Perinatal exposure to the phthalates DEHP, BBP, DINP, but not DEP, DMP or DOTP permanently alters androgen-dependent tissue development in Sprague-Dawley rats
Ostby, J; Price, M; Furr, J; Lambright, C; Hotchkiss, A; Parks, LG; Gray, LE, Jr
In previous studies, perinatal exposure to Di(n-butyl)phthalate (DBP) or bis(2-ethylhexyl)phthalate (DEHP) alters testicular, epididymal and accessory reproductive tissue development in rats (Gray et al, (1999) Toxicol Ind Health 15:94-118). Malformations observed in these studies include dihydrotestosterone (DHT)-dependent tissue alterations such as reduced anogenital distance at birth, hypospadias, permanent nipples and decreased prostate weights, and testosterone (T)-dependent tissue alterations such as testicular atrophy, epididymal agenesis, reduced seminal vesicle weights and undescended testes. Recent studies conducted in our laboratory have demonstrated that perinatal DEHP exposure lowers fetal testicular T synthesis, while androgen receptor binding was negative in in vitro studies for DBP, DEHP and their corresponding monoester metabolites at concentrations up to 10 and 20 uM for DBP and DEHP respectively. Testicular alterations have been reported in pubertal male rats exposed to phthalate esters with adjacent 4-6 carbon primary side chains (Foster et al, (1980) Toxicol Appl Pharmacol 54:392-398). Bis(2-ethylhexyl)phthalate (DEHP), benzyl butyl phthalate (BBP), and some diisononyl phthalate (DINP) isomers possess adjacent 4-6 carbon primary side chains, while diethyl phthalate (DEP), dimethyl phthalate (DMP) and dioctyl terephthalate (DOTP) do not. To examine the relative potency of these phthalates, timed-pregnant rats were gavaged daily with corn oil or with DEHP, BBP, DINP, DEP, DMP or DOTP (750 mg/kg-bw/2.5 mL vehicle) from gestational day 14 (sperm positive = GD1) through postnatal day 3. Males in the DEHP and BBP treatment groups displayed reduced anogenital distance at 2 days of age and males with areolas were observed in the DEHP, BBP and DINP dose groups at 13 days of age. Both of these DHT-dependent endpoints are predictive of the occurrence of more serious malformations after puberty. As anticipated, adult males exposed perinatally to DEP, DMP and DOTP were unaffected, while males in the DEHP (91%, P less than 0.0001), BBP (84%, P less than 0.0001) and DINP (7.7%, P less than 0.04) treatment groups displayed malformations of the testis, epididymis, accessory reproductive organs and external genitalia.
Pregnancy; Rats; Animal; Female; Sprague-Dawley; Phthalic Acids TOXICITY; Androgens PHYSIOLOGY; Abnormalities; Testis DRUG EFFECTS; Testis EMBRYOLOGY; Testis METABOLISM; Seminal Vesicles DRUG EFFECTS; Seminal Vesicles EMBRYOLOGY; Testosterone BIOSYNTHESIS; Prostate DRUG EFFECTS; Prostate EMBRYOLOGY; No cas rn; 57-85-2; 117-81-7; 85-68-7; 68515-48-0; 84-66-2; 131-11-3; 4654-26-6
