Sex-dependent dose response of gene expression modulation after ochratoxin A insult in F344 rats

The mycotoxin ochratoxin A (OTA) is a potent nephrocarcinogen, mainly in male rats. The aim of this study was to determine the time course of gene expression (GeneChip® Rat Gene 2.0 ST Array, Affymetrix) in kidney samples from male and female F344 rats, treated daily (p.o) with 0.50 mg/kg b.w. (body weight) of OTA for 7 or 21 days, and evaluate if there were differences between both sexes. After OTA treatment, there was an evolution of gene expression in the kidney over time, with more differentially expressed genes (DEG) at 21 days. The gene expression time course was different between sexes with respect to the number of DEG and the direction of expression (up or down): the female response was progressive and consistent over time, whereas males had a different early response with more DEG, most of them up-regulated. The statistically most significant DEG corresponded to metabolism enzymes (Akr1b7, Akr1c2, Adh6 down-regulated in females; Cyp2c11, Dhrs7, Cyp2d1, Cyp2d5 down-regulated in males) or transporters (Slc17a9 down-regulated in females; Slco1a1 (OATP-1) and Slc51b and Slc22a22 (OAT) down-regulated in males). Some of these genes had also a basal sex difference and were over-expressed in males or females with respect to the other sex.

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Gene expression kinetics of renal transporters induced by ochratoxin A in male and female F344 rats

Food and Chemical Toxicology ◽

10.1016/j.fct.2016.10.019 ◽

2016 ◽

Vol 98 ◽

pp. 169-178 ◽

Cited By ~ 6

Author(s):

Laura Pastor ◽

Ariane Vettorazzi ◽

Javier Campión ◽

Paul Cordero ◽

Adela López de Cerain

Keyword(s):

Gene Expression ◽

Ochratoxin A ◽

Male And Female ◽

Renal Transporters ◽

Kinetics Of ◽

F344 Rats ◽

Expression Kinetics

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Nonmonotonic Pathway Gene Expression Analysis Reveals Oncogenic Role of p27/Kip1 at Intermediate Dose

Cancer Informatics ◽

10.1177/1176935117740132 ◽

2017 ◽

Vol 16 ◽

pp. 117693511774013 ◽

Cited By ~ 2

Author(s):

Hien H Nguyen ◽

Susan C Tilton ◽

Christopher J Kemp ◽

Mingzhou Song

Keyword(s):

Gene Expression ◽

Pathway Analysis ◽

Dose Response ◽

Response Analysis ◽

Response Curves ◽

Cancer Pathways ◽

Pathway Gene ◽

Mechanistic Basis ◽

Functional Pathway ◽

Squamous Cell Papilloma

The mechanistic basis by which the level of p27Kip1 expression influences tumor aggressiveness and patient mortality remains unclear. To elucidate the competing tumor-suppressing and oncogenic effects of p27Kip1 on gene expression in tumors, we analyzed the transcriptomes of squamous cell papilloma derived from Cdkn1b nullizygous, heterozygous, and wild-type mice. We developed a novel functional pathway analysis method capable of testing directional and nonmonotonic dose response. This analysis can reveal potential causal relationships that might have been missed by other nondirectional pathway analysis methods. Applying this method to capture dose-response curves in papilloma gene expression data, we show that several known cancer pathways are dominated by low-high-low gene expression responses to increasing p27 gene doses. The oncogene cyclin D1, whose expression is elevated at an intermediate p27 dose, is the most responsive gene shared by these cancer pathways. Therefore, intermediate levels of p27 may promote cellular processes favoring tumorigenesis—strikingly consistent with the dominance of heterozygous mutations in CDKN1B seen in human cancers. Our findings shed new light on regulatory mechanisms for both pro- and anti-tumorigenic roles of p27Kip1. Functional pathway dose-response analysis provides a unique opportunity to uncover nonmonotonic patterns in biological systems.

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In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2007.01.008 ◽

2007 ◽

Vol 220 (2) ◽

pp. 216-224 ◽

Cited By ~ 43

Author(s):

Leire Arbillaga ◽

Amaia Azqueta ◽

Joost H.M. van Delft ◽

Adela López de Cerain

Keyword(s):

Gene Expression ◽

Ochratoxin A ◽

Gene Expression Data ◽

Expression Data

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Analysis of dose-response to hexanal-induced gene expression in A549 human alveolar cells

BioChip Journal ◽

10.1007/s13206-014-8202-3 ◽

2014 ◽

Vol 8 (2) ◽

pp. 75-82 ◽

Cited By ~ 9

Author(s):

Yoon Cho ◽

Mi-Kyung Song ◽

Han-Seam Choi ◽

Jae-Chun Ryu

Keyword(s):

Gene Expression ◽

Dose Response ◽

Alveolar Cells

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Validation study on urinary biomarkers of exposure for aflatoxin B1, ochratoxin A, fumonisin B1, deoxynivalenol and zearalenone in piglets

World Mycotoxin Journal ◽

10.3920/wmj2013.1549 ◽

2013 ◽

Vol 6 (3) ◽

pp. 299-308 ◽

Cited By ~ 44

Author(s):

S. Gambacorta ◽

H. Solfrizzo ◽

A. Visconti ◽

S. Powers ◽

A.M. Cossalter ◽

...

