Effects of perfluorooctanoic acid on mouse mammary gland development and differentiation resulting from cross-foster and restricted gestational exposures

U.S. EPA, ORD, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, USA.
Reproductive Toxicology (Impact Factor: 3.23). 12/2008; 27(3-4):289-98. DOI: 10.1016/j.reprotox.2008.11.054
Source: PubMed


The adverse consequences of developmental exposures to perfluorooctanoic acid (PFOA) are established in mice, and include impaired development of the mammary gland (MG). However, the relationships between timing or route of exposure, and consequences in the MG have not been characterized. To address the effects of these variables on the onset and persistence of MG effects in female offspring, timed pregnant CD-1 dams received PFOA by oral gavage over various gestational durations. Cross-fostering studies identified the 5mg/kg dose, under either lactational- or intrauterine-only exposures, to delay MG development as early as postnatal day (PND) 1, persisting beyond PND 63. Intrauterine exposure during the final days of pregnancy caused adverse MG developmental effects similar to that of extended gestational exposures. These studies confirm a window of MG sensitivity in late fetal and early neonatal life, and demonstrate developmental PFOA exposure results in early and persistent MG effects, suggesting permanent consequences.

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Available from: Suzanne Fenton, Dec 17, 2013
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    • "Only mice have been studied because the rapid excretion of PFOA in female rats (half life ∼4 h) precludes studies on mammary gland in that species [15]. Studies by White et al. [3] [10] showed that either gestational or lactational PFOA exposure in CD-1 mice impairs the development of the mammary gland. However, the underlying mechanisms are not well understood. "
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    ABSTRACT: Exposure to perfluorooctanoic acid (PFOA), a synthetic perfluorinated compound and an agonist of peroxisome proliferator-activated receptor α (PPARα), causes stunted mouse mammary gland development in various developmental stages. However, the underlying mechanisms remain poorly understood. We found that peripubertal PFOA exposure significantly inhibited mammary gland growth in both Balb/c and C57Bl/6 wild type mice, but not in C57Bl/6 PPARα knockout mice, and Balb/c mice were more sensitive to PFOA inhibition. PFOA caused (1) delayed or absence of vaginal opening and lack of estrous cycling during the experimental period; (2) decreases in ovarian steroid hormonal synthetic enzyme levels; and (3) reduced expression of estrogen- or progesterone-induced mammary growth factors. Supplementation with exogenous estrogen and/or progesterone reversed the PFOA inhibitory effect on mammary gland. These results indicate that PFOA effects on ovaries mediate its inhibition of mammary gland development in Balb/c and C57Bl/6 mice and that PPARα expression is a contributing factor.
    Full-text · Article · Mar 2012 · Reproductive Toxicology
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    • "Although numerous studies have shown persistent effects on the MG, few have evalu­ ated whether the changes could be revers­ ible. For example, in utero exposure to dioxin, Ziracin, PFOA, or BPA led to permanent changes in the adult MG (Fenton et al. 2002; Poulet et al. 2005; Vandenberg et al. 2007; White et al. 2009). In contrast, effects of genistein and ethinyl estradiol in male MG appeared to reverse after treatment withdrawal (Latendresse et al. 2009). "
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    ABSTRACT: Perturbations in mammary gland (MG) development may increase risk for later adverse effects, including lactation impairment, gynecomastia (in males), and breast cancer. Animal studies indicate that exposure to hormonally active agents leads to this type of developmental effect and related later life susceptibilities. In this review we describe current science, public health issues, and research recommendations for evaluating MG development. The Mammary Gland Evaluation and Risk Assessment Workshop was convened in Oakland, California, USA, 16-17 November 2009, to integrate the expertise and perspectives of scientists, risk assessors, and public health advocates. Interviews were conducted with 18 experts, and seven laboratories conducted an MG slide evaluation exercise. Workshop participants discussed effects of gestational and early life exposures to hormonally active agents on MG development, the relationship of these developmental effects to lactation and cancer, the relative sensitivity of MG and other developmental end points, the relevance of animal models to humans, and methods for evaluating MG effects. Normal MG development and MG carcinogenesis demonstrate temporal, morphological, and mechanistic similarities among test animal species and humans. Diverse chemicals, including many not considered primarily estrogenic, alter MG development in rodents. Inconsistent reporting methods hinder comparison across studies, and relationships between altered development and effects on lactation or carcinogenesis are still being defined. In some studies, altered MG development is the most sensitive endocrine end point. Early life environmental exposures can alter MG development, disrupt lactation, and increase susceptibility to breast cancer. Assessment of MG development should be incorporated in chemical test guidelines and risk assessment.
    Full-text · Article · Jun 2011 · Environmental Health Perspectives
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    • "The presence of numerous TEBs at PNDs 63 and 84 in the offspring of the PFOA-treated animals in this study are indicative of substantial mammary gland developmental delays. In the absence of control glands at PND 63, we compared our PFOA-treated glands to historical controls from previous studies (White et al., 2009 "
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    ABSTRACT: Perfluorooctanoic acid (PFOA) is an environmental contaminant that causes adverse developmental effects in laboratory animals. To investigate the low-dose effects of PFOA on offspring, timed-pregnant CD-1 mice were gavage dosed with PFOA for all or half of gestation. In the full-gestation study, mice were administered 0, 0.3, 1.0, and 3.0 mg PFOA/kg body weight (BW)/day from gestation days (GD) 1-17. In the late-gestation study, mice were administered 0, 0.01, 0.1, and 1.0 mg PFOA/kg BW/day from GD 10-17. Exposure to PFOA significantly (p < 0.05) increased offspring relative liver weights in all treatment groups in the full-gestation study and in the 1.0 mg PFOA/kg group in the late-gestation study. In both studies, the offspring of all PFOA-treated dams exhibited significantly stunted mammary epithelial growth as assessed by developmental scoring. At postnatal day 21, mammary glands from the 1.0 mg/kg GD 10-17 group had significantly less longitudinal epithelial growth and fewer terminal end buds compared with controls (p < 0.05). Evaluation of internal dosimetry in offspring revealed that PFOA concentrations remained elevated in liver and serum for up to 6 weeks and that brain concentrations were low and undetectable after 4 weeks. These data indicate that PFOA-induced effects on mammary tissue (1) occur at lower doses than effects on liver weight in CD-1 mice, an observation that may be strain specific, and (2) persist until 12 weeks of age following full-gestational exposure. Due to the low-dose sensitivity of mammary glands to PFOA in CD-1 mice, a no observable adverse effect level for mammary developmental delays was not identified in these studies.
    Full-text · Article · Apr 2011 · Toxicological Sciences
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