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Effects of Perfluorooctanoic Acid on Mouse Mammary Gland Development and Differentiation Resulting from Cross-Foster and Restricted Gestational Exposures
Citation:
WHITE, S. S., K. KATO, L. T. JIA, B. J. BASDEN, A. M. CALAFAT, E. P. HINES, J. P. STANKO, C. J. WOLF, B. D. ABBOTT, AND S. E. FENTON. Effects of Perfluorooctanoic Acid on Mouse Mammary Gland Development and Differentiation Resulting from Cross-Foster and Restricted Gestational Exposures. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 27(3-4):289-298, (2009).
Impact/Purpose:
This work, in direct response to research requested by OPPT, has identified the MG as a tissue that is sensitive to developmental perturbation by PFOA, and may be among the most sensitive endpoints studied to date. Knowledge of the lowest effective doses and the mode of action for the PFOA-induced MG effects will allow comparison with health results in epidemiological studies that are currently on-going, including that done by the NIEHS Breast Cancer and Environment Research Centers and the C8 Science Panel on the human health effects of PFOA. This type of research, in conjunction with internal dosimetry, should result in less uncertainty in risk assessment.
Description:
The adverse consequences of developmental exposures to perfluorooctanoic acid (PFOA) have been established, and include impaired development of the offspring mammary gland (MG). However, the relationship between the timing or route of exposure, and the phenotypic consequences in the MG has not been characterized. In the series of studies presented here, the effect of timing and route of PFOA exposure on the onset and persistence of the MG effects in female CD-1 mice are addressed. Timed-pregnant mice received 0, 3, or 5 mg PFOA/kg on gestation days (GD) 1-17, 7-17, 8-17, 10-17, 13-17, or 15-17, and were utilized in three different experiments. The first two studies, addressing the effects of route of exposure by cross-fostering litters, determined that the 5 mg/kg dose, under either lactational- or intrauterine-only exposures, was sufficient to delay MG development as early as postnatal day (PND) 1 and these effects persisted beyond 9 weeks postnatally. Dosimetry data on PND 1 from offspring exposed in utero demonstrated a substantial transplacental PFOA transfer, not previously documented this early in neonatal life. The final study, addressing possible windows of sensitivity in gestation, evaluated MG tissue at peripubertal and 18-month time points, and found that exposure during the final days (GD 15-17) of pregnancy alone caused adverse pup MG developmental effects similar to that seen with exposure during the last two-thirds of gestation (GD 7-17). These studies support the postulate that a window of MG sensitivity exists in late fetal and early neonatal life. Most importantly, these results demonstrate the persistence of MG effects beyond the age at which serum PFOA concentrations reach background levels, suggesting a permanent effect with life-long consequences.
