title: Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.
abstract: 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. In utero 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 in utero 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 in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Comish
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Ana Luiza
authors.initials: AL
authors.lastname: Drumond
authors.affiliation: MRC Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Hazel L
authors.initials: HL
authors.lastname: Kinnell
authors.affiliation: MRC Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Angabin
authors.initials: A
authors.lastname: Matin
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Meistrich
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Gunapala
authors.initials: G
authors.lastname: Shetty
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D003520:Cyclophosphamide / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D006080:Ovarian Follicle / Q000187:drug effects* / Q000528:radiation effects; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013076:Sperm Count; D013091:Spermatogenesis / Q000187:drug effects* / Q000528:radiation effects; D013736:Testicular Neoplasms / Q000209:etiology*; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide