Characterization of Xenobiotic-Induced Hepatocellular Enzyme Induction in Rats

Zabka, Tanja S.; Fielden, Mark R.; Garrido, Rosario; Tao, Jianhua; Fretland, Adrian J.; Fretland, Jennifer; Albassam, Mudher; Singer, Thomas P.; Kolaja, Kyle L.

doi:10.1177/0192623311406934

Cited by 35 publications

(37 citation statements)

References 30 publications

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“…Total (combined "weak" and "dark") TSH-positive areas presented no correlation to the hypertrophy scoring (data not shown), which indicated the lack of increase in the total TSH-immunoreactive cell population in the pituitary par distalis. An absence of hyperplasia (i.e., cell proliferation) in the pituitary gland was further supported by the lack of an RO2910-related increase in topoisomerase II immunoreactivity and thus of mitotic activity, as reported previously (Zabka et al 2011).…”

Section: Quantification Of Individual Cell Hypertrophy In Pituitary Gsupporting

confidence: 80%

“…1B). Refining the semi-quantitative histological interpretation, quantification demonstrated a statistically significant increase in all but the group 2 females and distinguished a dose-dependent response (Zabka et al 2011).…”

Section: Quantification Of Liver Hypertrophy and Correlation With Hismentioning

confidence: 94%

“…The reverse transcription reaction product was used for quantitative RT-PCR, using gene-specific dual-labeled probes and forward and reverse primers for drug metabolism genes as described (Zabka et al 2011). Data were normalized to the 18S rRNA content of each sample and graphed as fold induction relative to vehicle control rats.…”

Section: Quantitative Rt-pcr Of Drug Metabolism Genesmentioning

confidence: 99%

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Quantitative Histological Assessment of Xenobiotic-Induced Liver Enzyme Induction and Pituitary-Thyroid Axis Stimulation in Rats Using Whole-Slide Automated Image Analysis

Garrido

Zabka

Tao

et al. 2013

J Histochem Cytochem.

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Preclinical evaluation of a new compound, RO2910, identified a hypertrophic response in liver, thyroid gland, and pituitary gland (pars distalis). We aimed to develop and validate automated image analysis methods to quantify and refine the interpretation of semi-quantitative histology. Wistar-Han rats were administered RO2910 for 14 days. Liver, thyroid, and pituitary gland tissues were processed for routine histology and immunolabeled with anti–thyroid stimulating hormone (TSH) antibody (pituitary) and anti–topoisomerase II antibody (thyroid). Glass slides were scanned, image analysis methods were developed and applied to whole-slide images, and numerical results were compared with histopathology, circulating hormone levels, and liver enzyme mRNA expression for validation. Quantitative analysis of slides had strong individual correlation with semi-quantitative histological evaluation of all tissues studied. Hepatocellular hypertrophy quantification also correlated strongly with liver enzyme mRNA expression. In the pars distalis, measurement of TSH weak-staining areas correlated with both hypertrophy scores and circulating TSH levels. Whole-slide image analysis enabled automated quantification of semi-quantitative histopathology findings and a more refined interpretation of these data. The analysis also enabled a direct correlation with non-histological parameters using straightforward statistical analysis to provide a more refined dose- and sex-response relationship and integration among affected parameters. These findings demonstrate the utility of our image analysis to support preclinical safety evaluations.

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Section: Quantification Of Individual Cell Hypertrophy In Pituitary Gsupporting

confidence: 80%

Section: Quantification Of Liver Hypertrophy and Correlation With Hismentioning

confidence: 94%

Section: Quantitative Rt-pcr Of Drug Metabolism Genesmentioning

confidence: 99%

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Quantitative Histological Assessment of Xenobiotic-Induced Liver Enzyme Induction and Pituitary-Thyroid Axis Stimulation in Rats Using Whole-Slide Automated Image Analysis

Garrido

Zabka

Tao

et al. 2013

J Histochem Cytochem.

