Human Health Effects of Perfluorinated Compounds: Assessing Exposure in the Alaska Maternal Organic Monitoring Study and Testing Reproductive Toxicity in a Human Spermatogenesis Stem Cell Model Open Access

Clarkson-Townsend, Danielle (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/9p290960f?locale=en
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Abstract

Background: Perfluorinated compounds (PFCs) are persistent pollutants commonly used as surfactants. Human health effects of chronic exposure to PFCs are not well understood, especially for fertility, but previous studies have found associations with blood lipids.

Objective: I examined the association of total cholesterol and PFC exposure among Alaska Native pregnant women (2005-2006, 2010-2012) and compared PFC levels to pregnant women surveyed in National Health and Nutrition Examination Survey (NHANES) during 2005-2006. Reproductive toxicity of PFCs were also tested using a novel in vitro human spermatogenesis stem cell model.

Methods: Mean PFC exposures (PFHxS, PFOS, PFOA, Me-PFOSA-AcOH, PFNA, and PFDeA) were compared within AK MOMS cohorts and with pregnant women in NHANES (2005-2006). The association between PFC exposures and total cholesterol was calculated using multivariable linear regression. Reproductive toxicity of PFOS, PFOA and PFNA on human spermatogenesis was tested using an in vitro human spermatogenesis model. Impacts to apoptosis, cell cycle, gene expression, and spermatogonial differentiation were evaluated using flow cytometry, qPCR, and immunostaining for PLZF after chronic exposure.

Results: Mean PFNA and PFDeA exposures were significantly higher in women from AK MOMS compared to NHANES. PFC exposures overall decreased in women from AK MOMS from 2005-2006 to 2010-2012, except PFHxS, which increased. PFOS, PFDeA, and PFHxS were significantly associated with elevated total cholesterol. In vitro PFC exposure resulted in increased cell death, decreased haploid cells, and impacted gene expression related to lipid metabolism and spermatogenesis. These results suggest that PFOS, PFOA and PFNA impair male fertility.

Discussion: This analysis supports an association with PFCs and cholesterol. Some PFCs may be higher in AK MOMS because of bioaccumulation patterns and dietary exposure. PFHxS exposure may have increased over time because it is a newer replacement compound. Further studies are needed to confirm these results in other populations and examine the potential health impacts of PFNA, PFDeA, and PFHxS exposure. The in vitro analysis suggests that exposure negatively impacts spermatogenesis and parameters related to fertility. Future studies should focus on assessing other lipid-related outcomes, as well as the reproductive impacts of newer PFCs and PFC mixtures.

Table of Contents

Table of Contents

INTRODUCTION ...1

Perfluorinated Compounds: Brief Background and History...1

Perfluorinated Compounds in the Ecosystem...2

Routes of Exposure...6

Perfluorinated Compounds in Epidemiological Studies: Human Health...7

Perfluorinated Compounds and Lipid Metabolism...9

Perfluorinated Compounds and Reproduction...12

Modeling PFC Exposure...16

Human Spermatogenesis Model...17

Regulation...18

Objectives...19

METHODS ...21

Alaska Maternal Organic Monitoring Study Data...22

Inclusion and Exclusion Criteria...23

Data Analysis of AK MOMS...24

National Health and Nutrition Examination Survey Data...25

Data Analysis of NHANES...25

Stem Cell Culture and Differentiation...26

Apoptosis Assay...28

Immunostaining...28

Cell Cycle Assay...29

qPCR Assay...30

Reagents...31

Statistical Analysis of Cellular Endpoints...31

RESULTS ...32

Alaska Maternal Organic Monitoring Study...32

AK MOMS and NHANES...36

PFC Exposure and Lipids...39

PFC Exposure Causes Increased Apoptosis in Germ Cells...39

PFC Exposure Decreases Spermatogonial Viability...40

PFC Exposure Decreases Haploid Spermatids...42

PFC Exposure Affects Gene Expression...44

DISCUSSION ...46

Possible Mechanisms...50

Albumin as a Confounder?...53

Possibilities to Decrease Body Burden?...55

CONCLUSIONS...55

REFERENCES...57

TABLES ...77

FIGURES ...87

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