Endocrine disruption of gene expression and microRNA profiles in hippocampus and hypothalamus of California mice: Association of gene expression changes with behavioural outcomes.
Butler Mary C,Long Camryn N,Kinkade Jessica A,Green Madison T,Martin Rachel E,Marshall Brittney L,Willemse Tess E,Schenk A Katrin,Mao Jiude,Rosenfeld Cheryl S
Journal of neuroendocrinology
The hypothalamus and hippocampus are sensitive to early exposure to endocrine disrupting chemicals (EDCs). Two EDCs that have raised particular concerns are bisphenol A (BPA), a widely prevalent chemical in many common household items, and genistein (GEN), a phyto-oestrogen present in soy and other plants. We hypothesised that early exposure to BPA or GEN may lead to permanent effects on gene expression profiles for both coding RNAs (mRNAs) and microRNAs (miRs), which can affect the translation of mRNAs. Such EDC-induced biomolecular changes may affect behavioural and metabolic patterns. California mice (Peromyscus californicus) male and female offspring were developmentally exposed via the maternal diet to BPA (5 mg kg feed weight low dose [LD] and 50 mg kg feed weight upper dose [UD]), GEN (250 mg kg feed weight) or a phyto-oestrogen-free diet (AIN) control. Behavioural and metabolic tests were performed at 180 days of age. A quantitative polymerase chain reacttion analysis was performed for candidate mRNAs and miRs in the hypothalamus and hippocampus. LD BPA and GEN exposed California mice offspring showed socio-communication impairments. Hypothalamic Avp, Esr1, Kiss1 and Lepr were increased in LD BPA offspring. miR-153 was elevated but miR-181a was reduced in LD BPA offspring. miR-9 and miR-153 were increased in the hippocampi of LD BPA offspring, whereas GEN decreased hippocampal miR-7a and miR-153 expression. Correlation analyses revealed neural expression of miR-153 and miR-181a was associated with socio-communication deficits in LD BPA individuals. The findings reveal a cause for concern such that developmental exposure of BPA or GEN in California mice (and potentially by translation in humans) can lead to long standing neurobehavioural consequences.
10.1111/jne.12847
MicroRNAs: potential targets and agents of endocrine disruption in female reproduction.
Journal of toxicologic pathology
MicroRNAs are short non-coding RNAs that have been widely recognized as key mediators in the epigenetic control of gene expression and which are present in virtually all cells and tissues studied. These regulatory molecules are generated in multiple steps in a process called microRNA biogenesis. Distinct microRNA expression patterns during the different stages of oocyte and embryo development suggest important regulatory roles for these small RNAs. Moreover, studies antagonizing specific microRNAs and enzymes in microRNA biogenesis pathways have demonstrated that interference with normal miRNA function leads to infertility and is associated with some reproductive abnormalities. Endocrine disrupting chemicals such as Bisphenol A (BPA) are synthetic hormone mimics that have been found to negatively impact reproductive health. In addition to their direct effects on gene expression, these chemicals are widely implicated in the disruption of epigenetic pathways, including the expression and activity of miRNAs, thereby altering gene expression. In this review, the roles of microRNAs during mammalian oocyte and embryo development are outlined and the different mechanisms by which endocrine disruptors such as BPA interfere with these epigenetic regulators to cause reproductive problems is explored.
10.1293/tox.2019-0054
Low Dose of Bisphenol A Modulates Ovarian Cancer Gene Expression Profile and Promotes Epithelial to Mesenchymal Transition Via Canonical Wnt Pathway.
Hui Lin,Li Hongyi,Lu Guang,Chen Zhifeng,Sun Wenjie,Shi Yu,Fu Zhiqin,Huang Bo,Zhu Xinqiang,Lu Weiguo,Xia Dajing,Wu Yihua
Toxicological sciences : an official journal of the Society of Toxicology
The xenoestrogen bisphenol A (BPA) is a synthetic endocrine disrupting chemical, having the potential to increase the risk of hormone-dependent ovarian cancer. Thus, a deeper understanding of the molecular and cellular mechanisms is urgently required in the novel cell models of ovarian cancer which express estrogen receptors. To understand the possible mechanisms underlying the effects of BPA, human ovarian adenocarcinoma SKOV3 cells were exposed to BPA (10 or 100 nM) or 0.1% DMSO for 24 h, and then global gene expression profile was determined by high-throughput RNA sequencing. Also, enrichment analysis was carried out to find out relevant functions and pathways within which differentially expressed genes were significantly enriched. Transcriptomic analysis revealed 94 differential expression genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that these genes related to tumorigenesis and metastasis. Further studies were carried out to validate the results of functional annotation, which indicated that BPA (10 and 100 nM) increased migration and invasion as well as induced epithelial to mesenchymal transitions in SKOV3 and A2780 cells. Accordingly, environmentally relevant-dose BPA activated the canonical Wnt signaling pathway. Our study first comprehensively analyzed the possible mechanisms underlying the effects of BPA on ovarian cancer. Environmentally relevant doses of BPA modulated the gene expression profile, promoted epithelial to mesenchymal transition progress via canonical Wnt signaling pathway of ovarian cancer.
