Effects of in utero exposure to DI(n-Butyl) phthalate on development of male reproductive tracts in Sprague-Dawley rats.
The purpose of this study was to determine the effects of di(n-butyl) phthalate (DBP) administration on male reproductive organ development in F1 Sprague-Dawley rats following in utero exposure. During gestation days (GD) 10-19, pregnant rats were administered daily, orally, DBP at 250, 500, or 700 mg/kg or flutamide (1, 12.5, or 25 mg/kg/d) as a positive control. The male offspring were sacrificed at 31 d of age. DBP and flutamide dose-dependently significantly increased the incidence of hypospadias and cryptorchidism in F1 male offspring. The weights of testes and accessory sex organs (epididymides, seminal vesicles, ventral prostate, levator ani plus bulbocavernosus muscles (LABC), and Cowper's glands) were significantly reduced in DBP-treated animals. Furthermore, cauda agenesis of epididymides and ventral prostate atrophy were observed in high-dose 700-mg/kg DBP males. Anogenital distance (AGD) and levels of dihydrotestosterone (DHT) and testosterone were significantly decreased in the DBP (700 mg/kg/d)-treated groups. In particular, the expression of androgen receptor (AR) and 5α-reductase type 2 in the proximal penis was markedly depressed following administration of DBP (700 mg/kg/d) or flutamide (25 mg/kg/d). The expression of sonic hedgehog (Shh) in the urethral epithelium of the proximal penis was significantly less in the DBP (700 mg/kg/d)- or flutamide (25 mg/kg/d)-treated groups. In addition, DBP dose-dependently significantly increased the expression of estrogen receptor (ER α) in the undescended testis. Data demonstrated that in utero exposure to DBP produced several abnormal responses in male reproductive organs, and these effects may be due to disruption of the stage-specific expression of genes related to androgen-dependent organs development.
Health Effects Analysis Team, National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration, Seoul, South Korea.
Tae Sung
TS
Kim
Ki Kyung
KK
Jung
Soon Sun
SS
Kim
Il Hyun
IH
Kang
Jung Hee
JH
Baek
Hye-Seon
HS
Nam
Soon-Keun
SK
Hong
Byung Mu
BM
Lee
Jin Tae
JT
Hong
Ki Wan
KW
Oh
Hyung Sik
HS
Kim
Soon Young
SY
Han
Tae Seok
TS
Kang
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism; D001003:Anal Canal / Q000002:abnormalities / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003456:Cryptorchidism / Q000139:chemically induced / Q000473:pathology; D003993:Dibutyl Phthalate / Q000633:toxicity*; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D005485:Flutamide / Q000633:toxicity; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005837:Genitalia, Male / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D007021:Hypospadias / Q000139:chemically induced / Q000473:pathology; D008297:Male; D018811:Maternal Exposure; D009558:Nipples / Q000002:abnormalities / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010968:Plasticizers / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D053823:Hedgehog Proteins; D010968:Plasticizers; D012333:RNA, Messenger; D011944:Receptors, Androgen; C546888:Shh protein, rat; D003993:Dibutyl Phthalate; D005485:Flutamide; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase