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«Neurodevelopmental Outcomes Bo Y. Park, MPH A Thesis Submitted to the Faculty of Drexel University by Bo Y. Park in partial fulfillment of the ...»

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Fetal Testosterone and Early Autism Spectrum Disorder Related

Neurodevelopmental Outcomes

Bo Y. Park, MPH

A Thesis

Submitted to the Faculty

of

Drexel University

by

Bo Y. Park

in partial fulfillment of the

requirements for the degree

of

Doctor of Philosophy

June 2015

©Copyright 2015

Bo Y. Park. All Rights Reserved.

Dedication

For Eleanor and Evelyn.

Tough moments are the beautiful ones.

Acknowledgements

I am very fortunate to have had the opportunity to learn and grow surrounded by great people. I would like to extend my sincere thanks to many individuals that help turn this thesis into reality. First of all, this thesis would not have been possible without mentorship and inspiration from my advisor, Dr. Craig Newschaffer. Your passion and brilliance kept me challenged and fueled me through the hard times. I want to thank Dr.

Brian Lee for keeping me motivated throughout the journey and engaging me in thoughtprovoking discussions. I have learned a lot from conversations with Dr. Igor Burstyn on many essential aspects of dissertation that would have been underappreciated. I want to thank Dr. Loni Tabb for her insightful comments and warm encouragements throughout the dissertation process. I would also like to thank Dr. Andrew Whitehouse, Dr. Jeff Keelan, Dr. Nate Snyder, and Dr. Alex Frey for their inspiration and expertise that were crucial for this thesis.

I would also like to thank my partner in life and science, Ruofan, for being the critic, editor, and enthusiastic supporter of this long journey. I am lucky to have you to share my passion in science and love. I deeply appreciate you all for being part of this journey of learning and self-discovery.

TABLE OF CONTENTS

Abstract

OVERVIEW

AIMS

REFERENCES

CHAPTER 1. BACKGROUND

1.1 AUTISM SPECTRUM DISORDERS

1.12 The ASD Phenotype

1.2 NEUROPATHOLOGY

1.3 GENETIC RISK FACTORS

1.4 NON-HERITABLE RISK FACTORS

1.41 Parental age

1.42 Obstetric, perinatal and neonatal factors

1.43 Teratogens

1.5 SEX DISPARITY IN ASD

1.51 Fetal Testosterone

1.52 Biomarkers of Fetal Testosterone

1.53 Testosterone Agonists: Triclosan and Triclocarban

1.6 CONCLUSIONS

REFERENCES

CHAPTER 2. STUDY I: COMPARISON OF ANDROGEN MEASUREMENT IN

UMBILICAL CORD BLOOD AND MECONIUM SAMPLES

INTRODUCTION

METHODS

RESULTS

DISCUSSION

REFERENCES

TABLES

FIGURES

APPENDIX

CHAPTER 3. STUDY II: UMBILICAL CORD BLOOD ANDROGEN LEVELS AND

ASD-RELATED PHENOTYPES AT 12 MONTHS

INTRODUCTION

METHODS

RESULTS

DISCUSSION

REFERENCES

TABLES

FIGURES

APPENDIX

CHAPTER 4. STUDY III: TRICLOSAN OR TRICLOCARBAN EXPOSURE AND ASDRELATED PHENOTYPES AT 12 MONTHS

INTRODUCTION

METHODS

DISCUSSION

REFERENCES

TABLES

FIGURES

APPENDIX

CHAPTER 5. CONCLUSIONS

SUMMARY OF FINDINGS

FUTURE DIRECTIONS

REFERENCES

METHODS APPENDIX

1. USE OF MECONIUM IN PERINATAL EPIDEMIOLOGY: POTENTIAL BENEFITS AND PITFALLS... 143

2. MECONIUM PILOT STUDY

3. MECONIUM TOTAL ANDROGENS METHODS

4. TRICLOSAN AND TRICLOCARBAN CONTAINING PRODUCT LIST

5. THE EARLY AUTISM RISK LONGITUDINAL INVESTIGATION (EARLI) HOME WALKTHROUGH

SURVEY PERSONAL CARE PRODUCT USE QUESTIONS

6. TRICLOSAN OR TRICLOCARBAN CONTAINING PERSONAL CARE PRODUCT TEXT MATCHING 166

7. ADDITIONAL VALIDATION OF SELF-REPORTED PRODUCT BASED TRICLOSAN AND

TRICLOCARBAN EXPOSURE DURING PREGNANCY USING A VALIDATION STUDY DESIGN......... 169

ABSTRACT

Fetal Testosterone and Early Autism Spectrum Disorder Related Neurodevelopmental Outcomes Bo Y. Park, MPH Craig J. Newschaffer, PhD Aims: Despite widely acknowledged sex bias in Autism Spectrum Disorders (ASD), the underlying mechanisms are largely unknown. The goal of this dissertation was to examine whether differences in prenatal testosterone levels are a possible mechanism underlying the observed ASD sex difference. This was accomplished through three specific aims. First, meconium was examined as a novel prenatal androgen matrix to compare androgen levels across alternate matrices obtained at the delivery time point.