10.1093/toxsci/kfy107
Estrogen-regulated miRNA-27b is altered by bisphenol A in human endometrial stromal cells.
Reed Beverly G,Babayev Samir N,Chen Lucy X,Carr Bruce R,Word R Ann,Jimenez Patricia T
Reproduction (Cambridge, England)
MicroRNAs (miRs) are small molecules important for regulation of transcription and translation. The objective was to identify hormonally regulated miRs in human endometrial stromal cells and to determine the impact of the endocrine disruptor, bisphenol A (BPA), on those miRs. miR microarray analysis and multiple confirmatory cell preparations treated with 17β-estradiol (E2) and BPA altered miR-27b, let-7c, let-7e and miR-181b. Further, decidualization downregulated miR-27b. VEGFB and VEGFC were validated as targets of miR-27b. Identification of miR-27b target genes suggests that BPA and E2 downregulate miR-27b thereby leading to upregulation of genes important for vascularization and angiogenesis of the endometrium during the menstrual cycle and decidualization.
10.1530/REP-18-0041
Unhealthy Levels of Phthalates and Bisphenol A in Mexican Pregnant Women with Gestational Diabetes and Its Association to Altered Expression of miRNAs Involved with Metabolic Disease.
Martínez-Ibarra Alejandra,Martínez-Razo Luis Daniel,Vázquez-Martínez Edgar Ricardo,Martínez-Cruz Nayeli,Flores-Ramírez Rogelio,García-Gómez Elizabeth,López-López Marisol,Ortega-González Carlos,Camacho-Arroyo Ignacio,Cerbón Marco
International journal of molecular sciences
Several studies indicate that bisphenol A (BPA) and phthalates may have a role in the development of metabolic diseases using different molecular pathways, including epigenetic regulatory mechanisms. However, it is unclear whether exposure to these chemicals modifies serum levels of miRNAs associated with gestational diabetes mellitus (GDM) risk. In the present study, we evaluated the serum levels of miRNAs associated with GDM (miR-9-5p, miR-16-5p, miR-29a-3p and miR-330-3p) and urinary levels of phthalate metabolites (mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP) and mono(2-ethyl hexyl) phthalate (MEHP)) and bisphenol A in GDM patients and women without GDM during the second trimester of gestation. We observed higher levels of miR-9-5p, miR-29a-3p and miR-330-3p in sera of patients with GDM compared to non-diabetic subjects. Phthalates were detected in 97-100% of urine samples, while BPA only in 40%. Urinary MEHP and BPA concentrations were remarkably higher in both study groups compared to previously reported data. Unadjusted MEHP levels and adjusted BPA levels were higher in non-diabetics than in GDM patients ( = 0.03, = 0.02). We found positive correlations between adjusted urinary MBzP levels and miR-16-5p expression levels ( < 0.05), adjusted MEHP concentrations and miR-29a-3p expression levels ( < 0.05). We also found negative correlations between unadjusted and adjusted MBP concentrations and miR-29a-3p expression levels ( < 0.0001, < 0.05), unadjusted MiBP concentrations and miR-29a-3p expression levels ( < 0.01). Urinary MEHP levels reflect a striking exposure to di(2-ethylhexyl) phthalate (DEHP) in pregnant Mexican women. This study highlights the need for a regulatory strategy in the manufacture of several items containing endocrine disruptors in order to avoid involuntary ingestion of these compounds in the Mexican population.
10.3390/ijms20133343
A systematic review of microRNA expression studies with exposure to bisphenol A.
