Early-life exposure to di(2-ethylhexyl) phthalate impairs reproduction in adult female zebrafish (Danio rerio).

Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in various industrial and consumer products. It is not covalently bound within these products and leaches out during repeated use, heating, or cleaning. Main routes of environmental DEHP pollution are through the industrial and municipal wastewaters, which pollute aquatic environments.

Global gene expression analysis reveals a subtle effect of DEHP in human granulosa cell line HGrC1.

Di(2-ethylhexyl) phthalate (DEHP) is an endocrine disruptor that exerts anti-steroidogenic effects in human granulosa cells; however, the extent of this effect depends on the concentration of DEHP and granulosa cell models used for exposure. The objective of this study was to identify the effects of low- and high-dose DEHP exposure in human granulosa cells. We exposed human granulosa cell line HGrC1 to 3 nM and 25 μM DEHP for 48 h.

Global gene expression analysis reveals novel transcription factors associated with long-term low-level exposure of EA.hy926 human endothelial cells to bisphenol A.

Bisphenol A (BPA) is an endocrine disruptor that binds to estrogen receptors (ER); however, studies have shown that the ER pathway was not always the primary molecular mechanism of BPA's action in cells and that gene transcription could be altered by different exposure times and doses. Here, we sought to understand the correlation between the BPA-responsive genes that have associated biological functions and the transcription factors (TFs) involved in their regulation by repeatedly exposing human endothelial cells EA.hy926 to three nanomolar concentrations of BPA (10 M, 10 M, and 10 M) for 14 weeks, after which changes in global gene expression were determined by RNA sequencing.

An toxicogenomic approach in constructing the aflatoxin B1-mediated regulatory network of hub genes in hepatocellular carcinoma.

Aflatoxin B1 (AFB1) can cause hepatocellular carcinoma (HCC) through a mutagenic mode of action but can also lead to global changes in gene expression; however, the AFB1 network of molecular pathways involved in HCC is not known. Here, we used toxicogenomic data from human liver cells exposed to AFB1 to infer the network of AFB1-responsive molecular pathways involved in HCC. The following computational tools: STRING, MCODE, cytoHubba, iRegulon, kinase enrichment tool KEA3, and DAVID were used to identify protein-protein interaction network, hub genes, transcription factors (TFs), upstream kinases, and biological processes (BPs).

DEHP Decreases Steroidogenesis through the cAMP and ERK1/2 Signaling Pathways in FSH-Stimulated Human Granulosa Cells.

DEHP is an endocrine disruptor that interferes with the function of the female reproductive system. Several studies suggested that DEHP affects steroidogenesis in human and rodent granulosa cells (GC). Some studies have shown that DEHP can also affect the FSH-stimulated steroidogenesis in GC; however, the mechanism by which DEHP affects hormone-challenged steroidogenesis in human GC is not understood.

Dibutyl phthalate promotes angiogenesis in EA.hy926 cells through estrogen receptor-dependent activation of ERK1/2, PI3K-Akt, and NO signaling pathways.

Dibutyl phthalate (DBP) is an endocrine disruptor that has been widely used in various products of human use. DBP exposure has been associated with reproductive and cardiovascular diseases and metabolic disorders. Although dysfunction of the vascular endothelium is responsible for many cardiovascular and metabolic diseases, little is known about the effects of DBP on human endothelium.

Impact of Long-Term Low-Level DEHP Exposure on Gene Expression Profile in Human Granulosa Cells.

Here, we applied a model of long-term exposure of human granulosa cells to low environmentally relevant levels of di(2-ethylhexyl) phthalate (DEHP). This approach provides more relevant data regarding the impact of DEHP on the function of human granulosa cells. The immortalized human granulosa cells HGrC1 were exposed to 50 nM and 250 nM DEHP for four weeks.

Mapping DEHP to the adverse outcome pathway network for human female reproductive toxicity.

Adverse outcome pathways (AOPs) and AOP networks are tools for mechanistic presentation of toxicological effects across different levels of biological organization. These tools are used to better understand how chemicals impact human health. In this study, a four-step workflow was used to derive the AOP network of human female reproductive toxicity (HFRT-AOP) from five AOPs available in the AOP-Wiki and ten AOPs obtained from the literature.

Long-term in vitro exposure of human granulosa cells to the mixture of endocrine disrupting chemicals found in human follicular fluid disrupts steroidogenesis.

