BDE-47 Decreases Progesterone Levels in BeWo Cells by Interfering with Mitochondrial Functions and Genes Related to Cholesterol Transport.

Polybrominated diphenyl ethers (PBDEs) have been reported to exert reproductive endocrine toxicity, but the mechanisms for this process remain unclear. Currently available studies have concentrated on the enzymatic reactions during steroidogenesis, but the results are not consistent. In this study, we explored the effects of 2,2',4,4'-tertrabromodiphenyl ether (BDE-47) on progesterone biosynthesis and the potential mechanisms in human placental choriocarcinoma cells. The results showed that BDE-47 decreased progesterone production in a dose-dependent manner but had no effect on key enzymes (Cyp11a1 and 3β-HSD). BDE-47 exposure depolarized the mitochondrial membrane potential and downregulated adenosine triphosphate levels. The gene expression levels of Mfn2, Tspo, Atad3, Vdac1, Fis1, and Drp1, which are involved in mitochondrial dynamics and cholesterol transport, were disturbed. The demethylation of some CpG loci of mitochondrial biomarkers (Drp1, Opa1, Vdac2, and Atad3) was induced in the 1 μM BDE-47 exposure group, but no methylation change was observed with 50 μM treatment. Our findings unveiled that the reduction of progesterone synthesis induced by BDE-47 might be associated with cholesterol transportation, mitochondrial dynamics, and mitochondrial functions. These findings provide substantial data on the reproductive endocrine toxicity of PBDEs.

[1]  T. Xia,et al.  Promotion of mitochondrial fusion protects against developmental PBDE-47 neurotoxicity by restoring mitochondrial homeostasis and suppressing excessive apoptosis , 2020, Theranostics.

[2]  R. N. Saha,et al.  Epigenetic Effects of Polybrominated Diphenyl Ethers on Human Health , 2019, International journal of environmental research and public health.

[3]  C. Moraes,et al.  ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels , 2018, Journal of Cell Science.

[4]  Shanshan Yin,et al.  Prenatal exposure to polychlorinated biphenyl and umbilical cord hormones and birth outcomes in an island population. , 2018, Environmental pollution.

[5]  Kyungho Choi,et al.  Prenatal contribution of 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) to total body burden in young children. , 2018, The Science of the total environment.

[6]  A. Ball,et al.  Critical review of soil contamination by polybrominated diphenyl ethers (PBDEs) and novel brominated flame retardants (NBFRs); concentrations, sources and congener profiles. , 2017, Environmental pollution.

[7]  Yi-jun Zhou,et al.  Exposure to polybrominated diphenyl ethers and female reproductive function: A study in the production area of Shandong, China. , 2016, The Science of the total environment.

[8]  Shio Kumar Singh,et al.  Effect of polybrominated diphenyl ether (BDE-209) on testicular steroidogenesis and spermatogenesis through altered thyroid status in adult mice. , 2016, General and comparative endocrinology.

[9]  Yiqiang Cui,et al.  2,2',4,4'-Tetrabromodiphenyl ether injures cell viability and mitochondrial function of mouse spermatocytes by decreasing mitochondrial proteins Atp5b and Uqcrc1. , 2016, Environmental toxicology and pharmacology.

[10]  Zhe Wang,et al.  Effects of Polybrominated Diphenyl Ethers on Rat and Human 11β-Hydroxysteroid Dehydrogenase 1 and 2 Activities , 2016, Pharmacology.

[11]  H Fromme,et al.  Brominated flame retardants - Exposure and risk assessment for the general population. , 2016, International journal of hygiene and environmental health.

[12]  J. Domingo,et al.  Human exposure to PBDE and critical evaluation of health hazards , 2015, Archives of Toxicology.

[13]  R. Garavito,et al.  Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism , 2015, Science.

[14]  Miriam L Diamond,et al.  Stocks and flows of PBDEs in products from use to waste in the U.S. and Canada from 1970 to 2020. , 2015, Environmental science & technology.

