Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats

Abstract

Perfluorooctanesulfonate (PFOS) is a persistent acid found widely distributed in wildlife and humans. To understand the potential reproductive and developmental effects of PFOS, a two-generation reproduction study was conducted in rats. Male and female rats were dosed via oral gavage at dose levels of 0, 0.1, 0.4, 1.6, and 3.2 mg/(kg day) for 6 weeks prior to mating, during mating, and, for females, through gestation and lactation, across two generations. Due to substantial F 1 neonatal toxicity observed in the 1.6 and 3.2 mg/(kg day) groups, continuation into the second generation was limited to F 1 pups from the 0, 0.1, and 0.4 mg/(kg day) groups. No adverse effects were observed in F 0 females or their fetuses upon caesarean sectioning at gestation day 10. Statistically significant reductions in body-weight gain and feed consumption were observed in F 0 generation males and females at dose levels of 0.4 mg/(kg day) and higher, but not in F 1 adults. PFOS did not affect reproductive performance (mating, estrous cycling, and fertility); however, reproductive outcome, as demonstrated by decreased length of gestation, number of implantation sites, and increased numbers of dams with stillborn pups or with all pups dying on lactation days 1–4, was affected at 3.2 mg/(kg day) in F 0 dams. These effects were not observed in F 1 dams at the highest dose tested, 0.4 mg/(kg day). Neonatal toxicity in F 1 pups, as demonstrated by reduced survival and body-weight gain through the end of lactation, occurred at a maternal dose of 1.6 mg/(kg day) and higher while not at dose levels of 0.1 or 0.4 mg/(kg day) or in F 2 pups at the 0.1 or 0.4 mg/(kg day) dose levels tested. In addition to these adverse effects, slight yet statistically significant developmental delays occurred at 0.4 (eye opening) and 1.6 mg/(kg day) (eye opening, air righting, surface righting, and pinna unfolding) in F 1 pups. Based on these data, the NOAELs were as follows: reproductive function: F 0 ≥ 3.2 and F 1 ≥ 0.4 mg/(kg day); reproductive outcome: F 0 = 1.6 and F 1 ≥ 0.4 mg/(kg day); overall parental effects: F 0 = 0.1 and F 1 ≥ 0.4 mg/(kg day); offspring effects: F 0 = 0.4 and F 1 ≥ 0.4 mg/(kg day). To distinguish between maternal and pup influences contributing to the perinatal mortality observed in the two-generation study, a follow-up cross-foster study was performed. Results of this study indicated that in utero exposure to PFOS causally contributed to post-natal pup mortality, and that pre-natal and post-natal exposure to PFOS was additive with respect to the toxic effects observed in pups.