Examining the effects of gestational exposure to perfluorooctanoic acid on the developing and differentiating mammary gland, their consequences, and the possible modes of action by which they are mediated Public Deposited

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  • March 22, 2019
Creator
  • White, Sally S.
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Perfluorooctanoic acid (PFOA) is a persistent industrial compound, which is commonly detected in human and wildlife sera. Low-dose prenatal PFOA exposure negatively affects postnatal growth and survival with little prenatal effect, indicating the potential for PFOA to alter lactation in the nursing dam. These studies aim to understand the impact PFOA has on development and differentiation of the mammary gland (MG). To address this, timed-pregnant CD-1 mice were gestationally exposed to 0 or 5 mg PFOA/kg body weight. PFOA-treated dams exhibited significant histopathologic delays in MG lactational differentiation and alterations in milk protein gene expression, and their exposed female offspring displayed stunted mammary epithelial branching and growth. The roles of timing and route of exposure were then addressed by cross-fostering litters, and the 5 mg/kg dose, under either lactational- or intrauterine-only exposures, was determined sufficient to delay MG development as early as postnatal day (PND) 1, with effects persisting beyond PND63. The consequences to F1 lactational function and subsequent development of F2 offspring were investigated, and F1 dams exhibited delayed lactational differentiation, though no effect of early-life exposure on milk production or F2 offspring body weight was detected. Finally, the potential mode of action for the effects of PFOA on the MG was investigated, by treating pregnant wild-type (WT) and peroxisome proliferator-activated receptor alpha (PPARα) knock-out (KO) mice similarly with PFOA. At weaning, PFOA treatment caused diminished lactational differentiation in WT, but not KO dams. In offspring, however, effects of PFOA exposure were apparent in both strains at weaning, suggesting a non-PPARα mode of action may be responsible for offspring MG effects. In total, these studies defined a window of MG sensitivity in late fetal and early neonatal life, as well as the persistence of MG effects beyond the age at which serum PFOA concentrations reach background levels. This suggests a permanent, non-PPARα mediated effect in the offspring, though without clear functional consequences. The characterization of MG effects in light of PFOA dosimetry data, as well as the discovery that MG effects are not strictly controlled by PPARα, will greatly assist in the regulation of this compound.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Toxicology.
Advisor
  • Fenton, Suzanne
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