Gestational and Chronic Low-Dose PFOA Exposures and Mammary Gland Growth and Differentiation in Three Generations of CD-1 Mice

Abstract

Background: Prenatal exposure to perfluorooctanoic acid (PFOA), a ubiquitous industrial surfactant, has been reported to delay mammary gland development in female mouse offspring (F1) and the treated lactating dam (P0) after gestational treatments at 3 and 5 mg PFOA/kg/day.Objective: We investigated the consequences of gestational and chronic PFOA exposure on F1 lactational function and subsequent development of F2 offspring.Methods: We treated P0 dams with 0, 1, or 5 mg PFOA/kg/day on gestation days 1–17. In addition, a second group of P0 dams treated with 0 or 1 mg/kg/day during gestation and their F1 and F2 offspring received continuous PFOA exposure (5 ppb) in drinking water. Resulting adult F1 females were bred to generate F2 offspring, whose development was monitored over postnatal days (PNDs) 1–63. F1 gland function was assessed on PND10 by timed-lactation experiments. Mammary tissue was isolated from P0, F1, and F2 females throughout the study and histologically assessed for age-appropriate development.Results: PFOA-exposed F1 dams exhibited diminished lactational morphology, although F1 maternal behavior and F2 offspring body weights were not significantly affected by P0 treatment. In addition to reduced gland development in F1 females under all exposures, F2 females with chronic low-dose drinking-water exposures exhibited visibly slowed mammary gland differentiation from weaning onward. F2 females derived from 5 mg/kg PFOA-treated P0 dams displayed gland morphology similar to F2 chronic water exposure groups on PNDs 22–63.Conclusions: Gestational PFOA exposure induced delays in mammary gland development and/or lactational differentiation across three generations. Chronic, low-dose PFOA exposure in drinking water was also sufficient to alter mammary morphological development in mice, at concentrations approximating those found in contaminated human water supplies.

Per- and polyfluorinated substances (PFASs): Environmental challenges

“…In utero or early life exposure of rodents to PFOS, PFHxS or PFOA also caused developmental toxicities in adults, including pulmonary injuries [237], uterine and mammary gland development delays (or stimulation, depending on gender, strain and dose), sometimes at very low doses [26, 91,229,238,239]; glucose and lipid metabolic disorders [240];…”

“…has been confirmed to be a prominent (but not only) mechanism of action for many of the prevalent toxicities observed in rodents with PFOS and PFOA [218][219][220]235, 262-268], including hepatomegaly and peroxisome proliferation; developmental toxicity [229,239] immunotoxicity [225]; endocrine disruption [227]; tumorigenicity [269]. The binding sites of PFOA, PFOS and PFHxS in the PPAR and other nuclear receptor proteins have been modeled [270].…”

Evaluating chemical effects on mammary gland development: A critical need in disease prevention

“…Developing tissues in particular can be exquisitely sensitive to very low doses of EDs. BPA, atrazine [94], PFOA [95], and dioxin [80] have each been shown to affect the MG at doses below those typically used in toxicological studies conducted for regulatory purposes. Exposure to concentrations of BPA expected to produce circulating free BPA levels above nanomolar concentrations has been shown to alter MG development, gene and protein expression, histogenesis, or to induce mammary hyperplasia in over a dozen studies (reviewed in [93]).…”

“…In rodents, high doses of atrazine [100,101] and PFOA [95,102] have been shown to severely inhibit mammary development, which then affects lactation and impairs the growth of developing offspring. While these high doses are rarely seen in humans, it is possible that ecological systems may be exposed to levels that alter animals' development, impair lactation, and reduce offspring survival [43].…”

A special issue dedicated to a complex tissue

“…Although not addressed in this Special Issue, some EDCs have demonstrated long lasting and potentially permanent effects on the breast following only developmental exposures [29][30][31]. Trevino et al provide background evidence from the literature, in addition to preliminary data from their laboratory in the DEStreated MCF7 cell line, that these seemingly permanent effects may be directed by ER-mediated alteration in DNA and histone methylation through rapid, non-genomic mechanisms.…”