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Developmental Exposure to a Perfluorooctanesulfonic acid, Perfluorooctanoic acid, Perfluorohexanesulfonic Mixture Alters the Neonatal Lung Proteome

ABSTRACT: This study aimed to assess PFAS distribution and lung proteome changes in CD-1 offspring after gestational and lactational exposure to PFOS, PFOA, PFHxS, or a PFAS mix. A secondary aim was to evaluate how maternal exposure to a high fat diet (HFD) affected the latter endpoints. Pregnant CD-1 mice received PFOA, PFOS, PFHxS (1 mg/kg), a PFAS mix (1 mg/kg each), or vehicle. Dams were fed standard diet (SD) or high fat diet (HFD), and PFAS were administered from gestation day 1 to postnatal day 20. At PND 21, lung PFAS concentration was measured using LC-MS/MS, and proteomic analysis was conducted. Results from LC-MS/MS analysis showed a significant overall difference in PFOS, PFOA, and PFHxS levels and the treatment groups with PFHxS concentration were significantly higher compared to PFOS and PFOA. Proteomic analysis determined female pups exposed to maternal HFD Mix (Mix HFD female) and PFOS (PFOS HFD female) had the most differentially expressed proteins followed by PFOS SD male, Mix SD female, and Mix SD male. Canonical pathways like EIF2 signaling, mTOR signaling, and mitochondrial dysfunction were differentially modulated. This study provides insights into PFAS distribution, the molecular mechanism, biomarkers on the neonatal lung in animal models following perinatal exposure.

INSTRUMENT(S): ABSciex Triple TOF5600

ORGANISM(S): Mus <mouse, Genus> (ncbitaxon:10088)

SUBMITTER: Angela Slitt

PROVIDER: MSV000093587 | MassIVE | Wed Dec 06 10:18:00 GMT 2023

REPOSITORIES: MassIVE

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Project description:Objective Recent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity. Methods We used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system. Results Maternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD-programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self-renewal and activation of pathways regulating cell migration. Conclusions Our data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment. Examination of differentially expressed genes between gestational day 15 (+/- 0.5 days) C57BL/6 mouse fetal livers from diet-induced (60% fat diet) obese or control female mice.

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Developmental Exposure to a Perfluorooctanesulfonic acid, Perfluorooctanoic acid, Perfluorohexanesulfonic Mixture Alters the Neonatal Lung Proteome

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