Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice

<div><p>Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. <i>In utero</i> exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼70% of control and induced atrophic seminiferous tubules in ∼30% of the testes. When the <i>in utero</i> CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents <i>in utero</i> may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.</p></div

Use of ovary culture techniques in reproductive toxicology

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved. Acknowledgements The author's studies in this field are supported by MRC grants G1002118 (NS and RAA) and G110357 (RAA), MR/L010011/1 (PAF), the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 212885 (PAF) and the Wellcome Trust (080388 to PAF). AS was funded by a BBSRC CASE Studentship co-funded by AstraZeneca.Peer reviewedPublisher PD

Association of processed red meat and prostate cancer stage in Mexican-Americans: A population based case-control study

Objective: The objective of this study is to investigate the association between processed and unprocessed red meat consumption and prostate cancer (PCa) stage in a homogenous Mexican-American population. Methods: This population-based case-control study had a total of 582 participants (287 cases with histologically confirmed adenocarcinoma of the prostate gland and 295 age and ethnicity-matched controls) that were all residing in the Southeast region of Texas from 1998 to 2006. All questionnaire information was collected using a validated data collection instrument. Statistical Analysis: Descriptive analyses included Student\u27s t-test and Pearson\u27s Chi-square tests. Odds ratios and 95% confidence intervals were calculated to quantify the association between nutritional factors and PCa stage. A multivariable model was used for unconditional logistic regression. Results: After adjusting for relevant covariates, those who consume high amounts of processed red meat have a non-significant increased odds of being diagnosed with localized PCa (OR = 1.60 95% CI: 0.85 - 3.03) and total PCa (OR = 1.43 95% CI: 0.81 - 2.52) but not for advanced PCa (OR = 0.91 95% CI: 1.37 - 2.23). Interestingly, high consumption of carbohydrates shows a significant reduction in the odds of being diagnosed with total PCa and advanced PCa (OR = 0.43 95% CI: 0.24 - 0.77; OR = 0.27 95% CI: 0.10 - 0.71, respectively). However, consuming high amounts of energy from protein and fat was shown to increase the odds of being diagnosed with advanced PCa (OR = 4.62 95% CI: 1.69 - 12.59; OR = 2.61 95% CI: 1.04 - 6.58, respectively). Conclusion: Mexican-Americans who consume high amounts of energy from protein and fat had increased odds of being diagnosed with advanced PCa, while high amounts of carbohydrates reduced the odds of being diagnosed with total and advanced PCa

The hallmarks of COVID-19 disease

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that has caused a worldwide pandemic of the human respiratory illness COVID-19, resulting in a severe threat to public health and safety. Analysis of the genetic tree suggests that SARS-CoV-2 belongs to the same Betacoronavirus group as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Although the route for viral transmission remains a mystery, SARS-CoV-2 may have originated in an animal reservoir, likely that of bat. The clinical features of COVID-19, such as fever, cough, shortness of breath, and fatigue, are similar to those of many acute respiratory infections. There is currently no specific treatment for COVID-19, but antiviral therapy combined with supportive care is the main strategy. Here, we summarize recent progress in understanding the epidemiological, virological, and clinical characteristics of COVID-19 and discuss potential targets with existing drugs for the treatment of this emerging zoonotic disease

Fetal Radiation Exposure Induces Testicular Cancer in Genetically Susceptible Mice

The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC) into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES), an antiandrogen (flutamide), or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1) congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45 % to 100 % in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5–6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, i

Testicular germ cell tumor (TGCT) incidence and related characterization in 129.MOLF-L1 congenic mice with or without <i>in utero</i> flutamide, DES, or radiation treatment.

a<p>Mean ± SEM.</p>b<p>Values given as absolute number and percentage of mice, testes, or tumors analyzed.</p>c<p>Since the incidence of tumors in the DES-treated mice was not increased from historical controls or the concurrent flutamide controls, we did not complete this arm of the study, and cannot rigorously conclude that there is no increase in tumor incidence in DES-treated mice compared to a sham-treated control group.</p>d<p>Two cryptorchid testes (weights, 19 and 34 mg) were excluded from this average.</p>e<p>Significantly different between treated and control mice, Fisher's exact Chi square test: <i>P</i><0.01. Other differences were not significant (<i>P</i>≥0.05).</p>f<p>Significantly different between treated and control mice, <i>t</i> test: <i>P</i><0.01. Other differences were not significant (<i>P</i>≥0.05).</p

Breeding efficiency in 129.MOLF-L1 congenic mice with or without <i>in utero</i> flutamide, DES, or radiation treatment.

a<p>Values given as absolute number and percentage of total plug-positive females.</p>b<p>Mean ± SEM.</p

Morphology and histology of the testes in 4-week-old 129.MOLF-L1 male mice irradiated <i>in utero</i> with two doses of 0.8 Gy and controls.

<p>Testicular morphology showing bilateral (<b>A</b>) and unilateral (<b>B</b>) TGCTs from irradiated mice. Note that the testis without TGCT after <i>in utero</i> radiation exposure (B) is smaller than the normal untreated testis from a 4-week-old mouse (insert in B). Testis sections showing teratoma containing tissues apparently from multiple dermal origins identified by morphology (<b>C</b>), and TGCT containing only neuroepithelial cells (NE) (<b>D</b>). CA: cartilage; BM: bone marrow; MS: muscle, EEP: endodermal epithelium. ST: seminiferous tubule; BV: blood vessel. Sections from testes of 4-week old irradiated (<b>E</b>) and contol (<b>F</b>) mice without TGCT showing qualitatively normal spermatogenesis. Bar: 0.5 cm in A & B, and 50 µm in C–F.</p

Increased testicular germ cell tumor incidence (TGCT) in 129 and L1 mice exposed <i>in utero</i> to cyclophosphamide (CP) or radiation.

a<p>Values given as absolute number and percentage of mice, testes, or tumors analyzed.</p>b<p>Data from 129S5 and 129S1/SvImJ mice were pooled.</p>c<p>Significantly different between treated and control mice (<i>P</i><0.05; Fisher's exact test).</p>d<p>Significantly different between CP-exposed and irradiated mice of the same strain (<i>P</i><0.05; Fisher's exact test).</p>e<p>The odd number is due to the presence of only one testis in one of the mice analyzed, which was not considered for bilateral TGCT analysis.</p>f<p>Significantly different between treated and control mice (<i>P</i><0.05; <i>t</i> test).</p>g<p>Data from a previous study <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093311#pone.0093311-Shetty1" target="_blank">[5]</a> were included for comparison.</p

Reduction of testis weights and sperm counts in 8-week-old 129S1/SvImJ mice exposed to cyclophosphamide (CP) <i>in utero</i>.

a<p>Significantly different between treated and control mice (<i>P</i><0.01; <i>t</i>-test).</p