Identification of Novel Low-Dose Bisphenol A Targets in Human Foreskin Fibroblast Cells Derived from Hypospadias Patients

Qin, Xian; Kojima, Yoshiyuki; Mizuno, Kentaro; Ueoka, Katsuhiko; Muroya, Koji; Miyado, Mami; Zaha, Hiroko; Akanuma, Hiromi; Zeng, Qin; Fukuda, T.; Yoshinaga, Jun; Yonemoto, Junzo; Kohri, Kenjiro; Hayashi, Yutaro; Fukami, Maki; Ogata, Tsutomu; Sone, Hirohito

doi:10.1371/journal.pone.0036711

Cited by 18 publications

(20 citation statements)

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“…We have recently identified that MMP11 is a novel target of low dose of BPA exposure and that BPA can inhibit MMP11 expression in a dose-dependent manner in hFFCs derived from child HS patients. Furthermore, we found that mRNA levels of MMP11 were significantly lower in the HS group compared with the control and CO groups suggesting that the involvement of BPA in the development of HS might be related with the downregulation of MMP11 [17]. The results of this study are in accord with this hypothesis.…”

Section: Discussionsupporting

confidence: 85%

“…BPA has been detected in 92% of urine samples in a US reference population, suggesting that humans might be continuously exposed to this compound in their daily lives [16]. To better understand the molecular basis of the effect of low-dose BPA exposure on human reproductive health, we previously performed a genome-wide screen using human foreskin fibroblast cells (hFFCs) derived from child HS patients to identify novel targets of low-dose BPA exposure [17]. We reported that the expression of matrix metalloproteinase-11 ( MMP11 ), a well-known effector of development and normal physiology, was downregulated by BPA in a dose-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to MMP11 , neurotensin receptor 1 ( NTSR1 ), known to be involved in tumor progression by regulating a series of transforming functions such as cellular migration and invasion, was also selected as a candidate BPA-responsive gene [20]. We did not identify NTSR1 as a target of low-dose BPA in our previous genome-wide screen, probably owing to a lack of statistical significance [17]. However, this may indicate variability in gene expression levels among individuals in response to low-dose BPA exposure (Figure S1).…”

Section: Introductionmentioning

confidence: 99%

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Individual Variation of the Genetic Response to Bisphenol A in Human Foreskin Fibroblast Cells Derived from Cryptorchidism and Hypospadias Patients

et al. 2012

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Background/PurposeWe hypothesized that polymorphic differences among individuals might cause variations in the effect that environmental endocrine disruptors (EEDs) have on male genital malformations (MGMs). In this study, individual variation in the genetic response to low-dose bisphenol A (BPA) was investigated in human foreskin fibroblast cells (hFFCs) derived from child cryptorchidism (CO) and hypospadias (HS) patients.Methodology/Principal FindingshFFCs were collected from control children without MGMs (n = 5) and child CO and HS patients (n = 8 and 21, respectively). BPA exposure (10 nM) was found to inhibit matrix metalloproteinase-11 (MMP11) expression in the HS group (0.74-fold, P = 0.0034) but not in the control group (0.93-fold, P = 0.84) and CO group (0.94-fold, P = 0.70). Significantly lower levels of MMP11 expression were observed in the HS group compared with the control group (0.80-fold, P = 0.0088) and CO group (0.79-fold, P = 0.039) in response to 10 nM BPA. The effect of single-nucleotide polymorphism rs5000770 (G>A), located within the aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) locus, on individual sensitivity to low-dose BPA was investigated in the HS group. A significant difference in neurotensin receptor 1 (NTSR1) expression in response to 10 nM BPA was observed between AA and AG/GG groups (n = 6 and 15, respectively. P = 0.031). However, no significant difference in ARNT2 expression was observed (P = 0.18).Conclusions/SignificanceThis study advances our understanding of the specificity of low-dose BPA effects on human reproductive health. Our results suggest that genetic variability among individuals affects susceptibility to the effects of EEDs exposure as a potential cause of HS.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Individual Variation of the Genetic Response to Bisphenol A in Human Foreskin Fibroblast Cells Derived from Cryptorchidism and Hypospadias Patients

et al. 2012

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“…The arrays were scanned using a GenePix 4000B Microarray Scanner (Axon Instruments). Data normalization and analysis were performed with GeneSpring GX13.0 (Agilent Technologies) as previously described (27). All data are MIAME compliant, and the raw data were deposited in the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo; accession no.…”

