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. 2018 Nov:120:373-381.
doi: 10.1016/j.envint.2018.08.010. Epub 2018 Aug 17.

Intrauterine multi-metal exposure is associated with reduced fetal growth through modulation of the placental gene network

Maya A Deyssenroth  1 , Chris Gennings  1 , Shelley H Liu  2 , Shouneng Peng  3 , Ke Hao  3 , Luca Lambertini  4 , Brian P Jackson  5 , Margaret R Karagas  6 , Carmen J Marsit  7 , Jia Chen  8
Affiliations

Intrauterine multi-metal exposure is associated with reduced fetal growth through modulation of the placental gene network

Maya A Deyssenroth et al. Environ Int. 2018 Nov.

Abstract

Background: Intrauterine metal exposures and aberrations in placental processes are known contributors to being born small for gestational age (SGA). However, studies to date have largely focused on independent effects, failing to account for potential interdependence among these markers.

Objectives: We evaluated the inter-relationship between multi-metal indices and placental gene network modules related to SGA status to highlight potential molecular pathways through which in utero multi-metal exposure impacts fetal growth.

Methods: Weighted quantile sum (WQS) regression was performed using a panel of 16 trace metals measured in post-partum maternal toe nails collected from the Rhode Island Child Health Study (RICHS, n = 195), and confirmation of the derived SGA-related multi-metal index was conducted using Bayesian kernel machine regression (BKMR). We leveraged existing placental weighted gene coexpression network data to examine associations between the SGA multi-metal index and placental gene expression. Expression of select genes were assessed using RT-PCR in an independent birth cohort, the New Hampshire Birth Cohort Study (NHBCS, n = 237).

Results: We identified a multi-metal index, predominated by arsenic (As) and cadmium (Cd), that was positively associated with SGA status (Odds ratio = 2.73 [1.04, 7.18]). This index was also associated with the expression of placental gene modules involved in "gene expression" (β = -0.02 [-0.04, -0.01]) and "metabolic hormone secretion" (β = 0.02 [0.00, 0.05]). We validated the association between cadmium exposure and the expression of GRHL1 and INHBA, genes in the "metabolic hormone secretion" module, in NHBCS.

Conclusion: We present a novel approach that integrates the application of advanced bioinformatics and biostatistics methods to delineate potential placental pathways through which trace metal exposures impact fetal growth.

Keywords: Birth weight; Gene coexpression network; Multi-metal exposure; Placenta.

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Figures

Figure 1.
Figure 1.. Adjusted odds ratios and 95% CI for SGA status given a log unit increase in individual trace metal levels.
Borderline positive associations were observed between SGA status and As and Cd levels. An inverse association was observed between SGA status and Ni levels.
Figure 2.
Figure 2.. Association between metal composite levels and SGA status based on weighted quantile sum (WQS) regression analysis.
Two separate WQS indices were generated, one modeled in the positive direction and one modeled in the inverse direction with respect to SGA status. Adjusted logistic regression models revealed that a WQS index predominated by contributions from As and Cd associated with increased odds of SGA status and a WQS index predominated by Ni and Al was associated with decreased odds of SGA status.
Figure 3.
Figure 3.. Association between placenta gene network modules and SGA status.
Eigengene values of previously derived placental gene network modules were modeled against SGA status using covariate-adjusted logistic regression models. The gene expression (greenyellow) module is observed to be inversely associated with SGA status and the metabolic hormone secretion (salmon ) module is observed to be positively associated with SGA status.
Figure 4.
Figure 4.. Association between placental gene network modules and metal exposure.
Among the SGA associated modules, covariate-adjusted models revealed a borderline positive association between the metabolic hormone secretion (salmon) module and Cd exposure as well as the SGA-associated WQS index, and an inverse association between the gene expression (greenyellow) module and As exposure as well as the SGA-associated WQS index.
Figure 5.
Figure 5.. Connectivity map of the gene expression (greenyellow) module.
Fifty genes annotated as As-responsive genes in the Comparative Toxicogenomics Database (CTD) load onto the gene expression (greenyellow) module (red nodes). The outermost nodes depict the most highly interconnected genes, also known as hub genes, within this module.
Figure 6.
Figure 6.. qRT-PCR validation of the association between placental expression of metabolic hormone secretion (salmon) module genes and maternal Cd exposure in the NHBCS cohort.
Covariate-adjusted generalized linear models revealed a positive relationship between gene expression and maternal Cd levelsin the NHBCS, with the associations reaching statistical significance for GRHL1 and INHBA. These findings are consistent with observations in the RICHS cohort.
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