PMID- 11099647
OWN - NLM
STAT- MEDLINE
DCOM- 20010104
LR  - 20220409
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 58
IP  - 2
DP  - 2000 Dec
TI  - Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or 
      DOTP, alters sexual differentiation of the male rat.
PG  - 350-65
AB  - In mammals, exposure to antiandrogenic chemicals during sexual differentiation 
      can produce malformations of the reproductive tract. Perinatal administration of 
      AR antagonists like vinclozolin and procymidone or chemicals like 
      di(2-ethylhexyl) phthalate (DEHP) that inhibit fetal testicular testosterone 
      production demasculinize the males such that they display reduced anogenital 
      distance (AGD), retained nipples, cleft phallus with hypospadias, undescended 
      testes, a vaginal pouch, epididymal agenesis, and small to absent sex accessory 
      glands as adults. In addition to DEHP, di-n-butyl (DBP) also has been shown to 
      display antiandrogenic activity and induce malformations in male rats. In the 
      current investigation, we examined several phthalate esters to determine if they 
      altered sexual differentiation in an antiandrogenic manner. We hypothesized that 
      the phthalate esters that altered testis function in the pubertal male rat would 
      also alter testis function in the fetal male and produce malformations of 
      androgen-dependent tissues. In this regard, we expected that benzyl butyl (BBP) 
      and diethylhexyl (DEHP) phthalate would alter sexual differentiation, while 
      dioctyl tere- (DOTP or DEHT), diethyl (DEP), and dimethyl (DMP) phthalate would 
      not. We expected that the phthalate mixture diisononyl phthalate (DINP) would be 
      weakly active due to the presence of some phthalates with a 6-7 ester group. 
      DEHP, BBP, DINP, DEP, DMP, or DOTP were administered orally to the dam at 0.75 
      g/kg from gestational day (GD) 14 to postnatal day (PND) 3. None of the 
      treatments induced overt maternal toxicity or reduced litter sizes. While only 
      DEHP treatment reduced maternal weight gain during the entire dosing period by 
      about 15 g, both DEHP and DINP reduced pregnancy weight gain to GD 21 by 24 g and 
      14 g, respectively. DEHP and BBP treatments reduced pup weight at birth (15%). 
      Male (but not female) pups from the DEHP and BBP groups displayed shortened AGDs 
      (about 30%) and reduced testis weights (about 35%). As infants, males in the 
      DEHP, BBP, and DINP groups displayed femalelike areolas/nipples (87, 70, and 22% 
      (p < 0.01), respectively, versus 0% in other groups). All three of the phthalate 
      treatments that induced areolas also induced a significant incidence of 
      reproductive malformations. The percentages of males with malformations were 82% 
      (p < 0.0001) for DEHP, 84% (p < 0.0001) for BBP, and 7.7% (p < 0.04) in the DINP 
      group. In summary, DEHP, BBP, and DINP all altered sexual differentiation, 
      whereas DOTP, DEP, and DMP were ineffective at this dose. Whereas DEHP and BBP 
      were of equivalent potency, DINP was about an order of magnitude less active.
FAU - Gray, L E Jr
AU  - Gray LE Jr
AD  - Endocrinology Branch, MD 72, U.S. Environmental Protection Agency, National 
      Health and Environmental Effects Research Laboratory, Reproductive Toxicology 
      Division, Research Triangle Park, North Carolina 27711, USA. gray.earl@epa.gov
FAU - Ostby, J
AU  - Ostby J
FAU - Furr, J
AU  - Furr J
FAU - Price, M
AU  - Price M
FAU - Veeramachaneni, D N
AU  - Veeramachaneni DN
FAU - Parks, L
AU  - Parks L
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Androgen Antagonists)
RN  - 0 (Phthalic Acids)
RN  - 08X7F5UDJM (dimethyl phthalate)
RN  - C42K0PH13C (Diethylhexyl Phthalate)
RN  - UF064M00AF (diethyl phthalate)
RN  - YPC4PJX59M (butylbenzyl phthalate)
SB  - IM
MH  - Abnormalities, Drug-Induced
MH  - Androgen Antagonists/toxicity
MH  - Animals
MH  - Diethylhexyl Phthalate/toxicity
MH  - Female
MH  - Fetus/*drug effects
MH  - Humans
MH  - Male
MH  - Phthalic Acids/*toxicity
MH  - Pregnancy
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sex Differentiation/*drug effects
MH  - Sexual Behavior, Animal/drug effects
MH  - Species Specificity
EDAT- 2000/12/02 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/12/02 11:00
PHST- 2000/12/02 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/12/02 11:00 [entrez]
AID - 10.1093/toxsci/58.2.350 [doi]
PST - ppublish
SO  - Toxicol Sci. 2000 Dec;58(2):350-65. doi: 10.1093/toxsci/58.2.350.