A moderate physiological dose of benzyl butyl phthalate exacerbates the high fat diet-induced diabesity in male mice

Zhang, Jiän; Powell, Catherine A.; Kay, Matthew; Park, Min Hi; Meruvu, Sunitha; Choudhury, Mahua

doi:10.1093/toxres/tfaa037

Cited by 14 publications

(14 citation statements)

References 84 publications

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“…The obesogen hypothesis has opened a new area of study by connecting EDC research with metabolic diseases. Even though BBP has been suggested as an obesogen in an in vitro screening almost 8 years back (as per our knowledge), we were the first group to show in 2020 that BBP could lead to metabolic abnormalities in vivo . However, the specific mechanism or any role of the epigenetic pathway remains unknown.…”

Section: Discussionsupporting

confidence: 66%

“…The highest toxicities were observed during the embryonic development . Recent in vitro studies indicated BBP as an obesogen capable of inducing adipogenesis in 3T3-L1 preadipocytes and converting them into mature adipocytes. , In vivo , our group recently showed that the moderate concentrations of BBP in a high-fat diet (HFD) significantly increased the body weight of male C57BL6 mice due to the significant increment in the weight of the liver and adipose tissue . Since obesity and the associated metabolic syndrome are rising steadily in the industrialized world, it is imperative to understand the molecular mechanisms that occur with BBP exposure.…”

Section: Introductionmentioning

confidence: 99%

“…10,11 In vivo, our group recently showed that the moderate concentrations of BBP in a high-fat diet (HFD) significantly increased the body weight of male C57BL6 mice due to the significant increment in the weight of the liver and adipose tissue. 12 Since obesity and the associated metabolic syndrome are rising steadily in the industrialized world, it is imperative to understand the molecular mechanisms that occur with BBP exposure.…”

Section: ■ Introductionmentioning

confidence: 99%

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Butyl Benzyl Phthalate Promotes Adipogenesis in 3T3-L1 Cells via the miRNA-34a-5p Signaling Pathway in the Absence of Exogenous Adipogenic Stimuli

Meruvu

Zhang

Choudhury

2021

Chem. Res. Toxicol.

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Phthalates, a plasticizer group, are used extensively in many of the products we use every day. Public health concerns are growing as recent studies have implicated butyl benzyl phthalate (BBP) as an obesogen. However, BBP-induced epigenetic regulation during adipogenesis is still unknown. We investigated if BBP altered miR-34a-5p, a key miRNA involved in obesity, and regulated its downstream pathway. Differentiating 3T3-L1 cells were exposed to various doses of BBP without exogenous adipogenic stimuli, tested for adipogenesis markers (PPARγ and aP2), and stained for lipid accumulation with Oil Red O staining. We then measured the expression of miR-34a-5p and its target genes, Nampt and Sirt1, along with another significant epigenetic modulator, Sirt3. Furthermore, using antagomiR, we examined whether miR-34a-5p knockdown decreased adipogenesis. BBP exposure resulted in augmented expression levels of miR-34a-5p with an associated increase in adipogenesis. BBP significantly decreased the Nampt, Sirt1, and Sirt3 gene expression levels. However, a decrease in the protein expression was observed only for Nampt, indicating that miR-34a-5p under BBP exposure may regulate Sirt1/Sirt3 only at the transcriptional level. Interestingly, in the presence of BBP, knockdown of miR-34a-5p decreased adipogenesis in the differentiating 3T3-L1 cells. Furthermore, miR-34a-5p knockdown increased the Nampt protein expression levels as well as NAD + levels, indicating that miR-34a-5p regulates Nampt during BBP exposure. Additionally, the NAD + -dependent sirtuin activity decreased in BBP-treated cells and increased in miR-34a-5p knockdown cells with BBP treatment. BBP exposure demonstrated the involvement of epigenetic regulation by altering the expression patterns of miR-34a-5p and its target Nampt, which may perturb the energy homeostasis of the differentiating adipocytes by altering NAD + levels and sirtuin activity, resulting in increased adipogenesis.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Butyl Benzyl Phthalate Promotes Adipogenesis in 3T3-L1 Cells via the miRNA-34a-5p Signaling Pathway in the Absence of Exogenous Adipogenic Stimuli

Meruvu

Zhang

Choudhury

2021

Chem. Res. Toxicol.

