The food additive BHA modifies energy metabolism in the perfused rat liver

Pateis, Vanesa de Oliveira; Castro, Lorena dos Santos; Salla, Gabriela Bueno Franco; Comar, Jurandir Fernando; Parizotto, Ângela Valderrama; Peralta, Rosane Marina; Bracht, Adelar

doi:10.1016/j.toxlet.2018.10.005

Cited by 24 publications

(15 citation statements)

References 35 publications

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“…The liver is an essential metabolic organ in regulating energy homeostasis via multiple signaling molecules and pathways, which can be vulnerably affected by exogenous substances . Typically, many metabolism-disrupting chemicals could induce visceral obesity and insulin resistance, which played a key role in the development of hepatic steatosis. ,, As a widely used food antioxidant, 3-BHA has been shown to interfere with the energy metabolism by increasing glycolysis and inhibiting mitochondrial ATP generation in the perfused rat liver . Our previous study also suggested that 3-BHA could act as a potential obesogen by increasing intracellular TG levels, inducing adipocyte hypertrophy and regulating the transcription of the genes involved in adipogenesis .…”

Section: Discussionmentioning

confidence: 92%

3-tert-Butyl-4-hydroxyanisole Impairs Hepatic Lipid Metabolism in Male Mice Fed with a High-Fat Diet

Sun

Zhi

Yang

et al. 2022

Environ. Sci. Technol.

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3-tert-Butyl-4-hydroxyanisole (3-BHA), one of the widely used food antioxidants, has been found to act as a potential obesogen by promoting adipogenesis in vitro and inducing white adipose tissue development in vivo. Whether 3-BHA-induced visceral obesity was accompanied by a disruption of hepatic lipid homeostasis in mammals remained unclear. In this study, we evaluated the effect of 3-BHA on the development of nonalcoholic fatty liver disease (NAFLD) in male C57BL/6J mice. After 18 weeks of oral administration of 10 mg/kg 3-BHA, the mice fed with a high-fat diet (HFD) had higher hepatic triglyceride concentrations (0.32 mg/mg protein) and severer steatosis (1.57 for the NAFLD score) than the control ones. The in vivo hepatic lipid deposition disturbed by 3-BHA was transcriptionally regulated by the genes involved in lipid uptake, de novo lipogenesis, fatty acid oxidation, and lipid export. The in vitro studies further confirmed that 24 h of exposure to 50 μM 3-BHA could induce intracellular oleic acid (OA) uptake and triglyceride accumulation (1.5-fold of the OA control) in HepG2 cells. Lipidomic analysis indicated the perturbation of 3-BHA in the levels of 30 lipid species related to sphingolipids, glycerophospholipids, and glycerolipids under HFD conditions. The findings herein first revealed the disruption effect of 3-BHA on hepatic lipid homeostasis, thus exacerbating the development of HFD-induced NAFLD.

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Section: Discussionmentioning

confidence: 92%

3-tert-Butyl-4-hydroxyanisole Impairs Hepatic Lipid Metabolism in Male Mice Fed with a High-Fat Diet

Sun

Zhi

Yang

et al. 2022

Environ. Sci. Technol.

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“…A previous study found that high doses of BHA (500 and 750 μM) have toxic effects on the livers of rats . In addition, 0.5% BHA in chow fed to pregnant mice induced sleep deficit and slow learning in offspring .…”

Section: Introductionmentioning

confidence: 99%

“…A previous study found that high doses of BHA (500 and 750 μM) have toxic effects on the livers of rats. 18 In addition, 0.5% BHA in chow fed to pregnant mice induced sleep deficit and slow learning in offspring. 19 Therefore, it is important to study the neurotoxic effects of high doses of BHA on human brain development.…”

Section: ■ Introductionmentioning

confidence: 99%

Butylated Hydroxyanisole Exerts Neurotoxic Effects by Promoting Cytosolic Calcium Accumulation and Endoplasmic Reticulum Stress in Astrocytes