Farahani Masoumeh,Rezaei-Tavirani Mostafa,Arjmand Babak
Journal of applied toxicology : JAT
Bisphenol A (BPA), as a common industrial component, is generally consumed in the synthesis of polymeric materials. To gain a deeper understanding of the detrimental effects of BPA, BPA-induced microRNA (miRNA) alterations were investigated. A systematic search was performed in the PubMed, SCOPUS and Web of Science databases to evoke relevant published data up to August 10, 2019. We identified altered miRNAs that have been repeated in at least three studies. Moreover, miRNA homology analysis between human and nonhuman species was performed to determine the toxicity signatures of BPA in human exposure. In addition, to reflect the effects of environmental exposure levels of BPA, the study designs were categorized into two groups, including low and high doses according to the previous definitions. In total, 28 studies encountered our criteria and 17 miRNAs were identified that were differentially expressed in at least three independent studies. Upregulating miR-146a and downregulating miR-192, miR-134, miR-27b and miR-324 were found in three studies. MiR-122 and miR-29a were upregulated in four studies after BPA exposure, and miR-21 was upregulated in six studies. The results indicate that BPA at low-level exposures can also alter miRNA expression in response to toxicity. Finally, the miRNA-related pathways showed that BPA seriously can affect human health through various cell signaling pathways, which were predictable and consistent with existing studies. Overall, our findings suggest that further studies should be conducted to examine the role of miRNA level changes in human BPA exposure.
10.1002/jat.4025
Bisphenol S Triggers the Migration and Invasion of Pheochromocytoma PC12 Cells via Estrogen-Related Receptor α.
Journal of molecular neuroscience : MN
Pheochromocytoma (PCC) is a tumor of the adrenal medulla for which surgical resection is the only therapy approach. Risk factors responsible for the tumorigenesis and progression of PCC are not well illustrated. Our present study revealed that an industrial chemical, bisphenol S (BPS), can promote the migration and invasion of PCC PC12 cells, which was evidenced by the upregulation of fibronectin (FN) and matrix metalloproteinases (MMP-2 and MMP-9). The inhibitor of estrogen-related receptor α (ERRα), while not estrogen receptor α/β (ERα/β) or G protein-coupled estrogen receptor (GPER), can attenuate BPS-induced cell migration. Mechanically, BPS can increase the binding between ERRα and promoter of FN1 and then induce the expression of FN in PC12 cells. Further, BPS can induce the expression of miR-10b in PC12 cells via ERRα. The upregulated miR-10b inhibited the expression of KLF4, which can suppress the migration and invasion of cancer cells. BPS can trigger the mRNA and protein expression of ERRα in PC12 cells via a time-dependent manner. Collectively, our study revealed that nanomolar BPS can trigger the migration and invasion of PC12 cells via activation and upregulation of ERRα.
10.1007/s12031-018-1148-5
Effects of bisphenol A and bisphenol S on microRNA expression during bovine (Bos taurus) oocyte maturation and early embryo development.
Sabry Reem,Saleh Angela C,Stalker Leanne,LaMarre Jonathan,Favetta Laura A
Reproductive toxicology (Elmsford, N.Y.)
Bisphenol A (BPA) and its alternative, bisphenol S (BPS), are widespread endocrine disrupting compounds linked in several studies to poor female fertility. Sufficient oocyte competence and subsequent embryo development are highly dependent on oocyte maturation, an intricate process that is vulnerable to BPA. These effects as well as the effects of its analog, BPS, have not been fully elucidated. Although the harmful consequences of bisphenols on the reproductive system are largely due to interferences with canonical gene expression, more recent evidence implicates noncoding RNAs, including microRNAs (miRNA), as significant contributors. The aim of this work was to test the hypothesis that abnormal expression of key miRNAs during oocyte maturation and embryo development occurs following BPA and BPS exposure during maturation. Using qPCR, primary and mature forms of miR-21, -155, -34c, -29a, -10b, -146a were quantified in an in vitro bovine model of matured cumulus-oocyte complexes, fertilized embryos, and cultured cumulus cells after exposure to BPA or BPS at the LOAEL dose (0.05 mg/mL). Expression of miR-21, miR -155, and miR-29a were markedly increased (P = 0.02, 0.04, <0.0001) while miR-34c and miR-10b were decreased (P = 0.01, 0.01), after BPA treatment. miR-146a expression remained stable. BPS had no effects, suggesting may not exert its actions through these six miRNAs examined. Overall, this study indicates that BPA effects are likely miRNA specific rather than a global effect on miRNA synthesis and processing mechanisms and that its analog, BPS, may not possess the same properties required to interfere with these miRNAs during bovine oocyte maturation.
10.1016/j.reprotox.2020.12.001