Bagrodia, Aditya

Frazier, A Lindsay

Shioda, Toshihiro

Weiss, Robert S

eScholarship - University of California

UC San DiegoUC San Diego Previously Published WorksTitleComment on “Comment on ‘A Nested Case–Control Study of Serum Per- and Polyfluoroalkyl Substances and Testicular Germ Cell Tumors among U.S. Air Force Servicemen’”Permalinkhttps://escholarship.org/uc/item/6539c410JournalEnvironmental Health Perspectives, 131(12)ISSN1542-4359AuthorsShioda, ToshihiroWeiss, Robert SBagrodia, Adityaet al.Publication Date2023-12-01DOI10.1289/ehp14247Copyright InformationThis work is made available under the terms of a Creative Commons Attribution License, available at https://creativecommons.org/licenses/by/4.0/ Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaComment on “Comment on ‘A Nested Case–Control Study of Serum Per- andPolyfluoroalkyl Substances and Testicular Germ Cell Tumors among U.S. Air ForceServicemen’”Toshihiro Shioda,1,2,3 Robert S. Weiss,1,4 Aditya Bagrodia,1,5 and A. Lindsay Frazier1,61Malignant Germ Cell International Consortium (MaGIC), Dana-Farber Cancer Institute, Boston, Massachusetts, USA2Massachusetts General Hospital Krantz Family Center for Cancer Research, Charlestown, Massachusetts, USA3Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA4Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA5Department of Urology, University of California San Diego Health, San Diego, California, USA6Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts, USAhttps://doi.org/10.1289/EHP14247Refers to https://doi.org/10.1289/EHP13708In their recently published letter to the editor,1 Olsen et al. com-mented on the epidemiological study by Purdue et al.2 and theaccompanying “Invited Perspective” by Steenland.3 The nestedcase–control study by Purdue et al. detected a positive associationbetween the incidence rate of testicular germ cell tumors (TGCTs)and serum concentration of perfluorooctane sulfonic acid (PFOS)in active-dutyU.S.Air Force servicemen. In their letter, Olsen et al.presented their animal experiment in which ∼ 41-d-old maleSprague-Dawley rats exposed to PFOS via diet for 104 wk did notshow an increased incidence rate of testicular interstitial celltumors, which are also known as Leydig cell tumors (LCTs).1,4However, the conclusion stated in their letter—namely, that theirdata “did not support a PFOS-related effect on testicular tumors inrats”1—warrants further clarification because the data presentedbyOlsen et al., which focus on LCTs, are only tangentially relevantto the study by Purdue et al., who focus on TGCTs.First, an LCT is not a TGCT. Although both are “testiculartumors,” their cell of origin is completely different. LCTs derivefrom somatic Leydig cells, whereas the vast majority ( > 95%) ofTGCTs are Type II germ cell tumors that originate from early-stage germline precursor cells—namely, primordial germ cells, orprospermatogonia.5 It is not at all clear whether the absence ofLCTs has any bearing on risk of TGCT. Although overgrowthof dysfunctional Leydig cells and increased TGCT risk is a sign oftesticular dysgenesis syndrome,6 the absence of an increase in LCTincidence rate after exposure of rats to PFOS has no appreciablerelevance to human TGCT risk. Spontaneous or genetically engi-neered rodent models of TGCTs have been established,7 butwhether such models are suitable for assessment of the environ-mentally related risk of humanTGCTs remains to be examined.Second, the adequacy of the use of Sprague-Dawley rats forassessments of environmental risk factors of human LCTs hasbeen repeatedly challenged based on differences in mechanismsof LCT carcinogenesis between rodents and humans as well asstrong strain-specific differences in the incidence rate of sponta-neous LCTs (e.g., age F344 male rats show an LCT incidencerate of > 80%8).9–11Taken together, the comment by Olsen et al. needs to be inter-preted cautiously, because the absence of an increase in LCTincidence rate in rats after exposure to PFOS has only tangentialrelevance to human