Maternal PBDE exposure disrupts gut microbiome and promotes hepatic proinflammatory signaling in humanized PXR-transgenic mouse offspring over time.

Developmental exposure to the persistent environmental pollutant, polybrominated diphenyl ethers (PBDEs), is associated with increased diabetes prevalence. The microbial tryptophan metabolite, indole-3-propionic acid (IPA), is associated with reduced risk of type 2 diabetes and lower-grade inflammation and is a pregnane X receptor (PXR) activator. To explore the role of IPA in modifying the PBDE developmental toxicity, we orally exposed humanized PXR-transgenic (hPXR-TG) mouse dams to vehicle, 0.1 mg/kg/day DE-71 (an industrial PBDE mixture), DE-71+IPA (20 mg/kg/day), or IPA, from 4 weeks preconception to the end of lactation. Pups were weaned at 21 days of age and IPA supplementation continued in the corresponding treatment groups. Tissues were collected at various ages until 6 months of age (n = 5 per group). In general, the effect of maternal DE-71 exposure on the gut microbiome of pups was amplified over time. The regulation of hepatic cytokines and prototypical xenobiotic-sensing transcription factor target genes by DE-71 and IPA was age- and sex-dependent, where DE-71-mediated mRNA increased selected cytokines (Il10, Il12p40, Il1β [both sexes], and [males]). The hepatic mRNA of the aryl hydrocarbon receptor (AhR) target gene Cyp1a2 was increased by maternal DE-71 and DE-71+IPA exposure at postnatal day 21 but intestinal Cyp1a1 was not altered by any of the exposures and ages. Maternal DE-71 exposure persistently increased serum indole, a known AhR ligand, in age- and sex-dependent manner. In conclusion, maternal DE-71 exposure produced a proinflammatory signature along the gut-liver axis, including gut dysbiosis, dysregulated tryptophan microbial metabolism, attenuated PXR signaling, and elevated AhR signaling in postweaned hPXR-TG pups over time, which was partially corrected by IPA supplementation.