Title

Neurodevelopmental impacts of prenatal exposures to per- and poly-fluoroalkyl substances; multiple outcome assessments in childhood age 5 to 11 years

Date of Award

Fall 10-1-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Public Health

First Advisor

Liew, Zeyan

Abstract

Per- and poly-fluoroalkyl substances (PFAS) are synthetic fluorine-containing chemicals that are widely used in a variety of industrial and commercial applications. Several PFAS compounds were reported to be ubiquitously detected in blood samples collected from the general population since the 1990s. Concerns are raised that PFAS exposure among pregnant women could affect offspring neurodevelopment, mainly because of two reasons: a) PFAS can transfer across the placenta during early gestation making them a direct threat to fetal brain development, and b) PFAS can interfere with maternal endocrine homeostasis during pregnancy which has been suggested to play a crucial role on offspring neurodevelopment Findings from existing epidemiological studies that evaluated prenatal PFAS exposure effects on offspring neurodevelopment were mixed. Most of these studies were limited by sample size, the scope of outcome assessments, and the number of PFAS congeners studied. In addition, although thyroid hormone disrupting properties are generally considered as one potential pathway for the developmental neurotoxicity of PFAS exposure, no study has considered the mediating role of maternal endocrine hormones in the association between prenatal PFAS exposure and offspring neurodevelopment. In light of these limitations and inconsistent results from prior studies, the aims of this dissertation are to evaluate the association between prenatal exposures to six PFAS congeners and offspring neurodevelopment using multiple distinct endpoints, and to explore the mediating role of maternal thyroid hormones in these associations. Specifically, the primary aims of this dissertation are: a) to evaluate the association between prenatal exposure to PFAS and child’s facial dysmorphism at age 5 (Chapter 2, n=656); b) to evaluate the association between prenatal exposure to PFAS and child’s behavioral difficulties at the age 7 and 11 (Chapter 3, n=2832); and c) to evaluate the association between prenatal exposure to PFAS and child’s self-report mental health at age 11 (Chapter 4, n=2250). All these studies are based on data from the Danish National Birth Cohort. In brief, we observed that prenatal perfluorononanoic acid (PFDA) and PFAS mixtures were associated with a shorter palpebral fissure length at age 5. Perfluorononanoic acid (PFNA) was associated with externalizing behavioral difficulties at ages 7 and 11. The associations between PFAS and child mental health at age 11 were generally null, while a few associations of PFNA and perfluorohexan sulfonate (PFHxS) with depressive symptoms, stress, or psychosis-like experience warrant future research. Most of these associations observed are related to PFAS congeners that are less frequently studied in prior research. In the mediation analysis for behavioral outcomes, a small indirect mediating effect of PFAS was observed by affecting maternal thyroid hormones function in early pregnancy. In summary, our study provided the first epidemiological evidence that suggest multiple PFAS exposure might influence fetal craniofacial development. In addition, our projects also provided novel insights regarding early life PFAS exposures on childhood behavioral and mental health outcomes, characterized using validated questionnaires assessed by parents and children. Maternal thyroid function remains to be an important mechanistic pathway of PFAS neurotoxicity that needs to be considered. Findings in this dissertation have advanced our knowledge regarding neurodevelopmental effects of multiple PFAS compounds. These results can guide future research of adverse development health impacts associated with prenatal PFAS exposure and contribute to policy regulations of PFAS.

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