Oral Bisphenol A Worsens Liver Immune-Metabolic and Mitochondrial Dysfunction Induced by High-Fat Diet in Adult Mice: Cross-Talk between Oxidative Stress and Inflammasome Pathway.

Claudio Pirozzi,Chiara Annunziata,Oreste Gualillo,Gina Cavaliere,Mariano Stornaiuolo,Maria Pina Mollica,Federica Comella,Maria Carmela Ferrante,Giuseppina Mattace Raso,Anna Monnolo,Adriano Lama,Rosaria Meli,Clara Ruiz-Fernandez

doi:10.3390/antiox9121201

Claudio Pirozzi, Chiara Annunziata + Show 11 more

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https://doi.org/10.3390/antiox9121201

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Abstract

Lines of evidence have shown the embryogenic and transgenerational impact of bisphenol A (BPA), an endocrine-disrupting chemical, on immune-metabolic alterations, inflammation, and oxidative stress, while BPA toxic effects in adult obese mice are still overlooked. Here, we evaluate BPA’s worsening effect on several hepatic maladaptive processes associated to high-fat diet (HFD)-induced obesity in mice. After 12 weeks HFD feeding, C57Bl/6J male mice were exposed daily to BPA (50 μg/kg per os) along with HFD for 3 weeks. Glucose tolerance and lipid metabolism were examined in serum and/or liver. Hepatic oxidative damage (reactive oxygen species, malondialdehyde, antioxidant enzymes), and mitochondrial respiratory capacity were evaluated. Moreover, liver damage progression and inflammatory/immune response were determined by histological and molecular analysis. BPA amplified HFD-induced alteration of key factors involved in glucose and lipid metabolism, liver triglycerides accumulation, and worsened mitochondrial dysfunction by increasing oxidative stress and reducing antioxidant defense. The exacerbation by BPA of hepatic immune-metabolic dysfunction induced by HFD was shown by increased toll-like receptor-4 and its downstream pathways (i.e., NF-kB and NLRP3 inflammasome) amplifying inflammatory cytokine transcription and promoting fibrosis progression. This study evidences that BPA exposure represents an additional risk factor for the progression of fatty liver diseases strictly related to the cross-talk between oxidative stress and immune-metabolic impairment due to obesity.

Highlights

Bisphenol A (BPA) is considered one of the most widespread endocrine-disrupting chemicals (EDCs), substances affecting human health and impacting the endocrine system and immune and metabolic functions [1,2]
The increase in serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), and triglycerides induced by high-fat diet (HFD), was boosted by bisphenol A (BPA) (Table 1)
In the HFD + BPA group, body weight gain and food intake did not change compared to HFD mice, while a significant increase in fat mass was observed (STD = 2.823 ± 0.99 g; HFD = 10.68 ± 0.64 g, **** p < 0.0001 vs. Standard chow diet (STD); HFD + BPA = 13.91 ± 0.72 g, ## p < 0.01 vs. HFD)

Summary

Introduction

Bisphenol A (BPA) is considered one of the most widespread endocrine-disrupting chemicals (EDCs), substances affecting human health and impacting the endocrine system and immune and metabolic functions [1,2]. Many lines of evidence have highlighted the link between impaired immunity and obesity and their relationship with EDC exposure [3,4]. An increase in oxidative stress-associated inflammation has been hypothesized to be one of the major mechanisms in the pathogenesis of obesity-related diseases [5]. A rise in inflammatory cytokine levels drives a further increase in oxidative stress, sustaining a vicious cycle. In this regard, many toxic xenobiotics affect mitochondrial function and cause pro-oxidative conditions [6]

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