Section: Microarray Analysismentioning

confidence: 99%

“…The Ingenuity Pathway Analysis (IPA) program (Ingenuity Systems) was used to identify networks and canonical pathways associated with differentially expressed genes following ACR treatment as previously described (27).…”

Section: Network Generation and Pathway Analysismentioning

confidence: 99%

Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model

Qin¹,

Tatsukawa

Hitomi

et al. 2016

Cancer Prevention Research

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Acyclic retinoid (ACR) is a promising drug under clinical trials for preventing recurrence of hepatocellular carcinoma. The objective of this study was to gain insights into molecular basis of the antitumorigenic action of ACR from a metabolic point of view. To achieve this, comprehensive cationic and lipophilic liver metabolic profiling was performed in mouse diethylnitrosamine (DEN)-induced hepatic tumorigenesis model using both capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. ACR significantly counteracted against acceleration of lipogenesis but not glucose metabolism in DEN-treated mice liver, suggesting an important role of lipid metabolic reprogramming in the initiation step of hepatic tumorigenesis. Knowledge-based pathway analysis suggested that inhibition of linoleic acid metabolites such as arachidonic acid, a proinflammatory precursor, played a crucial role in the prevention by ACR of DEN-induced chronic inflammationmediated tumorigenesis of the liver. As a molecular mechanism of the ACR's effect to prevent the aberrant lipogenesis, microarray analysis identified that a key transcription regulator of both embryogenesis and tumorigenesis, COUP transcription factor 2, also known as NR2F2, was associated with the metabolic effect of ACR in human hepatocellular carcinoma cells. Our study provided potential therapeutic targets for the chemoprevention of hepatocellular carcinoma as well as new insights into the mechanisms underlying prevention of hepatic tumorigenesis.

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Hypospadias risk is increased with maternal residential exposure to hormonally active hazardous air pollutants

Sheth

Kovar

White

et al. 2019

Birth Defects Research

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Background: With the increasing birth prevalence of hypospadias, there is growing concern for pollutant exposure interfering with normal penile development. We assess the association between hypospadias and hormonally active hazardous air pollutants (HAHAPs) through a nationwide database of hazardous air pollutants and the Texas Birth Defects Registry (TBDR). Methods: Using the TBDR, we identified 8,981 nonsyndromic isolated hypospadias cases from 1999 to 2008. Birth certificate controls were matched for birth year at a 10:1 ratio to cases. Estimated HAHAP concentrations from the 2005 U.S. EPA National–Scale Air Toxics Assessment were used to assign exposure based on maternal residence at birth. Exposure levels were categorized as quintiles based on the distribution in controls. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each increasing exposure category of selected HAHAPs. Results: Of the 10 HAHAPs studied, seven were significantly associated with hypospadias risk. The HAHAP that was most strongly associated with hypospadias was phenol, which was associated with risk in all groups except the high exposure group. Cumulative HAHAP exposure demonstrated a modest increase in hypospadias risk (OR 1.15, 95% CI: 1.07–1.24, p < 0.001) in the medium and medium–high quintiles. Conclusions: While maternal exposure to some HAHAPs was significantly associated with the risk of hypospadias in male offspring, the effects were modest, and no dose–response effects were observed. Future work should employ biomarkers of exposure to better delineate the relationship.

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Identification of Novel Low-Dose Bisphenol A Targets in Human Foreskin Fibroblast Cells Derived from Hypospadias Patients

Cited by 18 publications

References 43 publications

Individual Variation of the Genetic Response to Bisphenol A in Human Foreskin Fibroblast Cells Derived from Cryptorchidism and Hypospadias Patients

Individual Variation of the Genetic Response to Bisphenol A in Human Foreskin Fibroblast Cells Derived from Cryptorchidism and Hypospadias Patients

Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model

Hypospadias risk is increased with maternal residential exposure to hormonally active hazardous air pollutants

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