PI3K/AKT/mTOR pathway mediated-cell cycle dysregulation contribute to malignant proliferation of mouse spermatogonia induced by microcystin-leucine arginine.

Environmental cyanotoxin exposure may be a trigger of testicular cancer. Activation of PI3K/AKT/mTOR signaling pathway is the critical molecular event in testicular carcinogenesis. As a widespread cyanotoxin, microcystin-leucine arginine (MC-LR) is known to induce cell malignant transformation and tumorigenesis. However, the effects of MC-LR on the regulatory mechanism of PI3K/AKT/mTOR pathway in seminoma, the most common testicular tumor, are unknown. In this study, mouse spermatogonia cell line (GC-1) and nude mice were used to investigate the effects and mechanisms of MC-LR on the malignant transformation of spermatogonia by nude mouse tumorigenesis assay, cell migration invasion assay, western blot, and cell cycle assay, and so forth. The results showed that, after continuous exposure to environmentally relevant concentrations of MC-LR (20 nM) for 35 generations, the proliferation, migration, and invasion abilities of GC-1 cells were increased by 120%, 340%, and 370%, respectively. In nude mice, MC-LR-treated GC-1 cells formed tumors with significantly greater volume (0.998 ± 0.768 cm3 ) and weight (0.637 ± 0.406 g) than the control group (0.067 ± 0.039 cm3 ; 0.094 ± 0.087 g) (P < .05). Furthermore, PI3K inhibitor Wortmannin inhibited the PI3K/AKT/mTOR pathway and its downstream proteins (c-MYC, CDK4, CCND1, and MMP14) activated by MC-LR. Blocking PI3K alleviated MC-LR-induced cell cycle disorder and malignant proliferation, migration and invasive of GC-1 cells. Altogether, our findings suggest that MC-LR can induce malignant transformation of mouse spermatogonia, and the PI3K/AKT/mTOR pathway-mediated cell cycle dysregulation may be an important target for malignant proliferation. This study provides clues to further reveal the etiology and pathogenesis of seminoma.

Exposure to metal-working fluids in the automobile industry and the risk of male germ cell tumours.

INTRODUCTION: In a previous analysis of a case-control study of testicular cancer nested in a cohort of automobile workers, we observed an increased risk for testicular cancer among workers who had ever been involved in occupational metal-cutting tasks. We investigated whether this risk increase was due to exposure to metal-working fluids (MWF). METHODS: Occupational exposure to MWF was assessed in detail using a job-specific questionnaire for metal-cutting work. We calculated ORs and associated 95% CIs individually matched for age (±2 years) and adjusted for a history of cryptorchidism by conditional logistic regression. RESULTS: The prevalence of exposure to MWF was 39.8% among cases and 40.1% among controls. For total germ cell tumours and seminomas we did not observe risk increases for metal-cutting tasks or occupational exposure to MWF (OR 0.95; 95% CI 0.69 to 1.32 and OR 0.88; 95% CI 0.58 to 1.35, respectively). However, dermal exposure to oil-based MWF was associated with an increased risk for non-seminomatous testicular cancer. Dermal exposure to oil-based MWF for more than 5000 h showed particularly high risk estimates (OR 4.72; 95% CI 1.48 to 15.09). DISCUSSION: Long-term dermal exposure to oil-based MWF was a risk factor for the development of non-seminomatous testicular germ cell cancer. Possible measures to reduce exposure include the introduction of engineering control measures such as venting or enclosing of machines, and enforcing the use of personal protective equipment during metal cutting.

Persistent organochlorine pesticides and risk of testicular germ cell tumors.