Lee

Lim

You

et al. 2019

J. Agric. Food Chem.

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Astrocytes provide nutritional support, regulate inflammation, and perform synaptic functions in the human brain. Although butylated hydroxyanisole (BHA) is a well-known antioxidant, several studies in animals have indicated BHAmediated liver toxicity, retardation in reproductive organ development and learning, and sleep deficit. However, the specific effects of BHA on human astrocytes and the underlying mechanisms are yet unclear. Here, we investigated the antigrowth effects of BHA through cell cycle arrest and downregulation of regulatory protein expression. The typical cell proliferative signaling pathways, phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase 1/2, were downregulated in astrocytes after BHA treatment. BHA increased the levels of pro-apoptotic proteins, such as BAX, cytochrome c, cleaved caspase 3, and cleaved caspase 9, and decreased the level of anti-apoptotic protein BCL-XL. It also increased the cytosolic calcium level and the expression of endoplasmic reticulum stress proteins. Treatment with BAPTA-AM, a calcium chelator, attenuated the increased levels of ER stress proteins and cleaved members of the caspase family. We further performed an in vivo evaluation of the neurotoxic effect of BHA on zebrafish embryos and glial fibrillary acidic protein, a representative astrocyte biomarker, in a gfap:eGFP zebrafish transgenic model. Our results provide clear evidence of the potent cytotoxic effects of BHA on human astrocytes, which lead to disruption of the brain and nerve development.

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“…The excess free radicals have devastating effects on health, leading to diseases such as cardiovascular disease (CVD), type 2 diabetes (T2D), Alzheimer's disease, and many types of cancer [4,5]. Well-known chemicals that are used as antioxidants such as butylated hydroxytoluene (BHT), tertiary butyl hydroquinone (Tert-BHQ), and butylated hydroxyanisole (BHA; E-320) have been reported to have some adverse effects on human health and are now restricted in some food products [6]. Hence, the discovery of novel peptide-based antioxidants, which are more biocompatible, would be beneficial for both the human health and food industries.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Multifunctional Octapeptide from Lingzhi with Antioxidant and Tyrosinase Inhibitory Activity

et al. 2022

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Ganoderma lucidum or Lingzhi is a fungus species widely known as a traditional medicine. Exploring the beneficial peptides by hydrolysis using pepsin and trypsin has been extensively performed to identify new bioactive natural products. A multifunctional peptide that expresses potential scavenging activity and tyrosinase inhibition is valuable in therapeutic and cosmetic applications. This study aimed to identify and investigate the effects of a novel multifunctional peptide from Lingzhi on the melanogenic enzymes in melanoma cells by a targeted-proteomics approach. The multifunctional peptide was de novo sequenced by LC-MS/MS to be NH2-PVRSSNCA-CO2H (octapeptide). This sequence was chemically synthesized by solid-phase peptide synthesis (SPPS). The antioxidant ability of the synthesized octapeptide was measured by the DPPH, ABTS, and FRAP assays. The results showed that the peptide exhibited an antioxidant activity equal to 0.121 ± 0.01 mg equivalent to ascorbic acid, 0.173 ± 0.03 mg equivalent to gallic acid, and 2.21 ± 0.23 mM equivalent to FeSO4, respectively, which is comparable to these well-known antioxidants. The proteomics approach identified a total of 5804 proteins and several pathways involved in the effects of the octapeptide in melanoma cells. Targeted proteomics revealed three specific proteins associated with pigmentation including Rab29, Dct, and Tyrp1. The Rab29 and Dct were upregulated whereas Tyrp1 was downregulated in the octapeptide treatment group. These findings could be used in the understanding of the molecular functions of the multifunctional octapeptide on melanogenic enzymes, supporting its potential as a therapeutic and cosmetic ingredient.

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The food additive BHA modifies energy metabolism in the perfused rat liver

Cited by 24 publications

References 35 publications

3-tert-Butyl-4-hydroxyanisole Impairs Hepatic Lipid Metabolism in Male Mice Fed with a High-Fat Diet

3-tert-Butyl-4-hydroxyanisole Impairs Hepatic Lipid Metabolism in Male Mice Fed with a High-Fat Diet

Butylated Hydroxyanisole Exerts Neurotoxic Effects by Promoting Cytosolic Calcium Accumulation and Endoplasmic Reticulum Stress in Astrocytes

Discovery of a Multifunctional Octapeptide from Lingzhi with Antioxidant and Tyrosinase Inhibitory Activity

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