title: Chemotherapy-induced late transgenerational effects in mice.
abstract: To our knowledge, there is no report on long-term reproductive and developmental side effects in the offspring of mothers treated with a widely used chemotherapeutic drug such as doxorubicin (DXR), and neither is there information on transmission of any detrimental effects to several filial generations. Therefore, the purpose of the present paper was to examine the long-term effects of a single intraperitoneal injection of DXR on the reproductive and behavioral performance of adult female mice and their progeny. C57BL/6 female mice (generation zero; G0) were treated with either a single intraperitoneal injection of DXR (G0-DXR) or saline (G0-CON). Data were collected on multiple reproductive parameters and behavioral analysis for anxiety, despair and depression. In addition, the reproductive capacity and health of the subsequent six generations were evaluated. G0-DXR females developed despair-like behaviors; delivery complications; decreased primordial follicle pool; and early lost of reproductive capacity. Surprisingly, the DXR-induced effects in oocytes were transmitted transgenerationally; the most striking effects being observed in G4 and G6, constituting: increased rates of neonatal death; physical malformations; chromosomal abnormalities (particularly deletions on chromosome 10); and death of mothers due to delivery complications. None of these effects were seen in control females of the same generations. Long-term effects of DXR in female mice and their offspring can be attributed to genetic alterations or cell-killing events in oocytes or, presumably, to toxicosis in non-ovarian tissues. Results from the rodent model emphasize the need for retrospective and long-term prospective studies of survivors of cancer treatment and their offspring.
authors: Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
authors: Loro L
authors: LL
authors: Kujjo
authors: Eun A
authors: EA
authors: Chang
authors: Ricardo J G
authors: RJ
authors: Pereira
authors: Shilpa
authors: S
authors: Dhar
authors: Brenda
authors: B
authors: Marrero-Rosado
authors: Satyaki
authors: S
authors: Sengupta
authors: Hongbing
authors: H
authors: Wang
authors: Jose B
authors: JB
authors: Cibelli
authors: Gloria I
authors: GI
authors: Perez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy; D001284:Atrophy; D001522:Behavior, Animal / Q000187:drug effects; D002872:Chromosome Deletion; D033481:Chromosomes, Mammalian / Q000235:genetics; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D040941:Heredity / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009215:Myometrium / Q000187:drug effects / Q000473:pathology; D009865:Oocytes / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000473:pathology / Q000637:transplantation; D010060:Ovulation / Q000187:drug effects; D010641:Phenotype; D012098:Reproduction / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008246:Lysophospholipids; D051028:bcl-2-Associated X Protein; C060506:sphingosine 1-phosphate; D004317:Doxorubicin; D013110:Sphingosine