Project Summary/Abstract Per- and polyfluoroalkyl substances (PFAS) are known endocrine disrupting chemicals (EDCs), and exposure to PFAS has been associated with adverse pregnancy outcomes, including spontaneous abortion (SAB), pre- term birth (PTB), and small for gestational age (SGA) births. However, less is known about 1) PFAS mixtures, 2) modifiable factors (e.g., perceived stress) and 3) underlying biological pathways of PFAS perinatal toxicity. Further, less research has been devoted to understanding the impact of PFAS in Black women, who remain understudied in environmental health research, but may have inequitable exposure to EDCs and a higher prev- alence of adverse pregnancy outcomes. The aims of this proposal are to investigate associations of a PFAS mixture with pregnancy outcomes (SAB, gestational age, birth size), describe the modifying role of perceived stress, and identify the biological pathways underlying PFAS perinatal toxicity using untargeted metabolomics data in a prospective cohort of Black women. We will leverage existing data from the Study of Environment, Lifestyle, and Fibroids (SELF), which is a cohort of reproductive-aged Black women from Detroit, MI. Partici- pants were recruited between 2010 and 2012 and were 23-35 years at enrollment. PFAS concentrations were measured in baseline plasma samples; pregnancy outcomes were prospectively assessed using structured questionnaires at follow-up visits; and all covariate data were collected in questionnaires or clinic visits at base- line and each follow-up visit. In the K99 phase of the award, Dr. Samantha Schildroth (PI) proposes the follow- ing aims: 1) evaluate the association of a PFAS mixture with pregnancy outcomes (SAB, gestational age, birth size); and 1B) in a sub-aim, examine perceived stress scores as a modifier of the PFAS mixture. The R00 phase of the award will build on the K99 phase by identifying biological pathways related to PFAS toxicity. This phase of the award will address the following aims: 2) identify metabolic pathways associated with PFAS using metabolomics data; 3A) quantify the mediating pathway(s) between the PFAS mixture and pregnancy out- comes that operate through metabolites identified in Aim 2; and 3B) in a sub-aim, examine the role of per- ceived stress as a modifier of the mediating pathway(s) identified in Aim 3A. The research in this proposal will address critical knowledge gaps in the literature by assessing the perinatal toxicity of PFAS mixtures in Black women, which will serve to inform public health interventions aimed at reducing inequities in adverse preg- nancy outcomes. In addition, this award will provide Dr. Schildroth with foundational training in perinatal epide- miology, metabolomics, environmental toxicology, and modifiable psychosocial factors under the guidance of an expert, interdisciplinary team of researchers, allowing for her successful transition into an independent re- searcher focused at the nexus of chemical mixtures, metabolomics, and women’s and children’s health.

Project Narrative Per- and polyfluoroalkyl substances (PFAS) are known endocrine disrupting chemicals that have been associated with adverse pregnancy outcomes, but less is known about their mixture, modifiable factors (e.g., perceived stress), and underlying biological pathways of toxicity, especially in Black women. This study aims to assess the association of a PFAS mixture with adverse pregnancy outcomes, examine perceived stress as a modifier of the PFAS mixture, and identify biological pathways underlying toxicity using untargeted metabolomics data in a prospective cohort of reproductive-aged Black women. The findings from this study will help to inform the current understanding of PFAS perinatal toxicity and public health interventions aimed at reducing inequities in adverse pregnancy outcomes among Black women.