synthesis of testosterone by Leydig cells. Due to these anti-androgenic effects of DEHP on the reproductive system, the aim of this study was to examine whether substitutes such as acetyl triethyl citrate (ATEC) and acetyl tributyl citrate (ATBC) also damaged the reproductive system. In particular, this study investigated the anti-androgenic effects and cytotoxicity of DEHP substitutes using castrated male Sprague--Dawley rats employing the in vivo Hershberger assay and in vitro mouse Leydig (TM3) cells and mouse fibroblast (NIH-3T3) cell lines. In the Hershberger assay, rats were administered testosterone propionate and ATEC or ATBC at 20, 100, or 500 mg/kg b.w./day or DEHP (500 mg/kg b.w./day). Controls received testosterone antagonist flutamide (positive control), testosterone only (negative control), or corn oil only (vehicle control). ATEC/ATBC treatment produced no significant differences compared with testosterone in 5-androgen-dependent tissues weights including ventral prostate, seminal vesicles, levator ani-bulbocavernosus muscle, Cowper's glands, and glans penis. In the 500 mg/kg ATBC group, there was a significant reduction in liver weight. The MTT assay revealed that cell viability of both TM3 and NIH-3T3 cells treated with ATEC was not markedly altered. However, ATBC significantly reduced TM3 and NIH-3T3 cell viability in a concentration-dependent manner. Further, ATBC reduced cell viability to greater extent in TM3 versus NIH-3T3 cells. Based upon the observed effects of citrate ester substitutes on reproductive tissue responses and cytotoxicity, ATEC compared to ATBC may be a better alternative to DEHP for potential commercial uses. ABBREVIATIONS: ATEC: acetyl triethyl citrate; ATBC: acetyl tributyl citrate; CG: Cowper's glands; DEHP: di-2-ethylhexyl phthalate; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; GP: glans penis; LABC: levator ani-bulbocavernosus muscle; MTT: methyl tetrazolium; NC: negative control; NT: untreated control; PC: positive control; SV: seminal vesicle; TP: testosterone propionate; VC: vehicle control; VP: ventral prostate.

Molecular and Treatment Characteristics of SMARCB1 or SMARCA4-Deficient Undifferentiated Tumor: Retrospective Case Series.

SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor has aggressive nature with a poor prognosis. Patients with this disease were diagnosed by immunohistochemistry or next-generation sequencing. Those who were able to receive a surgery tended to be cured, while the others treated with chemotherapy, radiation therapy, or immune checkpoint inhibitor were often insensitive to these therapies. However, one having CD274 (PD-L1) amplification showed the response to immune checkpoint inhibitor and a good prognosis. We believed that this report could provide promising information for determining the optimal treatment option.