Developmental programming: Preconceptional and gestational exposure of sheep to a real-life environmental chemical mixture alters maternal metabolome in a fetal sex-specific manner

Thangaraj, S. V.; Kachman, M.; Halloran, K. M.; Sinclair, K. D.; Lea, R.; Bellingham, M.; Evans, N. P.; Padmanabhan, V.

Abstract

Background
Everyday, humans are exposed to a mixture of environmental chemicals some of which have endocrine and/or metabolism disrupting actions which may contribute to non-communicable diseases. The adverse health impacts of real-world chemical exposure, characterized by chronic low doses of a mixture of chemicals, are only recently emerging. Biosolids derived from human waste represent the environmental chemical mixtures humans are exposed to in real life. Prior studies in sheep have shown aberrant reproductive and metabolic phenotypes in offspring after maternal biosolids exposure.

Objective
To determine if exposure to biosolids perturbs the maternal metabolic milieu of pregnant ewes, in a fetal sex-specific manner.

Methods
Ewes were grazed on inorganic fertilizer (Control) or biosolids-treated pastures (BTP) from before mating and throughout gestation. Plasma from pregnant ewes (Control n = 15, BTP n = 15) obtained mid-gestation were analyzed by untargeted metabolomics. Metabolites were identified using Agilent MassHunter. Multivariate analyses were done using MetaboAnalyst 5.0 and confirmed using SIMCA.

Results
Univariate and multivariate analysis of 2301 annotated metabolites identified 193 differentially abundant metabolites (DM) between control and BTP sheep. The DM primarily belonged to the super-class of lipids and organic acids. 15-HeTrE, oleamide, methionine, CAR(3:0(OH)) and pyroglutamic acid were the top DM and have been implicated in the regulation of fetal growth and development. Fetal sex further exacerbated differences in metabolite profiles in the BTP group. The organic acids class of metabolites was abundant in animals with male fetuses. Prenol lipid, sphingolipid, glycerolipid, alkaloid, polyketide and benzenoid classes showed fetal sex-specific responses to biosolids.

Discussion
Our study illustrates that exposure to biosolids significantly alters the maternal metabolome in a fetal sex-specific manner. The altered metabolite profile indicates perturbations to fatty acid, arginine, branched chain amino acid and one‑carbon metabolism. These factors are consistent with, and likely contribute to, the adverse phenotypic outcomes reported in the offspring.

Citation

Thangaraj, S. V., Kachman, M., Halloran, K. M., Sinclair, K. D., Lea, R., Bellingham, M., …Padmanabhan, V. (2023). Developmental programming: Preconceptional and gestational exposure of sheep to a real-life environmental chemical mixture alters maternal metabolome in a fetal sex-specific manner. Science of the Total Environment, 864, Article 161054. https://doi.org/10.1016/j.scitotenv.2022.161054

• Journal Article Type: Article
• Acceptance Date: Dec 15, 2022
• Online Publication Date: Dec 26, 2022
• Publication Date: Mar 15, 2023
• Deposit Date: Aug 16, 2023
• Publicly Available Date: Dec 27, 2023
• Journal: Science of The Total Environment
• Print ISSN: 0048-9697
• Electronic ISSN: 1879-1026
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 864
• Article Number: 161054
• DOI: https://doi.org/10.1016/j.scitotenv.2022.161054
• Public URL: https://nottingham-repository.worktribe.com/output/24417587
• Publisher URL: https://www.sciencedirect.com/science/article/abs/pii/S0048969722081578?via%3Dihub