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Peripubertal Bisphenol A Exposure Imparts Detrimental Acute and Aging-Related Changes in Body Composition, Cognition, and H2S Production and Signaling

ABSTRACT: Peripubertal endocrine disruption has immediate and lifelong consequences on health, cognition, and lifespan. Disruption comes from dietary, environmental, and pharmaceutical sources. The plasticizer Bisphenol A (BPA) is one such endocrine disrupting chemical (EDC). However, it’s unclear if peripubertal BPA exposure incites long-lasting physiological, neuro-cognitive, and/or longevity-related metabolic impairments. Catabolism of cysteine via transsulfuration enzymes produces hydrogen sulfide (H2S), a redox-modulating gasotransmitter causative to endocrine and metabolic homeostasis and improved cognitive function with age. As thyroid hormone (TH) regulates hepatic H2S production and BPA is a TH receptor antagonist, we hypothesized BPA exposure during peripubertal development impairs metabolic and neuro-cognitive/behavioral endpoints in aged mice, in part, due to altered peripheral H2S production. Results: To test this, male C57BL/6J mice at 5 weeks of age were orally exposed for 5 weeks to 250 ug BPA/kg defined as low dose group (LD BPA), or 250 mg BPA/kg defined as high dose group (HD BPA). Both LD and HD BPA exposure decreased lean mass and increased fat mass. These changes were accompanied by decreased serum total TH. Additionally, LD BPA had an anxiogenic effect while HD BPA caused cognitive deficits. Notably, HD BPA attenuated renal H2S production both acutely and during aging, which correlated with spatial memory deficits. Innovation and Conclusion: These findings provide a potential mechanism of action for the acute and long-term health impacts of BPA-induced peripubertal endocrine disruption and bolster the need for improved monitoring and limitation of adolescent BPA exposure.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Nazmin Bithi

LAB HEAD: Christopher Hine

PROVIDER: PXD025746 | Pride | 2021-05-25

REPOSITORIES: Pride

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Project description:In a recent egg injection study, we showed that in ovo exposure to perfluorohexane sulfonate (PFHxS) affects the pipping success of developing chicken (Gallus gallus domesticus) embryos. We also found evidence of thyroid hormone (TH) pathway interference at multiple levels of biological organization (i.e. somatic growth, mRNA expression and circulating free thyroxine levels). Based on these findings, we hypothesize that PFHxS exposure interferes with TH-dependent neurodevelopmental pathways. The present study investigates global transcriptional profiles of cerebral cortex tissue from chicken embryos following exposure to a solvent control, 890 or 38,000 ng PFHxS/g egg (n=4-5 per group); doses which lead to the adverse effects above. PFHxS significantly alters the expression (≥1.5-fold, p≤0.001) of 11 transcripts at the low dose (LD; 890 ng/g) and 101 transcripts at the high dose (HD; 38,000 ng/g). Functional enrichment analysis shows that PFHxS affects genes involved in tissue development and morphology, cellular assembly and organization, and cell-to-cell signalling. Pathway and interactome analyses suggest that genes may be affected through several potential regulatory molecules, including integrin receptors, myelocytomatosis viral oncogene and CCAAT/enhancer binding protein. This study identifies key functional and regulatory modes of PFHxS action involving TH-dependent and -independent neurodevelopmental pathways. Some of these TH-dependent mechanisms that occur during embryonic development include tight junction formation, signal transduction and integrin signaling, while TH-independent mechanisms include gap junction intercellular communication. Reference Design. Reference = pool of equal parts of all control and treated samples. Control groups and 2 treatment groups. Control samples were chicken embryonic cerebral cortex exposed DMSO only (solvent). Treatments were: chicken embryonic cerebral cortex exposed to 890 ng/g PFHxS (LD) and 38,000 ng/g PFHxS (HD).

Dataset Information

Peripubertal Bisphenol A Exposure Imparts Detrimental Acute and Aging-Related Changes in Body Composition, Cognition, and H2S Production and Signaling

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