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Title: Concurrent determination of bisphenol A pharmacokinetics in maternal and fetal rhesus monkeys

Abstract

Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for food can liners. Worldwide biomonitoring studies consistently find a high prevalence of BPA conjugates in urine (> 90%) in amounts consistent with aggregate exposure at levels below 1 μg/kg bw/d. The current study used LC/MS/MS to measure concurrently the pharmacokinetics of aglycone (active) and conjugated (inactive) deuterated BPA (d6) in maternal and fetal rhesus monkey serum, amniotic fluid, and placenta following intravenous injection in the dam (100 μg/kg bw). Internal exposures of the fetus to aglycone d6-BPA (serum AUC) were attenuated by maternal, placental, and fetal Phase II metabolism to less than half that in the dam. Levels of aglycone and conjugated d6-BPA measured in whole placenta were consistent with a role in metabolic detoxification. The monotonic elimination of aglycone d6-BPA from the fetal compartment accompanied by persistent conjugate levels provides further evidence arguing against the hypothesis that BPA conjugates are selectively deconjugated by either the placenta or fetus. These results also provide benchmarks to guide the interpretation of human cord blood, amniotic fluid, and placenta sampling and measurement strategies as a basis for estimating fetal exposures to BPA. Thismore » study in a non-human primate model provides additional pharmacokinetic data for use in PBPK modeling of perinatal exposures to BPA from food contact, medical devices, and other environmental sources. - Highlights: ► Maternal, placental, and fetal Phase II metabolism attenuate fetal exposure to BPA. ► Serum AUC for aglycone BPA in fetal monkeys is less than half of that in the dam. ► BPA profiles in monkey fetus rule out selective deconjugation and accumulation. ► BPA levels in monkey placenta are similar to other metabolically active tissues. ► Some published human cord blood data for BPA are inconsistent with these measurements.« less

Authors:
 [1];  [2];  [1];  [3];  [2];  [2]
  1. Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States)
  2. Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States)
  3. U.S. Food and Drug Administration and Priority One Services Corp, Jefferson, AR 72079 (United States)
Publication Date:
OSTI Identifier:
22285238
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 267; Journal Issue: 1; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMNIOTIC FLUID; AUC; BLOOD; FETUSES; INTRAVENOUS INJECTION; MACACUS; MASS SPECTROSCOPY; METABOLISM; PLACENTA; PLASTICS; POLYCARBONATES; PYRAZOLINES; URINE

