Maternal exposure to di-2-ethylhexyl phthalate (DEHP) depresses lactation capacity in mice

Increasing evidence shows that di-2-ethylhexyl phthalate (DEHP), mostly commonly used phthalate for the production of flexible polyvinyl chloride (PVC), has the potential to induce serious health risks in humans. However, the understanding of DEHP-induced lactation performance remains largely unknown. We sought to investigate the adverse effects of DEHP on lactation and examine the underlying mechanism linking DEHP exposure with the lactation alterations. We successfully adapted a maternal DEHP exposure model in female pregnant/lactating mice. Then we determined effects of DEHP exposure on food intake, body weight and milk production as well as the alterations in endocrine factors in lactating mice. The integrated metabonomic and transcriptomic analyses of the mammary gland were performed to measure the changed metabolites and genes related to DEHP exposure-induced lactation alterations. We observed the reduced food intake with elevated blood leptin and the decreased milk yield as well as the reduced levels of serum prolactin, growth hormone, insulin-like growth factor 1 and insulin after exposed to DEHP. Furthermore, 208 metabolites and 3452 genes were separately identified as differentially expressed features associated with DEHP exposure. Integrated metabonomic and transcriptomic analyses demonstrated that DEHP caused lactation depression mainly through impairing energy generation, inducing stress responses along with the hypoactivation of inflammation, reducing the production of antioxidants, disrupting hormone homeostasis and repressing the synthesis of milk constituents (the lower glucose availability for lactose synthesis; the disruption of milk fat globule membrane for lipid droplet formation; the ribosomal dysfunction and disruption of post-modifications for milk protein synthesis). We demonstrated that DEHP disrupted several lactation-related hormone homeostasis and multiple processes like energy insufficiency, inflammation activation, oxidative stress aggravation and disturbance of milk production in the mammary gland of female lactating mice. Our results provide valuable information for the health risk of plastic additive (DEHP) on female lactation dysfunction.