Placental lincRNA expression associated with prenatal toxic metals exposure and extreme birth weight Público

Hussey, Michael (Spring 2018)

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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 2: FORTY-SIX LINCRNA TRANSCRIPTS WITH FDR SIGNIFICANT CONTINUOUS-BIRTHWEIGHT ASSOCIATIONS                                                                                                    23

Figure 1: BIRTH WEIGHT-LINCRNA LINEAR REGRESSION RESULTS                                   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

References                                                                                                                                                  28

Appendices                                                                                                                                                 32

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


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