[15]  N. Andric,et al.  HBCDD-induced sustained reduction in mitochondrial membrane potential, ATP and steroidogenesis in peripubertal rat Leydig cells. , 2015, Toxicology and applied pharmacology.

[16]  S. Hauguel-de Mouzon,et al.  Obesity-induced down-regulation of the mitochondrial translocator protein (TSPO) impairs placental steroid production. , 2015, The Journal of clinical endocrinology and metabolism.

[17]  Laura A Martin,et al.  Mitochondrial cholesterol: mechanisms of import and effects on mitochondrial function , 2016, Journal of Bioenergetics and Biomembranes.

[18]  A. F. Castillo,et al.  Mitochondrial Fusion and ERK Activity Regulate Steroidogenic Acute Regulatory Protein Localization in Mitochondria , 2014, PloS one.

[19]  W. Miller.  Steroid hormone synthesis in mitochondria , 2013, Molecular and Cellular Endocrinology.

[20]  S. Stojilkovic,et al.  Acute effects of hexabromocyclododecane on Leydig cell cyclic nucleotide signaling and steroidogenesis in vitro. , 2013, Toxicology letters.

[21]  Yankai Xia,et al.  2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) decreases progesterone synthesis through cAMP-PKA pathway and P450scc downregulation in mouse Leydig tumor cells. , 2012, Toxicology.

[22]  V. Papadopoulos,et al.  Role of mitochondria in steroidogenesis. , 2012, Best practice & research. Clinical endocrinology & metabolism.

[23]  V. Gottifredi,et al.  Mitochondrial Fusion Is Essential for Steroid Biosynthesis , 2012, PloS one.

[24]  T. Veenstra,et al.  Identification of a dynamic mitochondrial protein complex driving cholesterol import, trafficking, and metabolism to steroid hormones. , 2012, Molecular endocrinology.

[25]  L. Scorrano,et al.  Optic Atrophy 1-Dependent Mitochondrial Remodeling Controls Steroidogenesis in Trophoblasts , 2012, Current Biology.

[26]  Laura N. Vandenberg,et al.  Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. , 2012, Endocrine reviews.

[27]  E. Gregoraszczuk,et al.  Polybrominated diphenylethers (PBDEs) act as apoptotic factors in the corpus luteum in addition to having a short-term stimulatory effect on progesterone secretion by luteal cells , 2012, Toxicology mechanisms and methods.

[28]  Kai-Lee Wang,et al.  Effects of polybrominated diphenyl ethers on steroidogenesis in rat Leydig cells. , 2011, Human reproduction.

[29]  V. Papadopoulos,et al.  ATP Synthesis, Mitochondrial Function, and Steroid Biosynthesis in Rodent Primary and Tumor Leydig Cells1 , 2011, Biology of reproduction.

[30]  L. Scorrano,et al.  Trichoplein/mitostatin regulates endoplasmic reticulum–mitochondria juxtaposition , 2010, EMBO reports.

[31]  Jun Liu,et al.  Acyl-coenzyme A binding domain containing 3 (ACBD3; PAP7; GCP60): an emerging signaling molecule. , 2010, Progress in lipid research.

[32]  Fang Wang,et al.  Relation between hypomethylation of long interspersed nucleotide elements and risk of neural tube defects. , 2010, The American journal of clinical nutrition.

[33]  V. Papadopoulos,et al.  Cholesterol transport in steroid biosynthesis: role of protein-protein interactions and implications in disease states. , 2009, Biochimica et biophysica acta.

[34]  Robert V Farese,et al.  The life of lipid droplets. , 2009, Biochimica et biophysica acta.

[35]  L. Scorrano,et al.  Mitofusin 2 tethers endoplasmic reticulum to mitochondria , 2008, Nature.

[36]  M. Kiriakidou,et al.  Structural and Functional Changes in Mitochondria Associated with Trophoblast Differentiation: Methods to Isolate Enriched Preparations of Syncytiotrophoblast Mitochondria. , 1997, Endocrinology.