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ToxSci Advance Access published online on June 30, 2008
Toxicological Sciences, 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

T. S. McMullin*, E. R. Lowe*, M. J. Bartels* and M.S. Marty*

* The Dow Chemical Company, Midland, MI

Please send all correspondence to: Sue Marty, Ph.D., Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Building 1803, Midland, MI, USA 48674, e-mail: mmarty{at}dow.com, Phone: (989) 636-6653, Fax: (989) 638-9863

Received March 9, 2008; revision received May 16, 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 (LD) 0 (day of birth), 1, 3, 5, 10, 15 and 20 (n≥5/time point). Fewer time points were sampled in Wistar rats, which showed similar patterns to CDs. Relative to non-pregnant dams, maternal serum protein levels (albumin, total protein and globulin) each decreased by ~20% during late gestation, whereas maternal serum lipids (triglycerides, LDL, and phospholipids) increased up to 4-fold. 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 2-3-fold 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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