Background: The placenta is the primary means by which fetal growth and development is regulated during pregnancy. Heavy metal exposure has been found to have explicit effects on infant birth weight – among other developmental outcomes – with placental dysfunction potentially playing a role in these effects. LincRNAs expression specific to the placenta may be a possible mediator of this exposure-outcome pathway.
Objectives: Assess the biological plausibility of lincRNA expression within the placenta mediating the effects of maternal exposure to cadmium, mercury and lead on birth weight outcomes.
Methods: Using linear and logistic modeling of lincRNA transcriptional expression in the placenta relative to birth weight, standardized birth weight categories and placental metal concentrations, we assessed associations with lincRNA expression in a subset of the Rhode Island Child Health Study (n = 199) with full RNA-sequencing data and metal-expression and metal-birth weight trends within a portion of this population with placental trace metal data available (n = 85).
Results: Of the 1198 lincRNA transcripts sequenced, 46 demonstrated FDR-significant (q<0.05) associations with birth weight when controlling for infant sex and maternal age, BMI, education level, and smoking during pregnancy. Further, we identified 4 of these transcripts associated with placental Cd concentrations, 13 with placental Hg, and 1 with placental Pb, with the majority demonstrating moderate increases in transcript expression with increasing exposure. Finally, logistic regression of transcript levels against large (LGA) and small (SGA) for gestational age birth categories yielded 11 and 19 significant associations, respectively, among the same 46 transcripts; SGA outcomes were also significantly associated with increasing placental cadmium concentrations within the cohort.
Conclusions: In this birth cohort study, we examined the relationship between LincRNA expression and both placental metal concentrations and birth weight (continuous and categorized), finding that differences in metal concentrations were associated with specific lincRNA expression variation, and that those transcripts also significantly associated with birth weight. Our research findings in regards to metal exposure and birth weight were consistent with the literature, and these results present the possibility of lincRNAs mediating causal pathways from these exposures to developmental outcomes.
Table of Contents
1. Introduction 1
1.1 TRACE METALS AND NEONATAL HEALTH 2
1.2 THE PLACENTA 4
1.3 LONG NON-CODING RNAS 5
1.4 STUDY OBJECTIVE 8
2. Methods 9
2.1 THE STUDY POPULATION 9
2.2 PLACENTAL SAMPLING 10
2.3 RNA SEQUENCING 11
2.4 QC FILTERING AND NORMALIZATION 11
2.5 LINEAR ANALYSIS OF DIFFERENTIAL LINCRNA EXPRESSION WITH BIRTH WEIGHT 12
2.6 ANALYSIS OF LOG-LINEAR ASSOCIATION OF LINCRNA EXPRESSION AND HEAVY METALS 12
2.6 LOGISTIC REGRESSION ANALYSIS 13
3. Results 14
3.1 STUDY POPULATION 14
3.2 BIRTH WEIGHT REGRESSION 14
3.3 METAL-TRANSCRIPT REGRESSION 15
3.4 LOGISTIC BIRTH OUTCOME ANALYSIS 16
4. Discussion 17
5. Tables & Figures 22
Table 1: DEMOGRAPHIC CHARACTERISTICS OF THE STUDY POPULATION 22
Table 2: FORTY-SIX LINCRNA TRANSCRIPTS WITH FDR SIGNIFICANT CONTINUOUS-BIRTHWEIGHT ASSOCIATIONS 23
Figure 1: BIRTH WEIGHT-LINCRNA LINEAR REGRESSION RESULTS 24
Table 3: NOMINAL-SIGNIFICANT LINEAR ASSOCIATIONS OF LINCRNA EXPRESSION WITH METALS AMONG BW-SIGNIFICANT TRANSCRIPT 24
Table 4: LINCRNA TRANSCRIPTS WITH SIGNIFICANT LOGISTIC ASSOCIATIONWITH LGA BIRTHS 25
Table 5: LINCRNA TRANSCRIPTS WITH SIGNIFICANT LOGISTIC ASSOCIATION WITH SGA BIRTHS 25
Figure 2: FULL RESULTS OF LOGISTIC REGRESSION OF LGA AND SGA BIRTH OUTCOMES ON TRANSCRIPT EXPRESSION 26
Table 6: LINEAR ASSOCIATION OF LINCRNA EXPRESSION WITH CADMIUM AMONG BW-SIGNIFICANT TRANSCRIPTS 32
Table 7: LINEAR ASSOCIATION OF LINCRNA EXPRESSION WITH MERCURY AMONG BW-SIGNIFICANT TRANSCRIPTS 33
Table 8: LINEAR ASSOCIATION OF LINCRNA EXPRESSION WITH LEAD AMONG BW-SIGNIFICANT TRANSCRIPTS 34
Table 9: FULL RESULTS OF LINEAR LINCRNA-BW REGRESSION 35
About this Master's Thesis
|Committee Chair / Thesis Advisor|
|Placental lincRNA expression associated with prenatal toxic metals exposure and extreme birth weight ()||2018-04-25||