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

• Published in: Toxicological sciences Vol. 105; no. 2; pp. 260 - 274
• Main Authors: McMullin, Tami S., Lowe, Ezra R., Bartels, Michael J., Marty, Mary Sue
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.10.2008
• Subjects: Amniotic Fluid - metabolism; Animals; Animals, Newborn; Female; Fetal Blood - metabolism; gestation; Gestational Age; Humans; Hydrogen-Ion Concentration; lactation; Lactation - metabolism; lipids; Lipids - blood; Male; Milk - metabolism; Models, Biological; perinatal; Pharmacokinetics; pregnancy; Protein Binding; proteins; Proteins - metabolism; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reproducibility of Results; Risk Assessment; Species Specificity; Time Factors; Toxicity Tests; lipids; perinatal; lactation; proteins; pregnancy; pharmacokinetics; gestation
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfn124

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.