Gestational PFOA exposure of mice is associated with altered mammary gland development in dams and female offspring.

Perfluorooctanoic acid (PFOA), with diverse and widespread commercial and industrial applications, has been detected in human and wildlife sera. Previous mouse studies linked prenatal PFOA exposure to decreased neonatal body weights (BWs) and survival in a dose-dependent manner. To determine whether effects were linked to gestational time of exposure or to subsequent lactational changes, timed-pregnant CD-1 mice were orally dosed with 5 mg PFOA/kg on gestation days (GD) 1-17, 8-17, 12-17, or vehicle on GD 1-17. PFOA exposure had no effect on maternal weight gain or number of live pups born. Mean pup BWs on postnatal day (PND) 1 in all PFOA-exposed groups were significantly reduced and decrements persisted until weaning. Mammary glands from lactating dams and female pups on PND 10 and 20 were scored based on differentiation or developmental stages. A significant reduction in mammary differentiation among dams exposed GD 1-17 or 8-17 was evident on PND 10. On PND 20, delays in normal epithelial involution and alterations in milk protein gene expression were observed. All exposed female pups displayed stunted mammary epithelial branching and growth at PND 10 and 20. While control litters at PND 10 and 20 had average scores of 3.1 and 3.3, respectively, all treated litters had scores of 1.7 or less, with no progression of duct epithelial growth evident over time. BW was an insignificant covariate for these effects. These findings suggest that in addition to gestational exposure, abnormal lactational development of dams may play a role in early growth retardation of developmentally exposed offspring.

[1]  A. Calafat,et al.  Developmental toxicity of perfluorooctanoic acid in the CD-1 mouse after cross-foster and restricted gestational exposures. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[2]  J. Giesy,et al.  Peer Reviewed: Perfluorochemical Surfactants in the Environment , 2002 .

[3]  E. K. Maloney,et al.  trans-Activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals. , 1999, Toxicology and applied pharmacology.

[4]  Jeffrey H Mandel,et al.  Perfluorooctanesulfonate and other fluorochemicals in the serum of American Red Cross adult blood donors. , 2003, Environmental health perspectives.

[5]  Toxicologist,et al.  Evaluating Human Health Risks from Exposure to Perfluorooctanoic Acid (PFOA): Recommendations to the Science Advisory Board's PFOA Review Panel , 2005 .

[6]  S. Fenton,et al.  Adverse effects of prenatal exposure to atrazine during a critical period of mammary gland growth. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[7]  Geary W Olsen,et al.  Comparison of human whole blood, plasma, and serum matrices for the determination of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and other fluorochemicals. , 2007, Environmental research.

[8]  D. Noonan,et al.  Mechanisms of peroxisome proliferation by perfluorooctanoic acid and endogenous fatty acids. , 1998, General pharmacology.

[9]  M. Morandi,et al.  Exposure Assessment in the National Children’s Study: Introduction , 2005, Environmental health perspectives.

[10]  T. Pineau,et al.  Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators , 1995, Molecular and cellular biology.

[11]  B. Trock,et al.  Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland , 2003, Nature Medicine.

[12]  M E Andersen,et al.  The acute toxicity of perfluorooctanoic and perfluorodecanoic acids in male rats and effects on tissue fatty acids. , 1983, Toxicology and applied pharmacology.

[13]  A. Calafat,et al.  Measurement of 18 perfluorinated organic acids and amides in human serum using on-line solid-phase extraction. , 2005, Analytical chemistry.

[14]  C. Lau,et al.  Effects of perfluorooctanoic acid exposure during pregnancy in the mouse. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[15]  C. Wood,et al.  Exposure parameters necessary for delayed puberty and mammary gland development in Long-Evans rats exposed in utero to atrazine. , 2004, Toxicology and applied pharmacology.

[16]  M Tanaka,et al.  The induction of peroxisome proliferation in rat liver by perfluorinated fatty acids, metabolically inert derivatives of fatty acids. , 1985, Journal of biochemistry.

[17]  F. Gonzalez,et al.  Peroxisome proliferator-activated receptor alpha activation during pregnancy severely impairs mammary lobuloalveolar development in mice. , 2006, Endocrinology.

[18]  M. Shani,et al.  Developmental regulation of the ovine β-lactoglobulin/human serum albumin transgene is distinct from that of the β-lactoglobulin and the endogenous β-casein genes in the mammary gland of transgenic mice , 1995 .

[19]  L. Shaw,et al.  Community Exposure to Perfluorooctanoate: Relationships Between Serum Concentrations and Exposure Sources , 2006, Journal of occupational and environmental medicine.

[20]  M S Christian,et al.  Rat and rabbit oral developmental toxicology studies with two perfluorinated compounds. , 2001, International journal of toxicology.

[21]  L. Birnbaum,et al.  Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[22]  Jeffrey H Mandel,et al.  Human donor liver and serum concentrations of perfluorooctanesulfonate and other perfluorochemicals. , 2003, Environmental science & technology.

[23]  K. Hansen,et al.  Compound-specific, quantitative characterization of organic fluorochemicals in biological matrices. , 2001, Environmental science & technology.

[24]  H. Özkaynak,et al.  Exposure Assessment Implications for the Design and Implementation of the National Children’s Study , 2005, Environmental health perspectives.

[25]  N. Kudo,et al.  Sex hormone-regulated renal transport of perfluorooctanoic acid. , 2002, Chemico-biological interactions.

[26]  J. Lakshmanan,et al.  Epidermal Growth Factor in Mouse Milk during Early Lactation: Lack of Dependency on Submandibular Glands , 1985, Pediatric Research.

[27]  W P Tate,et al.  Transferrin-gene expression in the rat mammary gland. Independence of maternal iron status. , 1990, The Biochemical journal.

[28]  Ian T Cousins,et al.  Sources, fate and transport of perfluorocarboxylates. , 2006, Environmental science & technology.

[29]  C. Sonnenschein,et al.  In Utero Exposure to Bisphenol A Alters the Development and Tissue Organization of the Mouse Mammary Gland1 , 2001, Biology of reproduction.

[30]  T. Oka,et al.  Growth control and differentiation in mammary epithelial cells. , 1989, Environmental health perspectives.

[31]  J. Giesy,et al.  Perfluorochemical surfactants in the environment. , 2002, Environmental science & technology.

[32]  David J. Waxman,et al.  trans-activation of PPARα and PPARγ by structurally diverse environmental chemicals , 1999 .

[33]  K. Helzlsouer,et al.  Historical Comparison of Perfluorooctanesulfonate, Perfluorooctanoate, and Other Fluorochemicals in Human Blood , 2005, Environmental health perspectives.