Kinetics of selected di-n-butyl phthalate metabolites and fetal testosterone following repeated and single administration in pregnant rats.
Human exposure to phthalic acid diesters occurs through a variety of pathways as a result of their widespread use in consumer products and plastics. Repeated doses of di-n-butyl phthalate (DBP) from gestation day (GD) 12 to 19 disrupt testosterone synthesis and male sexual development in the fetal rat. Currently little is known about the disposition of DBP metabolites, such as monobutyl phthalate (MBP) and its glucuronide conjugate (MBP-G), during gestation after repeated exposure to DBP. In order to gain a better understanding of the effect of repeated dosing on maternal and fetal metabolism and distribution, pregnant Sprague-Dawley rats were given a single dose of 500 mg/kg DBP on GD 19 or daily doses of 50, 100, and 500 mg/(kg day) from GD 12 to 19 via corn oil gavage. Dose-response evaluation revealed a non-linear increase in maternal and fetal plasma concentrations of MBP. Maternal and fetal MBP levels were slightly lower in animals after 8 days of dosing at 500 mg/(kg day). Fetal plasma MBP levels closely followed maternal plasma, while the appearance and elimination of MBP-G in fetal plasma were significantly delayed. MBP-G accumulated over time in the amniotic fluid. Inhibition of testosterone was rapid in fetal testes when exposed to DBP (500 mg/(kg day)) on GD 19. Within 24h, the level of inhibition in the fetus was similar between animals exposed to a single or multiple daily doses of 500 mg/(kg day). Examination of testosterone time-course data indicates a rapid recovery to normal levels within 24h post-dosing at DBP doses of 50 and 100 mg/(kg day), with a rebound to higher than normal concentrations at later time-points. MBP kinetics in fetal testes allows direct comparison of active metabolite concentrations and testosterone response in the fetal testes.
Clewell
Rebecca A
RA
The University of North Carolina, Chapell Hill, NC 27599, USA. rclewell@thehamner.org
Kremer
John J
JJ
Williams
Carla C
CC
Campbell
Jerry L
JL
Sochaski
Mark A
MA
Andersen
Melvin E
ME
Borghoff
Susan J
SJ
D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D015415:Biomarkers; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D003993:Dibutyl Phthalate / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D007202:Indicators and Reagents; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D010795:Phthalic Acids / Q000493:pharmacokinetics; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011786:Quality Control; D011804:Quinolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism*
D015415:Biomarkers; D007202:Indicators and Reagents; D010795:Phthalic Acids; D011804:Quinolines; D003993:Dibutyl Phthalate; D013739:Testosterone; C047117:bicinchoninic acid; C028577:monobutyl phthalate