Second, the association between cord blood testosterone and ASD-related 12 month phenotype was estimated in a high ASD risk cohort of multiplex families. Last, we investigated the relationship between widely used antimicrobials product use with potential androgenic activity and early autistic phenotypes.

Methods: Studies were based in the Early Autism Risk Longitudinal Investigation (EARLI) cohort, an enriched risk cohort following pregnant mothers who previously had a child with ASD diagnosis. Prenatal information on potential exposures, confounders, effect modifiers and two relevant biologic samples, cord blood and meconium, and early ASD-related behavioral phenotypes in the children born into the cohort were available for analysis.





Results: Testosterone (T) sex difference was observed in both cord blood and meconium and there was weak correlation between cord blood and meconium androgens. Umbilical cord blood T had a weak positive association with ASD related phenotype at 12 months.

We found that the association of prenatal testosterone and early ASD-related phenotype varied by the sex of older child with ASD (proband). 12 month autistic traits were unrelated to either prenatal or postpartum use of products that contain TCS or TCC.

Conclusion: Meconium and cord blood were both good media to measure prenatal androgen levels may be capturing different prenatal exposure windows. The association of prenatal testosterone early ASD-related phenotype was substantially different by proband sex indicating that androgen mediated mechanisms might be more important in families with female ASD in the pedigree. We found no evidence of an association between exposure to TCS/TCC and early ASD-related phenotype.

OVERVIEW Introduction The CDC estimates that 1 in 68 US children had an autism spectrum disorder (ASD) in 2010 (Centers for Disease Control and Prevention, 2014). The observed male to female prevalence ratio of roughly 4:1 is consistent with the vast majority of other epidemiologic studies around the world over the last several decades. Given the fact that this striking epidemiologic feature of ASD has long been acknowledged (Newschaffer et al., 2007), the sex prevalence difference is underplayed in discussions of candidate etiologic mechanisms. Although some mechanisms potentially driving this disparity have been ruled out (e.g., major X-linked risk genes (Gong et al., 2008)), an explicit focus on potential etiologic pathways consistent with this sex difference should be a priority in attempts to elucidate ASD causal mechanisms.

Impaired social interaction and communication are characteristics associated with ASD. These characteristics have also long been recognized as sexually dimorphic traits in typical development (Manson, 2008; Wallen, 2009), although debate continues around the exact magnitude, nature and generalizability of differences. Nonetheless, Baron Cohen (2002) has gone on to hypothesize that ASD may in fact be an extreme manifestation of male brain (Baron-Cohen, 2002). Androgens, such as testosterone, have an established role in fetal brain development and differentiation (Kimura, Okanoya, & Wada, 1999; Peper & Koolschijn, 2012). Fetal gonads and adrenal glands play the major role in prenatal androgen production (Baron-Cohen, Lutchmaya, & Knickmeyer, 2004; Blackburn, 2007) as early pregnancy placental androgen production is quickly surpassed by developing fetal organs with only low amounts of maternal androgen passively diffusing across the placenta (Atkinson, Campbell, Cawood, & Oakey, 1996; Sun et al., 2012). Elevated prenatal testosterone levels are associated with sex differences in play behavior (van de Beek, van Goozen, Buitelaar, & Cohen-Kettenis, 2009), spatial abilities (Chapman et al., 2006) and language difficulties (Keelan et al.,

2012) and defeminization of sex-typical play has been observed among girls diagnosed with ASD (Knickmeyer, Wheelwright, & Baron-Cohen, 2008). Although ASDs etiology is known to have a substantive genetic component (Jorde et al., 1991; Rosenberg et al., 2009), findings from neuropathology, brain gene expression, and twin and sibling concordance and recurrence studies indicate that environmental factors are also likely have also likely have a substantive impact on ASD risk (Amaral, Schumann, & Nordahl, 2008; Gronborg, Schendel, & Parner, 2013; Sandin et al., 2014). Therefore, investigation of environmental influences on pathways involving prenatal testosterone should also be a priority.

AIMS The aims of this dissertation are to evaluate meconium, baby‟s first stool, as a prenatal androgen matrix and to evaluate fetal testosterone dependent ASD using early ASDrelated behavioral phenotypes in children born into the EARLI (Early Autism Risk Longitudinal Investigation) cohort.

Three specific hypotheses were evaluated:

Study I: Fetal testosterone levels can be measured in meconium as well as cord blood and the sex difference in fetal testosterone is observable in both meconium and cord blood.

