Low-dose Bisphenol-A Promotes Epigenetic Changes at Pparγ Promoter in Adipose Precursor Cells.

Michele Longo,Pietro Formisano,Cecilia Nigro,Jamal Naderi,Francesco Oriente,Francesco Beguinot,Federica Zatterale,Claudia Miele

doi:10.3390/nu12113498

Abstract

Exposure to endocrine-disrupting chemicals such as Bisphenol-A (BPA) is associated with an increase in obesity prevalence. Diet is the primary cause of human exposure to this contaminant. BPA promotes obesity by inducing adipocyte dysfunction and altering adipogenesis. Contradictory evidence and unanswered questions are reported in the literature concerning the BPA effects on adipogenesis. To clarify this issue, we tested the effects of prolonged low-dose BPA exposure on different phases of adipogenesis in committed 3T3L1 and uncommitted NIH3T3 preadipocytes. Our findings show that BPA effects on the adipogenesis are mediated by epigenetic mechanisms by reducing peroxisome proliferator-activated receptor gamma (Pparγ) promoter methylation in preadipocytes. Nevertheless, in BPA-exposed 3T3L1, Pparγ expression only transiently increases as lipid accumulation at day 4 of differentiation, without altering the adipogenic potential of the precursor cells. In the absence of differentiation mix, BPA does not make the 3T3L1 an in vitro model of spontaneous adipogenesis and the effects on the Pparγ expression are still limited at day 4 of differentiation. Furthermore, BPA exposure does not commit the NIH3T3 to the adipocyte lineage, although Pparγ overexpression is more evident both in preadipocytes and during the adipocyte differentiation. Interestingly, termination of the BPA exposure restores the Pparγ promoter methylation and inflammatory profile of the 3T3L1 cells. This study shows that BPA induces epigenetic changes in a key adipogenic gene. These modifications are reversible and do not affect preadipocyte commitment and/or differentiation. We identify an alternative transcriptional mechanism by which BPA affects gene expression and demonstrate how the challenge of preventing exposure is fundamental for human health.

Highlights

In the last decade, the prevalence of obesity has risen significantly, but despite considerable attempts to establish the underlying mechanisms, the causes of the epidemic remain unclear [1,2].Importantly, type 2 diabetes, metabolic syndrome, cardiovascular disease, and cancer are associated with obesity prevalence [3,4,5].The causes of the alarming rise in the incidence of these diseases include excessive calorie consumption, food composition, physical inactivity, and exposure to environmental pollutants such as Nutrients 2020, 12, 3498; doi:10.3390/nu12113498 www.mdpi.com/journal/nutrientsNutrients 2020, 12, 3498 endocrine-disrupting chemicals (EDCs) [6]
All experiments were performed in cells between passages 4–6. 3T3L1 and NIH3T3 cells were seeded at a density of 6 × 104 cells per well and cultured in 3 mL of medium. 3T3L1 and NIH3T3 cells were treated with BPA (1 nM) or vehicle for 8 days before the induction of adipogenesis and during the differentiation process
We tested the effect of BPA exposure on Pparγ expression in murine 3T3L1 preadipocytes

Summary

Introduction

The prevalence of obesity has risen significantly, but despite considerable attempts to establish the underlying mechanisms, the causes of the epidemic remain unclear [1,2].Importantly, type 2 diabetes, metabolic syndrome, cardiovascular disease, and cancer are associated with obesity prevalence [3,4,5].The causes of the alarming rise in the incidence of these diseases include excessive calorie consumption, food composition, physical inactivity, and exposure to environmental pollutants such as Nutrients 2020, 12, 3498; doi:10.3390/nu12113498 www.mdpi.com/journal/nutrientsNutrients 2020, 12, 3498 endocrine-disrupting chemicals (EDCs) [6]. Programme on Chemical Safety (IPCS) of the World Health Organization (WHO), EDCs are exogenous substances or mixtures that alter the functions of the endocrine system and cause adverse health effects in an intact organism, or its progeny [12]. Such chemicals are ubiquitous and extensively contaminate food and water [12,13]. The primary source of these pollutants is mainly plastic food storage items, such as bottles and containers. Products in bottles and plastic containers have the highest concentrations of BPA independently of the specific nutrient category [16,17,18]

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