Gestational and Lactational Exposure to Potassium Perfluorooctanesulfonate (K+PFOS) in Rats: Toxicokinetics, Thyroid Hormone Status, and Related Gene Expression

Abstract

Perfluorooctanesulfonate (PFOS), a persistent and accumulative compound, is widely distributed in humans and wildlife. Human exposure can occur early in development, as evidenced by the detection of PFOS in umbilical cord blood and breast milk. As part of a developmental neurotoxicology study for which developmental endpoints, including those related to the developing nervous system, have been reported separately, groups of 25 pregnant Sprague Dawley rats were given daily oral doses of either vehicle control or potassium PFOS (K(+)PFOS) at 0.1, 0.3, and 1.0mg/kg-d from gestation day (GD) 0 (day positive for mating) through postnatal day (PND) 20. An additional 10 pregnant females per treatment group were treated through GD 19 and sacrificed on GD 20 in order to obtain maternal and fetal serum and tissue samples at the end of gestation. The present paper reports the results of samples of serum, liver, brain, and thyroid glands taken at various times to evaluate: (1) serum, liver, and brain PFOS concentrations by LC-MS/MS to establish the relationship between PFOS concentrations and study outcomes; (2) serum thyrotropin (TSH) concentrations by RIA; (3) thyroid follicular cell proliferation index by Ki-67 immunohistochemical staining; (4) thyroid follicle epithelial cell height and colloidal area by histomorphometric analysis; (5) selected liver mRNA transcripts by quantitative RT-PCR. PFOS concentrations in dam and pup serum, liver, and brain increased across treatment groups in approximate proportion to the proportional increases in maternal K(+)PFOS dose, and sex differences in PFOS concentrations were not apparent in pups on PND 21. In pups from K(+)PFOS maternal dose groups on PND 72, serum PFOS had decreased to about 3 and 11% of PND 21 concentrations in males and females, respectively, and liver PFOS had decreased to about 17% of PND 21 concentrations in both sexes. Liver PFOS concentrations were approximately 0.6-0.8 times serum PFOS in GD 20 fetuses, and increased to about 2-4 times serum concentrations on PND 4 and 21. GD 20 fetal and PND 4 pup brain PFOS concentrations were approximately 33% of the corresponding serum concentrations, dropping to approximately 10% by PND 21, in contrast to dam brain PFOS concentrations, which were approximately 4-9% of serum PFOS concentrations. Compared to controls, Cyp2b2 mRNA was increased (2.8-fold) in the 1.0mg/kg-d treatment-group dams on GD 20. In male pups on PND 21, Cyp4A1, ACoA, and Cyp2b2 were increased 2.1-, 1.5-, and 1.8-fold, respectively, and Cyp7A1 was decreased 3.5-fold. Serum TSH and thyroid follicular morphology were not altered by K(+)PFOS treatment. The mean number of proliferating thyroid follicular cells was increased 2.1-fold over control in GD 20 female fetuses from 1.0mg/kg-d-treated dams, yet the highest individual count was similar to that of controls (116 versus 113 in controls).