Abstract
Background
Prenatal cadmium (Cd) exposure has been implicated in both placental toxicity and adverse neurobehavioral outcomes. Placental microRNAs (miRNAs) may function to developmentally program adverse pregnancy and newborn health outcomes in response to gestational Cd exposure.
Methods
In a subset of the Rhode Island Child Health Study (RICHS, nā=ā115) and the New Hampshire Birth Cohort Study (NHBCS,ā=ā281), we used small RNA sequencing and trace metal analysis to identify Cd-associated expression of placental miRNAs using negative binomial generalized linear models. We predicted mRNAs targeted by Cd-associated miRNAs and relate them to neurobehavioral outcomes at birth through the integration of transcriptomic data and summary scores from the NICU Network Neurobehavioral Scale (NNNS).
Results
Placental Cd concentrations are significantly associated with the expression level of five placental miRNAs in NHBCS, with similar effect sizes in RICHS. These miRNA target genes overrepresented in nervous system development, and their expression is correlated with NNNS metrics suggestive of atypical neurobehavioral outcomes at birth.
Conclusions
Gestational Cd exposure is associated with the expression of placental miRNAs. Predicted targets of these miRNAs are involved in nervous system development and may also regulate placental physiology, allowing their dysregulation to modify developmental programming of early life health outcomes.
Impact
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This research aims to address the poor understanding of the molecular mechanisms governing adverse pregnancy and newborn health outcomes in response to Gestational cadmium (Cd) exposure.
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Our results outline a robust relationship between Cd-associated placental microRNA expression and NICU Network Neurobehavioral Scales (NNNS) at birth indicative of atypical neurobehavior.
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This study utilized healthy mother-infant cohorts to describe the role of Cd-associated dysregulation of placental microRNAs as a potential mechanism by which adverse neurobehavioral outcomes are developmentally programmed.
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Data availability
The data that support the findings of this study, and example code used in the current study, are available publicly from the UNC Dataverse repository at https://doi.org/10.15139/S3/KHXJ2G. Summary level results from the analyses conducted in the current study are included within the published article, and its Supplementary Information files.
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Acknowledgements
We acknowledge the cooperation of the participants enrolled in the RICHS and NHBCS, and the contributions of the research staff who also worked on RICHS and NHBCS.
Funding
This work was supported by the National Institutes of Health (NIH-NIGMS T32GM008490, NIH-NIEHS R24ES028507, NIH-NIEHS R01ES025145, NIH-NIEHS P30ES019776; NIH-NIGMS P20GM104416 and NIH-NIMHD R01MD011698).
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Study design: C.J.M., J.C., M.R.K., B.L., K.H., and D.C.K. Data collection: A.B., K.H., T.P., and B.P.J. Statistical analysis: J.M.T., E.K., P.W.T., and D.C.K. Interpretation of results: J.M.T., E.K., and P.W.T. Manuscript drafting and revisions: all authors.
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All participants provided written, informed consent and all protocols were approved by the IRBs at the Women & Infants Hospital of Rhode Island, Dartmouth College and Emory University, respectively.
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Tehrani, J.M., Kennedy, E., Tung, P.W. et al. Human placental microRNAs dysregulated by cadmium exposure predict neurobehavioral outcomes at birth. Pediatr Res 93, 1410ā1418 (2023). https://doi.org/10.1038/s41390-022-02201-w
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DOI: https://doi.org/10.1038/s41390-022-02201-w
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