Developmental Origins of Neurotoxicity of the PFAS GenX

PROJECT SUMMARY / ABSTRACT

Per- and polyfluoroalkyl substances (PFAS) are synthetic fluorine-containing compounds that are present in

many applications due to their non-stick and stain-resistant properties. Longer carbon chain compounds [C8;

e.g., perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS)], were phased out based on

health risks. Shorter carbon chain (4000 PFAS with most having limited to no toxicity information available.

Futhermore, some studies including our preliminary data indicate similar toxicity outcomes with some even

being more potent than the C8 compounds. Moreover, most PFAS are present in the environment in a mixture,

which can result in various mixture interactions. As such, a significant gap remains in our basic understanding

of DNT of PFAS and PFAS mixtures, mechanisms and functional impacts to the developing CNS, and the risk

of persistent neurotoxicity in the developmental origins of health and disease paradigm (DOHaD). PFAS of

particular concern are GenX (C6, replacement for PFOA) and PFBS (perfluorobutanesulfonic acid, C4,

replacement for PFOS). These PFAS alternatives are detected in environmental samples and in treated

drinking water. Questions remain on DNT and persistent neurotoxicity of a short-term developmental exposure

(e.g., the DOHaD paradigm). This question is significant considering GenX is reported to be more potent than

PFOA and is likely that co-exposure to GenX and PFOA will occur. Our CENTRAL HYPOTHESIS is that

exposure to GenX at early developmental stages will result in DNT targeting the DA system and persistent

neurotoxicity in adults with the combined effects of GenX and PFOA resulting in an additive toxicity response.

We will first define DNT of GenX using the zebrafish by assessing gross and fine morphological changes,

behavior, and targets associated with the DA system. Results will be compared to PFOA, PFBS, and

GenX/PFOA mixtures and alterations in the serotonergic system (aim 1). Second, we will assess persistent

neurotoxicity of the developmental PFAS exposure in the DOHaD paradigm (aim 2). The zebrafish, a well-

established model to study DNT and neurobehavior, will be used as an integrative vertebrate animal model to

assess short and long-term neurological outcomes. Several endpoints will be assessed to define mechanisms

of neurotoxicity from single and binary PFAS exposures to inform and guide future regulatory decisions.