BACKGROUND: Exposure to endocrine-disrupting chemicals, such as persistent organochlorine pesticides, has been suggested to increase the risk of testicular germ cell tumors (TGCTs). METHODS: To study the relationship of POP exposure to TGCT risk, prediagnostic serum samples from 754 case subjects and 928 control subjects enrolled in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study were analyzed for cis-nonachlor, trans-nonachlor, oxychlordane, total chlordanes, beta-hexachlorocyclohexane, mirex, p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), and p,p'-dichlorodiphenyltrichloroethane. Adjusted odds ratios (ORs) and their associated 95% confidence intervals (CIs) for the risk of TGCT overall and for the histological subgroups, seminoma and nonseminoma, were estimated using multivariable logistic regression. All statistical tests were two-sided. RESULTS: TGCT risk was statistically significantly associated with higher plasma levels of p,p'-DDE (for highest quartile [Q4] vs lowest quartile [Q1], OR = 1.71, 95% CI = 1.23 to 2.38, P(trend) = .0002) and of two chlordane components, cis-nonachlor (Q4 vs Q1, OR = 1.56, 95% CI = 1.11 to 2.18, P(trend) = .009) and trans-nonachlor (Q4 vs Q1, OR = 1.46, 95% CI = 1.07 to 2.00, P(trend) = .026). Seminoma risk was statistically significantly associated with p,p'-DDE (Q4 vs Q1, OR = 1.91, 95% CI = 1.22 to 2.99, P(trend) = .0008), cis-nonachlor (Q4 vs Q1, OR = 1.93, 95% CI = 1.27 to 2.93, P(trend) = .0045), trans-nonachlor (Q4 vs Q1, OR = 1.72, 95% CI = 1.11 to 2.67, P(trend) = .033), and a chlordane metabolite, oxychlordane (Q4 vs Q1, OR = 1.64, 95% CI = 1.04 to 2.60, P(trend) = .048), whereas nonseminoma risk showed a statistically significant association with p,p'-DDE only (Q4 vs Q1, OR = 1.63, 95% CI = 1.10 to 2.42, P(trend) = .0044). CONCLUSIONS: Increased exposure to p,p'-DDE may be associated with the risk of both seminomatous and nonseminomatous TGCTs, whereas exposure to chlordane compounds and metabolites may be associated with the risk of seminoma. Because evidence suggests that TGCT is initiated in very early life, it is possible that exposure to these persistent organic pesticides during fetal life or via breast feeding may increase the risk of TGCT in young men.

Bilateral testicular tumors in an infertile man previously treated with follicle-stimulating hormones.

A 43-year-old infertile man with oligozoospermia and normal serum gonadotropin and cytogenetic findings was treated with follicle-stimulating hormone for 1 year at our institution. Two years later, the patient presented with bilateral palpable testicular tumors. His beta-human chorionic gonadotropin and lactate dehydrogenase levels were elevated. Pathologic examination disclosed a pure seminoma in each testis (pT1N0M0). Adjuvant radiotherapy was administered. The tumors might have been induced by follicle-stimulating hormone treatment. Careful follow-up examination of the testis is necessary in men who have received hormonal treatment for infertility.

Testicular cancer and occupational exposures with a focus on xenoestrogens in polyvinyl chloride plastics.

In a case-control study of 148 cases of testicular cancer and 314 healthy controls information was collected on lifetime working histories and specific exposures. The main finding was a six-fold increase in the risk for seminoma, one type of testicular cancer, among plastic workers exposed to polyvinyl chloride (PVC). No overrisks were observed for other plastics than PVC. There may be an aetiological link to xenoestrogens, i.e. chemicals in the environment with oestrogenic properties. Phthalates are used in PVC as plasticizer and have oestrogenic properties that could promote the growth of endocrine sensitive tumour cells. However, this "endocrine disruptors" hypothesis must be further evaluated in experimental models with regard to the causative mechanisms of the oestrogenic tumour promotion.

Seminoma in a 31-year-old patient on long-term growth hormone therapy.

We describe a Caucasian male patient aged 31, who was referred to the Institute of Reproductive Medicine because of infertility and androgen deficiency and in whom we incidentally diagnosed a unilateral testicular tumor. The patient had received growth hormone (GH) since the age of 8 years. One case presenting with testicular neoplasm under growth hormone substitution has been described previously. In conclusion, it cannot be ruled out that GH treatment may be involved in the pathogenesis of germ cell tumor development. Special care should be exercised when patients with a history of maldescended testes require GH substitution. This care should include regular testicular ultrasonography at e.g. half-yearly intervals since sonography may detect testicular tumors long before they become clinically apparent.

Occupational exposure to polyvinyl chloride as a risk factor for testicular cancer evaluated in a case-control study.

Occupational exposures were assessed in a case-control study on testicular cancer using self-administered questionnaires. In total, answers were obtained for 148 (91%) cases and 315 (87%) controls. Of the cases, 101 had seminoma and 47 had embryonal testicular cancer. An increased odds ratio (OR) was found for exposure to polyvinyl chloride (PVC) yielding an OR of 6.6 (95% confidence interval, 1.4-32). The risk increased further if cases with self-reported cryptorchidism or orchitis were excluded. Six of the 7 exposed cases had seminoma. Exposure to other types of plastics did not significantly increase the risk of testicular cancer.