PMID- 12832361
OWN - NLM
STAT- MEDLINE
DCOM- 20040308
LR  - 20230411
IS  - 0268-1161 (Print)
IS  - 0268-1161 (Linking)
VI  - 18
IP  - 7
DP  - 2003 Jul
TI  - Human 'testicular dysgenesis syndrome': a possible model using in-utero exposure 
      of the rat to dibutyl phthalate.
PG  - 1383-94
AB  - BACKGROUND: The disorders comprising human 'testicular dysgenesis syndrome' (TDS) 
      may be increasing in incidence. TDS originates in fetal life but the mechanisms 
      are not known, and discerning them requires an animal model. METHODS AND RESULTS: 
      The study investigated whether male rats exposed in utero to dibutyl phthalate 
      [DBP; 500 mg/kg on gestational days (GD) 13-21] would provide a suitable model 
      for human TDS. DBP induced a high rate (>60%) of cryptorchidism (mainly 
      unilateral), hypospadias, infertility and testis abnormalities, similar to those 
      in human TDS. Cell-specific immunohistochemistry and confocal microscopy were 
      used to track development of Sertoli [anti-Mullerian hormone (AMH), Wilm's tumour 
      (WT-1) protein, p27(kip)], Leydig [3beta-hydroxysteroid dehydrogenase 
      (3beta-HSD)], germ (DAZL protein) and peritubular myoid (smooth muscle actin) 
      cells from fetal life to adulthood. In scrotal and cryptorchid testes of 
      DBP-exposed males, areas of focal dysgenesis were found that contained Sertoli 
      and Leydig cells, and gonocytes and partially formed testicular cords; these 
      dysgenetic areas were associated with Leydig cell hyperplasia at all ages. 
      Suppression ( approximately 90%) of testicular testosterone levels on GD 19 in 
      DBP-exposed males, coincident with delayed peritubular myoid cell 
      differentiation, may have contributed to the dysgenesis. Double 
      immunohistochemistry using WT-1 (expressed in all Sertoli cells) and p27(kip) 
      (expressed only in mature Sertoli cells) revealed immature Sertoli cells in 
      dysgenetic areas. DBP-exposed animals also exhibited Sertoli cell-only (SCO) 
      tubules, sporadically in scrotal and predominantly in cryptorchid, testes, or 
      foci of SCO within normal tubules in scrotal testes. In all SCO areas the Sertoli 
      cells were immature. Intratubular Leydig cells were evident in DBP-exposed 
      animals and, where these occurred, Sertoli cells were immature and 
      spermatogenesis was absent. Abnormal Sertoli cell-gonocyte interaction was 
      evident at GD 19 in DBP-exposed rats coincident with appearance of multinucleated 
      gonocytes, although these disappeared by postnatal day 10 during widespread loss 
      of germ cells. CONCLUSIONS: Abnormal development of Sertoli cells, leading to 
      abnormalities in other cell types, is our hypothesized explanation for the 
      abnormal changes in DBP-exposed animals. As the testicular and other changes in 
      DBP-exposed rats have all been reported in human TDS, DBP exposure in utero may 
      provide a useful model for defining the cellular pathways in TDS.
FAU - Fisher, Jane S
AU  - Fisher JS
AD  - MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The 
      Chancellor's Building, University of Edinburgh, 49 Little France Crescent, 
      Edinburgh EH16 4SB, UK.
FAU - Macpherson, S
AU  - Macpherson S
FAU - Marchetti, N
AU  - Marchetti N
FAU - Sharpe, Richard M
AU  - Sharpe RM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Reprod
JT  - Human reproduction (Oxford, England)
JID - 8701199
RN  - 2286E5R2KE (Dibutyl Phthalate)
RN  - 3XMK78S47O (Testosterone)
SB  - IM
MH  - Age Factors
MH  - Animals
MH  - Body Weight
MH  - *Dibutyl Phthalate
MH  - *Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Hyperplasia
MH  - Leydig Cells/pathology
MH  - Male
MH  - Organ Size
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects
MH  - Rats
MH  - *Rats, Wistar
MH  - Seminiferous Tubules/abnormalities/pathology
MH  - Sertoli Cells/pathology
MH  - Spermatozoa/pathology
MH  - Testicular Diseases/chemically induced/*pathology
MH  - Testis/*abnormalities/pathology
MH  - Testosterone/blood
EDAT- 2003/07/02 05:00
MHDA- 2004/03/09 05:00
CRDT- 2003/07/02 05:00
PHST- 2003/07/02 05:00 [pubmed]
PHST- 2004/03/09 05:00 [medline]
PHST- 2003/07/02 05:00 [entrez]
AID - 10.1093/humrep/deg273 [doi]
PST - ppublish
SO  - Hum Reprod. 2003 Jul;18(7):1383-94. doi: 10.1093/humrep/deg273.