Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP)

Ovacik, Meric; Sen, Banalata; Euling, Susan Y.; Gaido, Kevin W.; Ierapetritou, Marianthi G.; Androulakis, Ioannis P.

doi:10.1016/j.taap.2010.09.008

Cited by 13 publications

(7 citation statements)

References 54 publications

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“…We hypothesize that the multi-dimensional dynamics can be decomposed into intrinsic elements, identified via the SVD decomposition. 32,33,65 Singular value decomposition of the original data determined whether a pathway can generate at least one PAL, an indication that the pathway is active and should be further analyzed for multiple activity patterns in a manner that considers the inherent variability of the data. To account for the inherent variability in the experimental observations, the proposed bootstrap enabled us to identify likely intrinsic responses and further to assess a likelihood metric via corresponding p -values.…”

Section: Discussionmentioning

confidence: 99%

“…As an alternative to the meta-analysis approach, we recently proposed the mapping of transcriptomic data onto signaling and metabolic pathways which are scored based on the emerging activity of the pathway, as manifested via the obtained transcriptional data. [30][31][32][33] The pathway scoring expresses the overall, intrinsic dynamic of the pathway and its score does not rely on measuring a consistent set of transcriptional profiles across the various conditions-provided the score can be robustly determined (see "Methods" section).…”

Section: Gene Regulation and Systems Biologymentioning

confidence: 99%

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Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing

Acevedo

Berthel

DuBois

et al. 2019

Gene�Regul Syst Bio

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Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Gene Regulation and Systems Biologymentioning

confidence: 99%

Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing

Acevedo

Berthel

DuBois

et al. 2019

Gene�Regul Syst Bio

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“…Other studies in older animals showed that DBP preferentially targeted Sertoli cells 28 . Studies during fetal development showed that DBP was anti-androgenic resulting in decreased testosterone production by Leydig cells due to interference with steroidogenesis, down-regulating gene and/or protein expression essential for the steroidogenic pathway, and cholesterol transport and metabolism 29–31 . Suppression of both gonadotropin and testosterone production as well as decreased semen quality were observed in di(2-ethylhexyl)phthalate (DEHP) newly-exposed pre-pubertal and mature animals 32,33 , similar to our results on men newly exposed to high-DBP mesalamine.…”

Section: Discussionmentioning

confidence: 99%

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

Nassan

Coull

Skakkebæk

et al. 2018

Environmental Research

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Background Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease (IBD). Objectives Taking advantage of different mesalamine formulations with/without DBP, we assessed whether DBP from mesalamine (>1000× background) altered serum hormones. Methods Men (N=73) with IBD participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background) at baseline crossed-over for 4 months to DBP-mesalamine (high) and then crossed-back for 4 months to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). We divided H1BH2-arm at the median (H1<3 yrs or H1≥3 yrs). We estimated crossover and crossback % changes in serum reproductive hormones using multivariable linear mixed effect models. Results When B1HB2-arm (26 men, 134 samples) crossed-over, luteinizing hormone decreased 13.9% (95% confidence interval(CI): −23.6, −3.0) and testosterone, inhibin-B, and follicle-stimulating hormone (FSH) marginally decreased; after crossback all increased 8–14%. H1BH2-arm, H1≥3 yrs (25 men, 107 samples) had no changes at crossover or crossback whereas in H1BH2-arm, H1<3 yrs (22 men, 100 samples) after crossover, inhibin-B increased 13.2% (CI: 4.2, 22.9), FSH decreased 9.9% (CI: −17.9, −1.1) and after crossback, inhibin-B further increased 11.3%, and FSH marginally increased. Conclusions High-DBP exposure may disrupt pituitary-gonadal hormones that largely reversed after exposure removal, but only in men with no or short previous high-exposure history. Paradoxically, men with longer duration of high-DBP exposure, exposure removal did not change hormone levels, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and make it insensitive to exposure changes.

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“…Mouse and rat fetal Leydig cells share many similarities, such as stimulation of steroidogenesis by corticotrophin-releasing hormone (CRH) (McDowell et al, 2012), but mouse fetal Leydig cells are more resistant to the endocrine disrupting effect of phthalates than rat fetal Leydig cells (Gaido et al, 2007;Heger et al, 2012;Mylchreest et al, 2002;van den Driesche et al, 2015). In the rat, intrauterine exposure to DBP decreases the expression of genes required for cholesterol biosynthesis and consequently androgen production, but this does not happen in the mouse (Johnson, McDowell et al, 2011;Liu et al, 2005;Ovacik et al, 2013;Thompson et al, 2004). This difference in phthalatesensitivity between the mouse and rat is connected to the SREBP2-mediated (Sterol regulatory element-binding protein 2) control of genes required for cholesterol biosynthesis (Johnson et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Teratogenic effects of in utero exposure to di-(2-ethylhexyl)-phthalate (DEHP) in B6:129S4 mice

Ungewitter¹,

Rotgers²,

Bantukul³

et al. 2017

Toxicol. Sci.

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Intrauterine exposure to phthalates is known to cause disorders of male reproductive function including androgen insufficiency, decreased fertility, and germ cell defects in rodents. In this study, we set out to investigate the effects of intrauterine exposure to di-(2-ethylhexyl)-phthalate (DEHP) on fetal development of the B6:129S4 mouse strain. Time-mated pregnant C57BL/6 dams were exposed to 0, 5, 250, or 500 mg/kg DEHP with corn oil as the vehicle via oral gavage from embryonic days (E)7 to 16. Survival and gross morphology of the pups were analyzed one day after the last treatment. Anogenital distance (AGD) and testicular cell functions were examined in male embryos to confirm the known effects of phthalate exposure. DEHP exposure significantly reduced the survival rate of fetuses in the 250 and 500 mg/kg dosage groups compared with the control and 5 mg/kg groups. Exposure to 250 and 500 mg/kg DEHP was teratogenic and induced exencephaly and limb malformations such as polydactyly in the B6:126S4 embryos. No gross malformations were observed in control or 5 mg/kg DEHP groups. In male embryos, exposure to both 5 and 250 mg/kg DEHP in utero was sufficient to induce the formation of multinucleated germ cells in the testes and widespread changes in mRNA expression of germ cell, interstitium and Sertoli cell-associated genes. These findings reveal that intrauterine DEHP exposure has a strong teratogenic, and lethal impact on the fetuses of B6:129S4 mouse strain.

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Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP)

Cited by 13 publications

References 54 publications

Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing

Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

Teratogenic effects of in utero exposure to di-(2-ethylhexyl)-phthalate (DEHP) in B6:129S4 mice

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