Placental Genomic Imprinting, Toxic Metals, And Child Growth And Neurobehavioral Development Open Access

Abstract

The placenta plays a critical role in fetal development, influencing growth and neurobehavioral development. Imprinted genes are highly regulated and play a key role in fetal development through, in part, their control of placental function. These genes are also thought to be sensitive to exposures to stressors and environmental toxicants. Using data from the New Hampshire Birth Cohort Study (NHBCS), we sought to first investigate the potential association between variation in imprinted gene expression and exposure to toxic metals in the placenta, including arsenic, mercury, lead, manganese, and cadmium, and secondly to investigate whether the identified pattern of expression of imprinted genes associated with metal exposure was associated with newborn and early childhood neurodevelopmental and growth outcomes. Neurodevelopment was assessed with using the Social Response Scales-2 (SRS-2) and growth by examining clinical measures at birth and through age 2 years. We identified associations only between cadmium exposures and imprinted gene expression, with increasing cadmium concentrations associated with reduced expression of H19 (q=0.003), IGF2 (q=0.043), and IGF2AS (q=0.028) and with increased expression of MEST (q=0.044), DLX5 (q=0.043), PHLDA2 (q=0.028), GAA (q=0.043) and ABCA1 (q=0.044). Further, in linear models controlled for confounders, we noted associations between placental expression of MEST and the SRS-2 measure of social awareness and between expression of PHLDA2 and social communication (p<0.05). We also noted, in multivariable linear models, associations between increasing expression of MEST and increased birthweight, as well as increased weight for age z-score and weight for age percentile at 12 months and 24 months (p=0.013, p=0. 036; p=0.012; p=0.023; p=0.004). Expression of placental PHLDA2 was also associated with weight for age percentile at 24 months. These analyses suggest that imprinted genes with variable expression associated to cadmium exposure are also related to child neurobehavioral and growth outcomes, in a prospective fashion, supportive of our hypothesis of the key role of imprinted genes in the placenta relative to neurobehavioral and growth outcomes. Understanding how altered expression of imprinted genes as critical regulators of development disrupts postnatal development may indicate the overall relevancy of this specific epigenetic mechanism.

Table of Contents

Background/Introduction……………………………………………………..………....…….1

Neurotoxic Effects of Metals………………………………………………….………1

Toxic Metals and Fetal Growth…………………………………….………………3

Sources of Toxic Metal Exposures……………………………...……………..….…3

Importance of the Placenta ……………………..…………………..……....…4

Placental Metal Concentrations…………………………….……………..…...4

Imprinted Genes………………………………………………………….…...5

Study Objectives………………………………………………………….…..6

Methods.......................................................................................................................................7

Study Population…………………………………………………..………...7

Placenta Samples………………………………………………….…………...8

Data Analysis……………………………………………………………………8

Results………………………………………………………………………………………....10

Descriptive Characteristics of the Cohort……………………………..……….10

Correlations between Metals in the Placenta………………………….………10

Imprinted Genes……………………………………………………….…...10

Neurodevelopment Outcome Relative to Gene Expression……………………..11

Growth Outcome Relative to Gene Expression……………………..………......11

Discussion……………………………………………………………………………………..12

Conclusions and Recommendations…………...…………..………………………………...12

References………………..…………………………………………….……………….……..14

Tables & Figures…………………………………………………………………….………..18

Supplemental Tables..................................................................................................................24

About this Master's Thesis

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School	Rollins School of Public Health
Department	Environmental Health
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Environmental Health Health Sciences, Epidemiology
Keyword	neurobehavioral exposure pediatric placenta newborn in utero genes imprinting children growth metals epigenetics
Committee Chair / Thesis Advisor	Marsit, Carmen , Emory University
Committee Members	Tolbert, Paige, Emory University
Partnering Agencies	Does not apply (no collaborating organization)

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