Mono-2-ethylhexyl phthalate induces the expression of genes involved in fatty acid synthesis in HepG2 cells

Bai, Jianying; He, Zhen; Li, Yaofu; Jiang, Xuexia; Yu, Hongmei; Tan, Qingyuan

doi:10.1016/j.etap.2019.04.004

Cited by 31 publications

(22 citation statements)

References 44 publications

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“…Bai et al evaluated MEPH effect on lipids accumulation in HepG2 cells, showing an increase in DNL in the initial hours of exposure due to increased expression of limiting enzymes such as FAS, acetyl-CoA carboxylase-1 (ACC1), and stearoyl-CoA desaturase-1 (SCD1). Interestingly, in later stages of exposure, a detriment of DNL was observed, probably mediated by compensatory mechanisms, so it is assumed that MEPH may also contribute to fatty acid transport to the liver [ 96 ].…”

Section: Mechanisms Of Action Of Endocrine-disrupting Chemicals In Nafldmentioning

confidence: 99%

Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review

Cano

Pérez

Angarita

et al. 2021

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.

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Section: Mechanisms Of Action Of Endocrine-disrupting Chemicals In Nafldmentioning

confidence: 99%

Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review

Cano

Pérez

Angarita

et al. 2021

IJMS

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“…Several studies have previously shown that exposures to MEHP or parent compound DEHP increased lipid accumulation in vitro or hepatic steatosis in vivo. [64][65][66] However, to our knowledge, this is the first study demonstrating that exposures during the embryonic period alone are capable of inducing lasting steatosis into the larval period.…”

Section: Discussionmentioning

confidence: 78%

Embryonic exposures to mono-2-ethylhexyl phthalate induce larval steatosis in zebrafish independent of Nrf2a signaling

Sant

Moreau

Williams

et al. 2020

J Dev Orig Health Dis

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Mono-2-ethylhexyl phthalate (MEHP) is the primary metabolite of the ubiquitous plasticizer and toxicant, di-2-ethylhexyl phthalate. MEHP exposure has been linked to abnormal development, increased oxidative stress, and metabolic syndrome in vertebrates. Nuclear factor, Erythroid 2 Like 2 (Nrf2), is a transcription factor that regulates gene expression in response to oxidative stress. We investigated the role of Nrf2a in larval steatosis following embryonic exposure to MEHP. Wild-type and nrf2a mutant (m) zebrafish embryos were exposed to 0 or 200 μg/l MEHP from 6 to either 96 (histology) or 120 hours post fertilization (hpf). At 120 hpf, exposures were ceased and fish were maintained in clean conditions until 15 days post fertilization (dpf). At 15 dpf, fish lengths and lipid content were examined, and the expression of genes involved in the antioxidant response and lipid processing was quantified. At 96 hpf, a subset of animals treated with MEHP had vacuolization in the liver. At 15 dpf, deficient Nrf2a signaling attenuated fish length by 7.7%. MEHP exposure increased hepatic steatosis and increased expression of peroxisome proliferator-activated receptor alpha target fabp1a1. Cumulatively, these data indicate that developmental exposure alone to MEHP may increase risk for hepatic steatosis and that Nrf2a does not play a major role in this phenotype.

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“…The occurrence of metabolic diseases after phthalate exposure might be linked to the activation of peroxisome proliferator-activated receptors (PPARs) [ 25 , 26 ], which are modulated by the sterol regulatory element binding proteins (SREBPs) [ 27 ]. In experimental studies, the disruption of gene expression related to fatty acid metabolism was suggested as a plausible mechanism in the development of NAFLD after phthalate exposure [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. However, there is a lack of clinical evidence to support the phthalates-NAFLD relationships.…”

Section: Introductionmentioning

confidence: 99%

Urinary Phthalate Levels Associated with the Risk of Nonalcoholic Fatty Liver Disease in Adults: The Korean National Environmental Health Survey (KoNEHS) 2012–2014

Yang

Kim

Hong

2021

IJERPH

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The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Recent experimental studies suggested that phthalates might induce NAFLD. Therefore, this study aimed to investigate the relationship between phthalates metabolites and NAFLD in the human population. This cross-sectional analysis was performed using data from the Korean National Environmental Health Survey II (2012–2014) among Korean adults (n = 5800). NAFLD was diagnosed using the hepatic steatosis index (HSI) in the absence of other causes of chronic liver diseases. Among the participants (mean age 46 years, 47.5% male), the prevalence of NAFLD was associated with urinary levels of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-benzyl phthalate (MBzP), and mono-n-butyl phthalate (MnBP) compared to the reference group. In the multivariate model, the odds ratios (ORs), 95% confidence interval (CI) for NAFLD were 1.33 (1.00–1.78) and 1.39 (1.00–1.92) in the 3rd and 4th quartile of MEHHP, respectively. Based on the study findings, high levels of urinary phthalates are associated with the prevalence of NAFLD in Korean adults. Further investigation is required to elucidate the causal relationship.

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Mono-2-ethylhexyl phthalate induces the expression of genes involved in fatty acid synthesis in HepG2 cells

Cited by 31 publications

References 44 publications

Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review

Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review

Embryonic exposures to mono-2-ethylhexyl phthalate induce larval steatosis in zebrafish independent of Nrf2a signaling

Urinary Phthalate Levels Associated with the Risk of Nonalcoholic Fatty Liver Disease in Adults: The Korean National Environmental Health Survey (KoNEHS) 2012–2014

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