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“…Interestingly enough, our group recently showed that the male C57BL6 mice exposed to moderate concentrations of BBP in a high fat diet (HFD) showed significant increases in body weight due to significant increases in weight of liver and adipose tissue . BBP with HFD also showed significant increases in fasting blood glucose, glucose intolerance, and insulin intolerance when compared to HFD alone.…”

Section: Discussionmentioning

confidence: 99%

Benzyl Butyl Phthalate Induced Early lncRNA H19 Regulation in C3H10T1/2 Stem Cell Line

Zhang

Choudhury

2021

Chem. Res. Toxicol.

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Exposure to endocrine-disrupting chemicals used in plastic manufacturing may contribute to the current obesity and diabetes epidemic. Our previous study demonstrated that benzyl butyl phthalate (BBP) induced adipogenesis in the C3H10T1/2 stem cell line. Here we investigated if BBP deregulated long noncoding RNA H19 and its downstream pathway and whether BBP plays a role in the insulin signaling pathway during adipocyte diiferentiation. Cells treated with an 8 day BBP regimen showed that H19 expression was decreased at day 2 with 50 μM BBP exposure (p < 0.05). However, no significant changes were observed from day 4 to day 8. Expression of miRNA-103/107, H19 regulated miRNAs, was upregulated at day 2 (p < 0.05) but not from day 4 to day 8. Similarly, expression of the let-7 family members (a, b, c, d, f, and g) was also significantly increased at day 2 (p < 0.05 or p < 0.01), except for let-7e. Both let-7 and miRNA-103/107 are targets of H19 and play roles in insulin signaling. Insulin receptor substrate (IRS)-1, one of the key insulin signal transduction regulators, was significantly downregulated from day 2 to day 8 (p < 0.05). Gene expression of insulin receptor (IR) and IRS-2 were not altered by BBP exposure. The ratio of IRS1/IRS2 was significantly decreased from day 2 to day 8. On day 4, phospho-Akt protein expression was significantly decreased (p < 0.05). In conclusion, BBP exposure may lead to metabolic dysregulation by altering vital epigenetic regulators such as lncRNA H19 and its target microRNAs at an earlier stage, which further regulates insulin signaling.

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“…BBP exposure in C57BL/6 mice was also shown to potentiate the adipogenic effect of HFD through an increase in liver and adipose tissue mass, also inducing insulin resistance, although the effect was observed only in moderate, but not low or high, doses [210].…”

Section: Phthalatesmentioning

confidence: 97%

The Role of Persistent Organic Pollutants in Obesity: A Review of Laboratory and Epidemiological Studies

Aaseth

Javorac

Djordjevic

et al. 2022

Toxics

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Persistent organic pollutants (POPs) are considered as potential obesogens that may affect adipose tissue development and functioning, thus promoting obesity. However, various POPs may have different mechanisms of action. The objective of the present review is to discuss the key mechanisms linking exposure to POPs to adipose tissue dysfunction and obesity. Laboratory data clearly demonstrate that the mechanisms associated with the interference of exposure to POPs with obesity include: (a) dysregulation of adipogenesis regulators (PPARγ and C/EBPα); (b) affinity and binding to nuclear receptors; (c) epigenetic effects; and/or (d) proinflammatory activity. Although in vivo data are generally corroborative of the in vitro results, studies in living organisms have shown that the impact of POPs on adipogenesis is affected by biological factors such as sex, age, and period of exposure. Epidemiological data demonstrate a significant association between exposure to POPs and obesity and obesity-associated metabolic disturbances (e.g., type 2 diabetes mellitus and metabolic syndrome), although the existing data are considered insufficient. In conclusion, both laboratory and epidemiological data underline the significant role of POPs as environmental obesogens. However, further studies are required to better characterize both the mechanisms and the dose/concentration-response effects of exposure to POPs in the development of obesity and other metabolic diseases.

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A moderate physiological dose of benzyl butyl phthalate exacerbates the high fat diet-induced diabesity in male mice

Cited by 14 publications

References 84 publications

Butyl Benzyl Phthalate Promotes Adipogenesis in 3T3-L1 Cells via the miRNA-34a-5p Signaling Pathway in the Absence of Exogenous Adipogenic Stimuli

Butyl Benzyl Phthalate Promotes Adipogenesis in 3T3-L1 Cells via the miRNA-34a-5p Signaling Pathway in the Absence of Exogenous Adipogenic Stimuli

Benzyl Butyl Phthalate Induced Early lncRNA H19 Regulation in C3H10T1/2 Stem Cell Line

The Role of Persistent Organic Pollutants in Obesity: A Review of Laboratory and Epidemiological Studies

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