Keyword(s):

Ochratoxin A ◽

Dose Response ◽

Fumonisin B1 ◽

Correlation Coefficients ◽

Urinary Biomarkers ◽

Post Dose ◽

Toxigenic Fungi ◽

Biomarkers Of Exposure ◽

Commission Recommendation ◽

Aflatoxin B

The multi-biomarker approach was used to validate urinary biomarkers in piglets administered boluses contaminated with mixtures of deoxynivalenol (DON), aflatoxin B1 (AFB1), fumonisin B1 (FB1), zearalenone (ZEA) and ochratoxin A (OTA) at different concentrations. Boluses contaminated with mycotoxins were prepared by slurrying and freezedrying feed material fortified with culture extracts of selected toxigenic fungi. Piglets were individually placed in metabolic cages to collect urine before gavage and 24 h post dose. Urine samples were hydrolysed with β-glucuronidase and analysed by a multi-biomarker LC-MS/MS method developed and validated to identify and measure biomarkers of FB1, OTA, DON, ZEA and AFB1. Urinary levels of FB1, OTA, DON + de-epoxy-deoxynivalenol, ZEA + alphazearalenol and aflatoxin M1 were selected as biomarkers of FB1, OTA, DON, ZEA and AFB1, respectively. Mean percentages of dietary mycotoxins excreted as biomarkers in 24 h post dose urine were 36.8% for ZEA, 28.5% for DON, 2.6% FB1, 2.6% for OTA and 2.5% for AFB1. A good correlation was observed between the amount of mycotoxins ingested and the amount of relevant biomarkers excreted in 24 h post dose urine. Linear dose-response correlation coefficients ranged between 0.68 and 0.78 for the tested couples of mycotoxin/biomarker. The good sensitivity of the LC-MS/MS method and the good dose-response correlations observed in this study permitted to validate the selected mycotoxin biomarkers in piglets at dietary levels close to the maximum permitted levels reported in Commission Directive 2003/100/EC for AFB1 and the guidance values reported in Commission Recommendation 2006/576/EC for DON, ZEA, OTA and FB1.

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Testing for Trends in Dose-Response Microarray Experiments: A Comparison of Several Testing Procedures, Multiplicity and Resampling-Based Inference

Statistical Applications in Genetics and Molecular Biology ◽

10.2202/1544-6115.1283 ◽

2007 ◽

Vol 6 (1) ◽

Cited By ~ 14

Author(s):

Dan Lin ◽

Ziv Shkedy ◽

Dani Yekutieli ◽

Tomasz Burzykowski ◽

Hinrich W.H. Göhlmann ◽

...

Keyword(s):

Gene Expression ◽

Dose Response ◽

Multiple Testing ◽

Pharmaceutical Research ◽

Ratio Test ◽

Familywise Error Rate ◽

Response Level ◽

Data Set ◽

Monotonic Trend ◽

Testing Procedures

Dose-response studies are commonly used in experiments in pharmaceutical research in order to investigate the dependence of the response on dose, i.e., a trend of the response level toxicity with respect to dose. In this paper we focus on dose-response experiments within a microarray setting in which several microarrays are available for a sequence of increasing dose levels. A gene is called differentially expressed if there is a monotonic trend (with respect to dose) in the gene expression. We review several testing procedures which can be used in order to test equality among the gene expression means against ordered alternatives with respect to dose, namely Williams' (Williams 1971 and 1972), Marcus' (Marcus 1976), global likelihood ratio test (Bartholomew 1961, Barlow et al. 1972, and Robertson et al. 1988), and M (Hu et al. 2005) statistics. Additionally we introduce a modification to the standard error of the M statistic. We compare the performance of these five test statistics. Moreover, we discuss the issue of one-sided versus two-sided testing procedures. False Discovery Rate (Benjamni and Hochberg 1995, Ge et al. 2003), and resampling-based Familywise Error Rate (Westfall and Young 1993) are used to handle the multiple testing issue. The methods above are applied to a data set with 4 doses (3 arrays per dose) and 16,998 genes. Results on the number of significant genes from each statistic are discussed. A simulation study is conducted to investigate the power of each statistic. A R library IsoGene implementing the methods is available from the first author.

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