Reproductive toxicity and pharmacokinetics of di-n-butyl phthalate (DBP) following dietary exposure of pregnant rats

• Published in: Birth defects research. Part B. Developmental and reproductive toxicology Vol. 86; no. 4; pp. 345 - 354
• Main Authors: Struve, Melanie F., Gaido, Kevin W., Hensley, Janan B., Lehmann, Kim P., Ross, Susan M., Sochaski, Mark A., Willson, Gabrielle A., Dorman, David C.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-08-2009
• Subjects: Administration, Oral; Amniotic Fluid - chemistry; Androgen Antagonists - administration & dosage; Androgen Antagonists - pharmacokinetics; Androgen Antagonists - toxicity; Animals; anti-androgen; Biotransformation; Body Weight - drug effects; Dibutyl Phthalate - administration & dosage; Dibutyl Phthalate - pharmacokinetics; Dibutyl Phthalate - toxicity; Dose-Response Relationship, Drug; endocrine disruptor; Female; Gas Chromatography-Mass Spectrometry; Gene Expression Regulation, Developmental - drug effects; Genitalia, Male - drug effects; Genitalia, Male - embryology; Genitalia, Male - pathology; Gestational Age; Glucuronides - analysis; Glucuronides - blood; Glucuronides - pharmacokinetics; Glucuronides - urine; Male; phthalate; Phthalic Acids - analysis; Phthalic Acids - blood; Phthalic Acids - urine; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Scavenger Receptors, Class B - drug effects; Steroids - biosynthesis; Testis - drug effects; Testis - embryology; Testis - metabolism; Testis - pathology; Testosterone - biosynthesis
• ISSN: 1542-9733; 1542-9741
• DOI: 10.1002/bdrb.20199

Most rodent developmental toxicity studies of dibutylphthalate (DBP) have relied on bolus gavage dosing. This study characterized the developmental toxicity of dietary DBP. Pregnant CD rats were given nominal doses of 0, 100, or 500 mg DBP/kg/day in diet (actual intake 0, 112, and 582 mg/kg/day) from gestational day (GD) 12 through the morning of GD 19. Rats were killed 4 or 24 hr thereafter. DBP dietary exposure resulted in significant dose‐dependent reductions in testicular mRNA concentration of scavenger receptor class B, member 1; steroidogenic acute regulatory protein; cytochrome P450, family 11, subfamily a, polypeptide 1; and cytochrome P450 family 17, subfamily a, polypeptide 1. These effects were most pronounced 4 hr after the end of exposure. Testicular testosterone was reduced 24 hr post‐exposure in both DBP dose groups and 4 hr after termination of the 500‐mg DBP/kg/day exposure. Maternal exposure to 500 mg DBP/kg/day induced a significant reduction in male offspring's anogenital distance indicating in utero disruption of androgen function. Leydig cell aggregates, increased cord diameters, and multinucleated gonocytes were present in DBP‐treated rats. Monobutyl phthalate, the developmentally toxic metabolite of DBP, and its glucuronide conjugate were found in maternal and fetal plasma, amniotic fluid, and maternal urine. Our results, when compared to previously conducted gavage studies, indicate that approximately equal doses of oral DBP exposure of pregnant rats, from diet or gavage, result in similar responses in male offspring. Birth Defects Res (Part B), 86:345–354, 2009. © 2009 Wiley‐Liss, Inc.