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

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.