Most in vitro studies examine the effects of a single ED or a mixture of EDs on granulosa cells using short-term exposure; however, this approach is unlikely to reflect long-term, real-life exposures that are common in humans. We established an in vitro model that mimics long-term exposure of granulosa cells to real-life ED mixture. Human granulosa cells, HGrC1, were exposed to the mixture consisting of bisphenol A, polychlorinated biphenyl 153, benzo[a]pyrene, and perfluorooctanesulfonate in concentrations found in human follicular fluid (MIX) for 48 h and 4 weeks.

Integration of data from the in vitro long-term exposure study on human endothelial cells and the in silico analysis: A case of dibutyl phthalate-induced vascular dysfunction.

General population is exposed to dibutyl phthalate (DBP) through continuous use of various consumer products. DBP exhibits its effects mainly on the endocrine and reproductive system but it can also affect the function of the vasculature; however, the underlying mechanisms behind DBP-induced vascular dysfunction are not fully understood. To infer pathways, molecular functions, biological processes, and human diseases associated with DBP exposure, we integrated the toxicogenomic data obtained from the 4-week-long exposure of human vascular endothelial cells (ECs) to three environmentally relevant concentrations of DBP with the in silico analysis.

Integration of data from the cell-based ERK1/2 ELISA and the Comparative Toxicogenomics Database deciphers the potential mode of action of bisphenol A and benzo[a]pyrene in lung neoplasm.

Chemicals can activate a variety of signaling pathways, initiating changes in gene expression and cellular functions. Here, we combined experimental data on the chemical-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation with the Comparative Toxicogenomics Database (CTD) to connect signaling, genes, and phenotypes to reveal the potential chemical's mode of action (MOA) responsible for the disease state. Experimental data on ERK1/2 activation were derived from the cell-based phospho-ERK1/2 ELISA on human alveolar epithelial cells A549.

Biological effects of chronic and acute exposure of human endothelial cell line EA.hy926 to bisphenol A: New tricks from an old dog.

Although epidemiological and animal studies suggest a possible correlation between bisphenol A (BPA) exposure and atherosclerosis, very few in vitro mechanistic and functional studies regarding the effect of BPA on vascular cells have been conducted. Here, we applied a "real-life" exposure scenario by continuously exposing human endothelial cell (EC) line EA.hy926 to environmentally relevant concentrations of BPA (10, 10, and 10 M) during 14 weeks.

Rosiglitazone increases expression of steroidogenic acute regulatory protein and progesterone production through PPARγ-EGFR-ERK1/2 in human cumulus granulosa cells.

The mechanism by which rosiglitazone (ROSI: a thiazolidinedione (TZD)) affects steroid production in undifferentiated human granulosa cells is not known. In this study, cultured human cumulus granulosa cells were exposed to ROSI and pharmacological inhibitors of the extracellular signal-regulated kinase 1/2 (ERK1/2), epidermal growth factor receptor (EGFR) and peroxisome proliferator-activated receptor gamma (PPARγ) signalling pathways. Expression of progesterone biosynthetic enzymes, PPARγ and PPARα, progesterone production and ERK1/2 activation were analysed.

BPA activates EGFR and ERK1/2 through PPARγ to increase expression of steroidogenic acute regulatory protein in human cumulus granulosa cells.

Bisphenol A (BPA) negatively affects steroid production in human luteinized granulosa cells (GC). This study was designed to address two important questions: (1) whether BPA exerts the same disruptive effect in human cumulus granulosa cells (hCGC) and (2) to reveal the molecular mechanism underlying the BPA's action on steroidogenesis. We used cultured hCGC since these cells exert the properties of GC from early antral follicles.

T-2 toxin downregulates LHCGR expression, steroidogenesis, and cAMP level in human cumulus granulosa cells.

Our goals were to investigate whether environmentally relevant doses of T-2 toxin can affect human ovarian granulosa cells' function and to reveal the potential mechanism of T-2 toxin's action. Results showed that T-2 toxin strongly attenuated luteinizing hormone/choriogonadotropin receptor (LHCGR) mRNA expression in follicle-stimulating hormone (FSH)-stimulated human cumulus granulosa cells. Addition of human chorionic gonadotropin was not able to elicit maximal response of ovulatory genes amphiregulin, epiregulin, and progesterone receptor.

Environmental mixture with estrogenic activity increases Hsd3b1 expression through estrogen receptors in immature rat granulosa cells.

Humans are exposed not only to single endocrine disruptors, but also to chemical mixtures that can adversely affect their reproductive health. Steroidogenesis in reproductive tissues is emerging as the key target of endocrine disruptor action. Here, we analyzed the effect of environmental chemical mixtures with estrogenic activity on steroidogenic processes in immature rat granulosa cells and whether the observed steroidogenic effects were mediated through estrogen receptors.