Maternal di(2-ethylhexyl) phthalate (DEHP) exposure alters offspring gut microbiota and the colonic transcriptome in a sex-specific manner

Maternal exposure to the plasticizer DEHP during gestation and lactation programs lasting sex-specific alterations in offspring intestinal health. This study investigated the transgenerational effects of perinatal DEHP exposure on offspring intestinal health using a C57BL/6 mouse model. Dams were exposed to 0, 40, or 400 ppm DEHP via their diet during gestation and lactation. We analyzed the growth phenotypes, intestinal histology, gut microbiota, and colonic transcriptomics of the offspring. We found that perinatal DEHP exposure did not affect the growth of dams or offspring but induced significant intestinal structural damage. In both male and female offspring, this damage manifested as reduced colon length and decreased colonic goblet cell counts. This common insult triggered strongly divergent downstream responses. Colonic transcriptomics revealed that female offspring displayed a robust defense characterized by the significant upregulation of xenobiotic metabolism pathways (e.g., the expression of the cytochrome P450 genes Cyp3a44 and Cyp3a25 ). Conversely, male offspring showed a muted transcriptional response skewed toward immune modulation. The gut microbiota was reshaped in a sex-dependent manner: male offspring exhibited increased microbial diversity and a decrease in Bacteroides species, whereas females showed enrichment of the mucin-degrading Akkermansia muciniphila . Integrated functional analysis predicted a male-biased shift toward host-microbe energy metabolism and a female-biased shift toward lipid and detoxification pathways. These findings demonstrate that maternal DEHP exposure compromises intestinal barrier integrity and establishes sexually dimorphic microbiota–host metabolic axes, providing a novel mechanism for the developmental programming of long-term disease susceptibility by environmental endocrine disruptors.