Citation Formats

Patterson, Tucker A., Twaddle, Nathan C., Roegge, Cindy S., Callicott, Ralph J., Fisher, Jeffrey W., and Doerge, Daniel R., E-mail: daniel.doerge@fda.hhs.gov. Concurrent determination of bisphenol A pharmacokinetics in maternal and fetal rhesus monkeys. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2012.12.006.
Patterson, Tucker A., Twaddle, Nathan C., Roegge, Cindy S., Callicott, Ralph J., Fisher, Jeffrey W., & Doerge, Daniel R., E-mail: daniel.doerge@fda.hhs.gov. Concurrent determination of bisphenol A pharmacokinetics in maternal and fetal rhesus monkeys. United States. doi:10.1016/J.TAAP.2012.12.006.
Patterson, Tucker A., Twaddle, Nathan C., Roegge, Cindy S., Callicott, Ralph J., Fisher, Jeffrey W., and Doerge, Daniel R., E-mail: daniel.doerge@fda.hhs.gov. 2013. "Concurrent determination of bisphenol A pharmacokinetics in maternal and fetal rhesus monkeys". United States. doi:10.1016/J.TAAP.2012.12.006.
@article{osti_22285238,
title = {Concurrent determination of bisphenol A pharmacokinetics in maternal and fetal rhesus monkeys},
author = {Patterson, Tucker A. and Twaddle, Nathan C. and Roegge, Cindy S. and Callicott, Ralph J. and Fisher, Jeffrey W. and Doerge, Daniel R., E-mail: daniel.doerge@fda.hhs.gov},
abstractNote = {Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for food can liners. Worldwide biomonitoring studies consistently find a high prevalence of BPA conjugates in urine (> 90%) in amounts consistent with aggregate exposure at levels below 1 μg/kg bw/d. The current study used LC/MS/MS to measure concurrently the pharmacokinetics of aglycone (active) and conjugated (inactive) deuterated BPA (d6) in maternal and fetal rhesus monkey serum, amniotic fluid, and placenta following intravenous injection in the dam (100 μg/kg bw). Internal exposures of the fetus to aglycone d6-BPA (serum AUC) were attenuated by maternal, placental, and fetal Phase II metabolism to less than half that in the dam. Levels of aglycone and conjugated d6-BPA measured in whole placenta were consistent with a role in metabolic detoxification. The monotonic elimination of aglycone d6-BPA from the fetal compartment accompanied by persistent conjugate levels provides further evidence arguing against the hypothesis that BPA conjugates are selectively deconjugated by either the placenta or fetus. These results also provide benchmarks to guide the interpretation of human cord blood, amniotic fluid, and placenta sampling and measurement strategies as a basis for estimating fetal exposures to BPA. This study in a non-human primate model provides additional pharmacokinetic data for use in PBPK modeling of perinatal exposures to BPA from food contact, medical devices, and other environmental sources. - Highlights: ► Maternal, placental, and fetal Phase II metabolism attenuate fetal exposure to BPA. ► Serum AUC for aglycone BPA in fetal monkeys is less than half of that in the dam. ► BPA profiles in monkey fetus rule out selective deconjugation and accumulation. ► BPA levels in monkey placenta are similar to other metabolically active tissues. ► Some published human cord blood data for BPA are inconsistent with these measurements.},
doi = {10.1016/J.TAAP.2012.12.006},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 267,
place = {United States},
year = 2013,
month = 2
}
  • Bisphenol A (BPA) is a high-production volume industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA in urine of > 90% of Americans aged 6-60 is controversial because of the potential for endocrine disruption, particularly during perinatal development, as suggested by in vitro, experimental animal, and epidemiological studies. The current study used LC/MS/MS to measure serum pharmacokinetics of aglycone (active) and conjugated (inactive) BPA in adult and neonatal rhesus monkeys by oral (PND 5, 35, 70) and intravenous injection (PND 77) routes using d6-BPA to avoid sample contamination. Themore » concentration-time profiles observed in adult monkeys following oral administration of 100 {mu}g/kg bw were remarkably similar to those previously reported in human volunteers given a similar dose; moreover, minimal pharmacokinetic differences were observed between neonatal and adult monkeys for the receptor-active aglycone form of BPA. Circulating concentrations of BPA aglycone were quite low following oral administration (< 1% of total), which reflects the redundancy of active UDP-glucuronosyl transferase isoforms in both gut and liver. No age-related changes were seen in internal exposure metrics for aglycone BPA in monkeys, a result clearly different from developing rats where significant inverse age-related changes, based on immaturity of Phase II metabolism and renal excretion, were recently reported. These observations imply that any toxicological effect observed in rats from early postnatal exposures to BPA could over-predict those possible in primates of the same age, based on significantly higher internal exposures and overall immaturity at birth.« less
  • One compensatory mechanism for marginal zinc intake may be through an enhanced absorption of zinc. Such a compensatory mechanism could be of value to the neonate, as poor zinc nutriture during early life has severe consequences on growth and development. We studied the uptake of zinc by 3-month-old infant rhesus monkeys born to dams fed control diets 100 micrograms of zinc per gram of diet or zinc-restricted diets (4 micrograms of zinc per gram of diet). Zinc uptake/retention was studied by feeding 3-month-old infant monkeys that had fasted an infant formula containing zinc 65 by gavage. Whole body radioactivity wasmore » counted immediately after intubation and on days 10 and 17 after intubation. Regardless of dietary group, 65-zinc retention was high, ranging from 33% to 71% of the dose fed to the monkeys. There were no significant differences between the two dietary groups in the percentage of zinc retention at days 10 and 17. Independent of the dietary group, there was no correlation between plasma zinc and zinc absorption. A positive correlation was found between weight gain and zinc retention in the marginal zinc infants, while a negative correlation between weight gain and zinc retention was observed in the control infants. These observations suggest that the mechanisms underlying growth may be different in infants born to dams fed control vs marginal zinc diets.« less
  • Female rats on the 13th to 19th day of gestation were given 300 r whole- body radiation and injected intravenously with Evan's blue. No transmission of serum albumin, which binds the dye from maternal to fetal circulation, could be detected in either irradiated or control animals. The results indicate that mice resemble rats and dogs rather than monkeys and rabbits with respect to mother-to- fetus transmission of serum albumin. (H.H.D.)