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Gestational Exposure to Perfluorooctanoic Acid (PFOA): Alterations in Motor Related Behaviors

David R. Goulding, Sally S. White, Sandra J. McBride, Suzanne E. Fenton, and G. Jean Harry.
Neurotoxicology (2017) DOI: https://doi.org/10.1016/j.neuro.2016.11.008 PMID: 27888120


Publication


Abstract

Perfluoroalkyl and polyfluoroalkyl substances are used in commercial applications and developmental exposure has been implicated in alterations in neurobehavioral functioning. While associations between developmental perfluorooctanoic acid (PFOA) exposure and human outcomes have been inconsistent, studies in experimental animals suggest alterations in motor related behaviors. To examine a dose-response pattern of neurobehavioral effects following gestational exposure to PFOA, pregnant CD-1 mice received PFOA (0, 0.1, 0.3, 1.0mg/kg/day) via oral gavage from gestational day 1-17 and the male offspring examined. Motor activity assessments on postnatal day (PND)18, 19, and 20 indicated a shift in the developmental pattern with an elevated activity level observed in the 1.0mg/kg/day dose group on PND18. In the adult, no alterations were observed in body weights, activity levels, diurnal pattern of running wheel activity, startle response, or pre-pulse startle inhibition. In response to a subcutaneous injection of saline or nicotine (80μg/kg), all animals displayed a transient increase in activity likely associated with handling with no differences observed across dose groups. Inhibition of motor activity over 18days of 400μg/kg nicotine injection was not significantly different across dose groups. Hyperactivity induced by 2mg/kg (+)-methamphetamine hydrochloride intraperitoneal injection was significantly lower in the 1.0mg/kg/day PFOA dose group as compared to controls. Taken together, these data suggest that the effects on motor-related behaviors with gestational PFOA exposure do not mimic those reported for acute postnatal exposure. Changes were not observed at dose levels under 1.0mg/kg/day PFOA. Further examination of pathways associated with methamphetamine-induced activity is warranted.

Figures


Figure 1. Total ambulatory activity (counts) over 20 min at postnatal day (PND) 18, 19, and 20.

Data represent means (±SEM) response in male mice gestationally exposed to vehicle (0.0) or PFOA (0.1, 0.3, 1.0 mg/kg/day; n = 5–7 per dose group). *significantly different by Bonferroni tests as compared to controls (p < 0.002) or as compared to PND 20 (p < 0.002).

Figure 2. Startle reactivity and prepulse inhibition (PPI) in 2-month-old male mice.

Startle reactivity and prepulse inhibition (PPI) in 2-month-old male mice gestationally exposed to vehicle (0.0) or PFOA (0.1, 0.3, 1.0 mg/kg/day; n = 14–17 per dose group). (A) log10–scale plots of mean ± SEM of startle amplitude (Vmax) in response to 120 dB pulses over four blocks of 5 trials showing a decrease over blocks (p < 0.001). (B) Percent startle habituation calculated as the attenuation in startle response from the first block to the fourth block. (C) Vmax recorded in no-stimulus trials. (D) Percent inhibition of 120 dB response from pre-pulse stimulus intensities of 3, 6, or 12 dB above background. Data represent means ± SEM.

Figure 3. Running wheel activity over 12 days.

Daily wheel rotations during (A) light phase and (B) dark phase in 2 month old male mice gestationally exposed to vehicle (0.0) or PFOA (0.1, 0.3, 1.0 mg/kg/day; n = 12 per dose group). (C) total rotations recorded during dark phase of day 1 and day 12. (D–G) Hourly rotations recorded during day 1 and day 2 for (D) controls, and PFOA dose groups of (E) 0.1, (F) 0.3, and (G) 1.0 mg/kg/day. Shaded areas represent dark phase. Data represent means ± SEM.

Figure 4. Running wheel activity over 12 days.

Hourly running wheel rotations recorded during day 1–day 12 in adult CD-1 male mice exposed gestationally to vehicle (0.0) or 0.1, 0.3, and 1.0 mg PFOA/kg/day. Shaded areas represent dark phase of each day. Data represent mean total rotations occurring over a 1 h interval showing a gradual increase over days. (n = 12 per dose group).

Figure 5. Ambulatory activity following nicotine.

(A) Ambulatory activity levels (counts) in 5-min epochs for 40 min followed by an acute injection (arrow) of (A) saline or (B) nicotine base (80 μg/kg, sc.) and activity measured over 50 min in 6-month-old male mice gestationally exposed to PFOA or vehicle (n: vehicle 0.0 = 6; 0.1 = 5; 0.3 = 4; 1.0 = 5). A transient increase in activity level was noted following injections. (C) Total ambulatory activity levels (counts) over 15 min on day 0 following a sc. injection of saline (baseline). Total ambulatory activity levels (counts over 15 min) on days 1–8 initiated 5 min following sc. injection of 400ug/kg nicotine base (pH 7.2). Once daily nicotine injections were continued on days 9–17. On day 18, total ambulatory activity levels were recorded over 15 min (scatter plot) initiated 5 min following sc. injection of 400 μg/kg nicotine base. Data represents mean ± SEM (n = 5–7 per dose group).

Figure 6. Ambulatory activity following methamphetamine.

(A) Baseline ambulatory activity level (counts) in 5 min epochs over 50 min followed by sc injection of methamphetamine (2 mg/kg; arrow) and activity measured in 5-min epochs over 60 min in adult male mice gestational exposed to PFOA. (n = 10-12 per dose group). (B) Total ambulatory activity level following amphetamine injection. *statistically significant (p < 0.05) as compared to controls as determined by Williams test.