Study II: Fetal testosterone level is associated with early ASD-related phenotype.

Study III: Maternal prenatal triclosan/triclocarban-containing product use is associated with early ASD-related phenotype in the child.

Theses hypotheses were tested by pursuing the following Specific Aims:

Aim 1: Characterize meconium and cord blood as matrices for fetal testosterone measurement.

1a. Compare fetal testosterone levels as measured in umbilical cord blood and

–  –  –

Aim 2: Estimate the association between fetal testosterone levels in cord blood and ASDrelated behaviors (measured principally by the AOSI total score) at 12 months.

Aim 3: Estimate the association between prenatal TCS/TCC containing product use and

–  –  –

Amaral, D. G., Schumann, C. M., & Nordahl, C. W. (2008). Neuroanatomy of autism. Trends in neurosciences, 31(3), 137-145. doi: 10.1016/j.tins.2007.12.005 Atkinson, G., Campbell, D. J., Cawood, M. L., & Oakey, R. E. (1996). Steroids in human intrauterine fluids of early pregnancy. Clinical endocrinology, 44(4), 435-440.

Baron-Cohen, S. (2002). The extreme male brain theory of autism. Trends in cognitive sciences, 6(6), 248-254.

Baron-Cohen, S., Lutchmaya, S., & Knickmeyer, R. (2004). Prenatal Testosterone in Mind. United States: The MIT Press.

Blackburn, Susan Tucker. (2007). Maternal, Fetal, & Neonatal Physiology: A Clinical Perspective (Vol. 3rd). Philadelphia: Saunders.

Centers for Disease Control and Prevention. (2014). Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ, 63(2), 1-21.

Chapman, E., Baron-Cohen, S., Auyeung, B., Knickmeyer, R., Taylor, K., & Hackett, G. (2006).

Fetal testosterone and empathy: evidence from the empathy quotient (EQ) and the "reading the mind in the eyes" test. Social neuroscience, 1(2), 135-148.

doi:

10.1080/17470910600992239 Gong, X., Bacchelli, E., Blasi, F., Toma, C., Betancur, C., Chaste, P.,... Bourgeron, T. (2008).

Analysis of X chromosome inactivation in autism spectrum disorders. American journal of medical genetics.Part B, Neuropsychiatric genetics : the official publication of the

International Society of Psychiatric Genetics, 147B(6), 830-835. doi:

10.1002/ajmg.b.30688; 10.1002/ajmg.b.30688 Gronborg, T. K., Schendel, D. E., & Parner, E. T. (2013). Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study. JAMA Pediatr, 167(10), 947-953. doi: 10.1001/jamapediatrics.2013.2259 Jorde, L. B., Hasstedt, S. J., Ritvo, E. R., Mason-Brothers, A., Freeman, B. J., Pingree, C.,... Mo, A.

(1991). Complex segregation analysis of autism. American Journal of Human Genetics, 49(5), 932-938.

Keelan, J. A., Mattes, E., Tan, H., Dinan, A., Newnham, J. P., Whitehouse, A. J.,... Hickey, M.

(2012). Androgen concentrations in umbilical cord blood and their association with

maternal, fetal and obstetric factors. PloS one, 7(8), e42827. doi:

10.1371/journal.pone.0042827; 10.1371/journal.pone.0042827 Kimura, T., Okanoya, K., & Wada, M. (1999). Effect of testosterone on the distribution of vasotocin immunoreactivity in the brain of the zebra finch, Taeniopygia guttata castanotis. Life Sciences, 65(16), 1663-1670.

Knickmeyer, R. C., Wheelwright, S., & Baron-Cohen, S. B. (2008). Sex-typical play:

masculinization/defeminization in girls with an autism spectrum condition. J Autism Dev Disord, 38(6), 1028-1035. doi: 10.1007/s10803-007-0475-0 Manson, J. E. (2008). Prenatal exposure to sex steroid hormones and behavioral/cognitive

outcomes. Metabolism: clinical and experimental, 57 Suppl 2, S16-21. doi:

10.1016/j.metabol.2008.07.010; 10.1016/j.metabol.2008.07.010 Newschaffer, C. J., Croen, L. A., Daniels, J., Giarelli, E., Grether, J. K., Levy, S. E.,... Windham, G.

C. (2007). The epidemiology of autism spectrum disorders. Annual Review of Public Health, 28, 235-258. doi: 10.1146/annurev.publhealth.28.021406.144007 Peper, J. S., & Koolschijn, P. C. (2012). Sex steroids and the organization of the human brain. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32(20), 6745-6746. doi: 10.1523/JNEUROSCI.1012-12.2012 Rosenberg, R. E., Law, J. K., Yenokyan, G., McGready, J., Kaufmann, W. E., & Law, P. A. (2009).

Characteristics and concordance of autism spectrum disorders among 277 twin pairs.



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