Transcriptomic, proteomic, and metabolomic analyses identify candidate pathways linking maternal cadmium exposure to altered neurodevelopment and behavior

• Published in: Scientific reports Vol. 11; no. 1; pp. 16302 - 18
• Main Authors: Hudson, Kathleen M., Shiver, Emily, Yu, Jianshi, Mehta, Sanya, Jima, Dereje D., Kane, Maureen A., Patisaul, Heather B., Cowley, Michael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.08.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/136; 631/337/2019; 631/337/475; 631/378/2571; 631/378/2606; 631/378/3919; Animal models; Animals; Body Weight - drug effects; Body Weight - genetics; Cadmium; Cadmium - toxicity; Exposure; Female; Fetal Development - drug effects; Fetal Development - genetics; Fetuses; Heavy metals; HOX gene; Humanities and Social Sciences; Humans; Hypoxia; Maternal Exposure; Metabolites; Metabolomics; Metabolomics - methods; Mice; Mice, Inbred C57BL; Mitochondrial DNA; Molecular modelling; multidisciplinary; Myelin; Neurodevelopment; Neurodevelopmental Disorders - chemically induced; Neurodevelopmental Disorders - genetics; Offspring; Placenta; Placenta - drug effects; Placental transfer; Pregnancy; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - genetics; Proteomics; Proteomics - methods; Public concern; Retinoic acid; Retinoids; Science; Science (multidisciplinary); Signal transduction; Transcriptome - genetics; Transcriptomics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-95630-2

Cadmium (Cd) is a ubiquitous toxic heavy metal of major public concern. Despite inefficient placental transfer, maternal Cd exposure impairs fetal growth and development. Increasing evidence from animal models and humans suggests maternal Cd exposure negatively impacts neurodevelopment; however, the underlying molecular mechanisms are unclear. To address this, we utilized multiple -omics approaches in a mouse model of maternal Cd exposure to identify pathways altered in the developing brain. Offspring maternally exposed to Cd presented with enlarged brains proportional to body weights at birth and altered behavior at adulthood. RNA-seq in newborn brains identified exposure-associated increases in Hox gene and myelin marker expression and suggested perturbed retinoic acid (RA) signaling. Proteomic analysis showed altered levels of proteins involved in cellular energy pathways, hypoxic response, and RA signaling. Consistent with transcriptomic and proteomic analyses, we identified increased levels of retinoids in maternally-exposed newborn brains. Metabolomic analyses identified metabolites with significantly altered abundance, supportive of changes to cellular energy pathways and hypoxia. Finally, maternal Cd exposure reduced mitochondrial DNA levels in newborn brains. The identification of multiple pathways perturbed in the developing brain provides a basis for future studies determining the mechanistic links between maternal Cd exposure and altered neurodevelopment and behavior.