TGCT risk.References1. Olsen GW, Chang S, Taiwo OA. 2023. Comment on “a nested case-control studyof serum per- and polyfluoroalkyl substances and testicular germ cell tumorsamong U.S. Air Force servicemen. Environ Health Perspect 131(9):98001, PMID:37751326, https://doi.org/10.1289/EHP13708.2. Purdue MP, Rhee J, Denic-Roberts H, McGlynn KA, Byrne C, Sampson J, et al.2023. A nested case-control study of serum per- and polyfluoroalkyl substancesand testicular germ cell tumors among U.S. Air Force servicemen. EnvironHealth Perspect 131(7):77007, PMID: 37458713, https://doi.org/10.1289/EHP12603.3. Steenland K. 2023. Invited perspective: the slow road to finding out whether the“forever” chemicals cause chronic disease. Environ Health Perspect 131(7):71305,PMID: 37458711, https://doi.org/10.1289/EHP13212.4. Thomford PJ. 2002. Final Report: 104-Week Dietary Chronic Toxicity andCarcinogenicity with Perfluorooctanesulfonic Acid Potassium Salt (PFOS;T-6295)in Rats. 6329-183. Madison, WI: Covance Laboratories, Inc.5. Oosterhuis JW, Looijenga LHJ. 2019. Human germ cell tumours from a develop-mental perspective. Nat Rev Cancer 19(9):522–537, PMID: 31413324, https://doi.org/10.1038/s41568-019-0178-9.6. van den Driesche S, Kilcoyne KR, Wagner I, Rebourcet D, Boyle A, Mitchell R,et al. 2017. Experimentally induced testicular dysgenesis syndrome originatesin the masculinization programming window. JCI Insight 2(6):e91204, PMID:28352662, https://doi.org/10.1172/jci.insight.91204.7. Pierpont TM, Lyndaker AM, Anderson CM, Jin Q, Moore ES, Roden JL, et al.2017. Chemotherapy-induced depletion of OCT4-positive cancer stem cells in amouse model of malignant testicular cancer. Cell Rep 21(7):1896–1909, PMID:29141221, https://doi.org/10.1016/j.celrep.2017.10.078.8. Weber K. 2017. Differences in types and incidence of neoplasms inWistar Han andSprague-Dawley rats. Toxicol Pathol 45(1):64–75, PMID: 28068893, https://doi.org/10.1177/0192623316672075.9. Cook JC, Klinefelter GR, Hardisty JF, Sharpe RM, Foster PM. 1999. RodentLeydig cell tumorigenesis: a review of the physiology, pathology, mechanisms,and relevance to humans. Crit Rev Toxicol 29(2):169–261, PMID: 10213111,https://doi.org/10.1080/10408449991349203.10. Steinbach TJ, Maronpot RR, Hardisty JF. 2015. Human relevance of rodentLeydig cell tumors. In: Hamilton & Hardy’s Industrial Toxicology. Harbison RD,Bourgeois MM, Johnson GT, eds. Hoboken, NJ: Wiley & Sons, Inc.11. Davis TE. 1995. Interstitial cell adenoma of the rat testis: why is it such a prob-lem in toxicology studies using Sprague-Dawley rats? Toxicol Pathol 23(1):83–86, PMID: 7770704, https://doi.org/10.1177/019262339502300110.Address correspondence to Toshihiro Shioda, Massachusetts General HospitalKrantz Family Center for Cancer Research, Building 149 – Room 7.222, 13thStreet, Charlestown, MA 02129 USA. Email: tshioda@mgh.harvard.eduThe authors declare they have no conflicts of interest related to this work todisclose.Note to readers with disabilities: EHP strives to ensure that all journalcontent is accessible to all readers. However, some figures and SupplementalMaterial published in EHP articles may not conform to 508 standards due tothe complexity of the information being presented. If you need assistanceaccessing journal content, please contact ehpsubmissions@niehs.nih.gov. Ourstaff will work with you to assess and meet your accessibility needs within 3working days.Environmental Health Perspectives 128001-1 131(12) December 2023A Section 508–conformant HTML version of this articleis available at https://doi.org/10.1289/EHP14247.Letter to the Editor

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Comment on “Comment on ‘A Nested Case–Control Study of Serum Per- and Polyfluoroalkyl Substances and Testicular Germ Cell Tumors among U.S. Air Force Servicemen’”

Comment on “Comment on ‘A Nested Case–Control Study of Serum Per- and Polyfluoroalkyl Substances and Testicular Germ Cell Tumors among U.S. Air Force Servicemen’”

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