title: Induction and persistence of abnormal testicular germ cells following gestational exposure to di-(n-butyl) phthalate in p53-null mice.
abstract: Phthalate esters are commonly used plasticizers found in many household  items, personal care products, and medical devices. Animal studies have shown  that in utero exposure to di-(n-butyl) phthalate (DBP) within a  critical window during gestation causes male reproductive tract abnormalities  resembling testicular dysgenesis syndrome. Our studies utilized p53-deficient  mice for their ability to display greater resistance to apoptosis during  development. This model was chosen to determine whether multinucleated germ  cells (MNG) induced by gestational DBP exposure could survive postnatally and  evolve into testicular germ cell cancer. Pregnant dams were exposed to DBP  (500 mg/kg/day) by oral gavage from gestational day 12 until birth. Perinatal  effects were assessed on gestational day 19 and postnatal days 1, 4, 7, and 10  for the number of MNGs present in control and DBP-treated p53-heterozygous and  null animals. As expected, DBP exposure induced MNGs, with greater numbers  found in p53-null mice. Additionally, there was a time-dependent decrease in  the incidence of MNGs during the early postnatal period. Histologic  examination of adult mice exposed in utero to DBP revealed persistence of  abnormal germ cells only in DBP-treated p53-null mice, not in p53-heterozygous  or wild-type mice. Immunohistochemical staining of perinatal MNGs and adult  abnormal germ cells was negative for both octamer-binding protein 3/4 and  placental alkaline phosphatase. This unique model identified a role for p53 in  the perinatal apoptosis of DBP-induced MNGs and provided insight into the  long-term effects of gestational DBP exposure within a p53-null  environment.
authors.affiliation: Department of Pathology and Laboratory Medicine and the Center for Statistical Sciences, Brown University, Providence, RI, USA.
authors.forename: Camelia M
authors.initials: CM
authors.lastname: Saffarini
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Heger
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hall
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003993:Dibutyl Phthalate / Q000633:toxicity*; D005260:Female; D058851:GPI-Linked Proteins / Q000032:analysis; D006059:Gonadal Dysgenesis / Q000139:chemically induced / Q000473:pathology; D007527:Isoenzymes / Q000032:analysis; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D050814:Octamer Transcription Factor-3 / Q000032:analysis; D010968:Plasticizers / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013094:Spermatozoa / Q000187:drug effects* / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D058851:GPI-Linked Proteins; D007527:Isoenzymes; D050814:Octamer Transcription Factor-3; D010968:Plasticizers; D016159:Tumor Suppressor Protein p53; D003993:Dibutyl Phthalate; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental