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ToxSci Advance Access originally published online on June 30, 2008
Toxicological Sciences 2008 105(2):260-274; doi:10.1093/toxsci/kfn124
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Dynamic Changes in Lipids and Proteins of Maternal, Fetal, and Pup Blood and Milk during Perinatal Development in CD and Wistar Rats

Tami S. McMullin, Ezra R. Lowe, Michael J. Bartels and Mary Sue Marty1

The Dow Chemical Company, Midland, Michigan 48674

1 To whom correspondence should be addressed at Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Building 1803, Midland, MI 48674. Fax: (989) 638-9863. E-mail: mmarty{at}dow.com.

Received March 9, 2008; accepted May 26, 2008


  Abstract

An understanding of the physiological factors that regulate perinatal dosimetry is essential to improve the ability of physiologically based (PB) pharmacokinetic (PK) models to predict chemical risks to children. However, the impact of changing maternal/offspring physiology on PK during gestation and lactation remains poorly understood. This research determined lipid and protein changes in blood, milk and amniotic fluid of CD and Wistar dams, fetuses and neonates to improve the precision of perinatal PBPK modeling. Samples were collected from time-mated CD dams, fetuses, and pups on gestation day (GD) 18 and 20 (sperm positive = GD 0) or lactation day 0 (day of birth), 1, 3, 5, 10, 15, and 20 (n ≥ 5 per time point). Fewer time points were sampled in Wistar rats, which showed similar patterns to CDs. Relative to nonpregnant dams, maternal serum protein levels (albumin, total protein and globulin) each decreased by ~20% during late gestation, whereas maternal serum lipids (triglycerides, low density lipoproteins, and phospholipids) increased up to fourfold. These physiological changes can impact maternal PK of both protein-bound and lipophilic chemicals. During lactation, triglycerides in milk were greater than 100-fold higher than maternal serum, favoring the disposition of lipophilic chemicals into milk and potentially increasing neonatal rodent exposure during critical stages of postnatal development. Serum protein levels in pups were two- to threefold lower than adults at birth, which may increase the bioavailability of protein-bound compounds. These data will aid in the interpretation of perinatal toxicity studies and improve the accuracy of predictive perinatal PBPK models.

Key Words: pharmacokinetics; perinatal; gestation; lactation; lipids; proteins; pregnancy.


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