SUMMARY
Per- and polyfluoroalkyl substances and their derivatives (PFAS) are industrial chemicals that are wide-
spread in the environment, including blood serum of wildlife and humans. Their pervasiveness and long half-life
raises the questions about their toxicity, especially with regards to the effect on the developing fetus. Several
studies have demonstrated that these compounds cross the placenta, are found in the umbilical cord blood, and
can cause neurodevelopmental abnormalities in the offspring of the exposed mothers, including early pregnancy
loss, low birth weight, hyperactivity, decreased head circumference and behavior problems. However, the
molecular mechanisms following PFAS exposure, such as dysregulated genes and pathways, especially in the
context of human brain development, remain unexplored. Here, we are proposing to use human induced
pluripotent stem cell (iPSC) derived models such as neural progenitor cells (NPCs), spheroids and brain cortical
organoids, to fill in this knowledge gap. We hypothesize that PFAS impact early brain development by
dysregulating transcriptional programs of NPCs that are involved in proliferation, cell cycle and survival.
We also hypothesize that these early alterations will have significant impact on the formation of cortical
networks. We are proposing the following Specific Aims to test these hypotheses: (1) Investigate dose-
dependent impact of PFAS on neural progenitor cell cycle, cell viability and proliferation; (2) Perform genome-
wide pooled genetic screens with CRISPRi/a sgRNA libraries to identify modifier genes and pathways upon
PFAS treatment; (3) Validate the impact of PFAS on long-term neurodevelopment in cortical organoids models
and identify cell populations impacted by PFAS. Our study will identify genes, molecular and cellular pathways
dysregulated by PFAS exposure across various stages of brain development, modeled in vitro. It has a potential
to uncover new mechanisms behind PFAS exposure, and to predict the impact of PFAS on developing human
brain network function.
