Developmental perfluorooctane sulfonate (PFOS) exposure alters gene expression in nucleus accumbens and prefrontal cortex and impairs cognition in rats: A transcriptomic and mediation analysis

TL;DR

Exposure to PFOS during development in rats alters gene activity in brain regions linked to decision-making and causes cognitive issues.

Contribution

Identifies specific genes and pathways in the brain affected by PFOS exposure that mediate cognitive impairments.

Findings

PFOS exposure altered gene expression in the nucleus accumbens, prefrontal cortex, and hippocampus.

DEGs like NAT8F2 and ABCG3 were linked to impaired cognitive flexibility and impulsive decision-making.

Pathways such as ECM-receptor interaction and glutathione metabolism were associated with PFOS effects.

Abstract

Growing evidence suggests that developmental exposure to
perfluorooctanesulfonic acid (PFOS) is linked to neurobehavioral outcomes.
Pregnant female rats were exposed to PFOS (15 mg/L) or Tween vehicle through
drinking water until the offspring were weaned at three weeks of age. As adults,
cognitive flexibility and impulsive decision-making were assessed in 8
PFOS-exposed and 8 vehicle-exposed rats using extradimensional set-shifting and
delay discounting tasks, respectively. Cognitive flexibility was measured by the
number of trials required to reach the criterion, while impulsive
decision-making was quantified as the area under the curve (AUC) of the percent
preference for the large reward lever (% CHL), response omissions (% omit), and
response latency (in second) at delays of 0, 15, 30, and 45 s. Brain tissues
from the nucleus accumbens, prefrontal cortex, and hippocampus were extracted
for bulk RNA sequencing. Differential gene expression analysis and gene set
enrichment analysis were performed. Mediation analysis was performed to assess
the mediated effect of DEGs in the associations between PFOS and neurobehavioral
tests. We identified 62 differentially expressed genes (DEGs) in the nucleus
accumbens, 34 in the hippocampus, and 59 in prefrontal cortex tissues due to
PFOS exposure. We also found DEGs, including NAT8F2,
AC080157.1, ABCG3, and
ENSRNOG00000063145 mediated between PFOS and
neurobehavioral assessments. Pathways that were associated with both PFOS
exposure and neurobehavioral outcomes (% CHL and % omit) included extracellular
matrix-receptor interaction, focal adhesion, and glutathione metabolism in the
nucleus accumbens. Developmental PFOS exposure may alter gene expression in the
nucleus accumbens and prefrontal cortex and was associated with impaired
cognitive flexibility and impulsive decision-making. These exploratory findings
highlight potential pathways, including ECM-receptor interaction and glutathione
metabolism, that warrant further validation.

Figures