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“…Most recently, an in vivo study reported that rats underwent significant thyroid gland weight gain when exposed to MP and BP doses of 1000 mg/kg BW/day (Vo et al, 2010). Such a weight change might be explained by activation of a feedback loop in response to low TH blood levels, stimulating the thyroid gland to produce more THs and potentially leading to hypertrophy and corresponding increase in thyroid gland weight (Zabka et al, 2011). The same study by Vo et al (2010) also demonstrated that exposure to doses ranging from 62.5 to 1000 mg/kg BW/day of MP, PP, isopropyl paraben, and isobutyl paraben significantly diminished T4 levels.…”

Section: Discussionmentioning

confidence: 99%

Relationship between urinary triclosan and paraben concentrations and serum thyroid measures in NHANES 2007–2008

Koeppe

Ferguson

Colacino

et al. 2013

Science of The Total Environment

183

106

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Triclosan and parabens are broad spectrum antimicrobials used in a range of consumer products. In vitro and animal studies have suggested the potential for these compounds to disrupt thyroid function, though studies in humans have been limited. The objective of the study was to assess the relationship of urinary concentrations of triclosan and parabens with serum thyroid measures in a large, representative sample of the US population. We conducted an exploratory, cross-sectional analysis of data on urinary biomarkers of triclosan and paraben exposure and serum thyroid measures obtained from 1,831 subjects (ages ≥12 years) as part of the 2007–2008 National Health and Nutrition Examination Survey (NHANES). We found evidence of some inverse associations between parabens and circulating thyroid hormone levels in adults, with the strongest and most consistent associations among females. We also observed a positive association between triclosan and total triiodothyonine (T3) concentrations in adolescents. These results, in accordance with the in vitro and animal literature, suggest that paraben, and potentially triclosan, exposures may be associated with altered thyroid hormone levels in humans. Further research is needed for confirmation and to determine the potential clinical significance of these findings.

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“…Following the OeCD tG 407 which includes endpoints for thyroid hormone disruption, Higashihara et al found effects on thyroid hormone level in addition to changes in thyroid and pituitary weight (Higashihara et al, 2007). While the exact mechanism of action is not yet elucidated, BPF did not affect cell proliferation in both the t-screen and the tSH-screen, suggesting that its main mechanism of acwith other pathways (Roy and Mugesh, 2006b;Cao et al, 2010;Gayrard et al, 2011;Zabka et al, 2011;Kosuda et al, 1997;Grover et al, 2007;liu and Brent, 2010). thus, with the exception of t4 and tSH, the effects of the selected thyroid-active compounds on pituitary and thyroid organ weights in vivo are not likely to be due to a direct effect on cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

In vitro pituitary and thyroid cell proliferation assays and their relevance as alternatives to animal testing

Jomaa

2013

ALTEX

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Summary This study investigates the in vitro effect of eleven thyroid-active compounds known to affect pituitary and/or thyroid weights in vivo, using the proliferation of GH3 rat pituitary cells in the so-called "T-screen," and of FRTL-5 rat thyroid cells in a newly developed test denoted "TSH-screen" to gain insight into the relative value of these in vitro proliferation tests for an integrated testing strategy (ITS) for thyroid activity. Pituitary cell proliferation in the T-screen was stimulated by three out of eleven tested compounds, namely thyrotropin releasing hormone (TRH), triiodothyronine (T3) and thyroxine (T4). Of these three compounds, only T4 causes an increase in relative pituitary weight, and thus T4 was the only compound for which the effect in the in vitro assay correlated with a reported in vivo effect. As to the newly developed TSH-screen, two compounds had an effect, namely, thyroid-stimulating hormone (TSH) induced and T4 antagonized FRTL-5 cell proliferation. These effects correlated with in vivo changes induced by these compounds on thyroid weight. Altogether, the results indicate that most of the selected compounds affect pituitary and thyroid weights by modes of action different from a direct thyroid hormone receptor (THR) or TSH receptor (TSHR)-mediated effect, and point to the need for additional in vitro tests for an ITS. Additional analysis of the T-screen revealed a positive correlation between the THR-mediated effects of the tested compounds in vitro and their effects on relative heart weight in vivo, suggesting that the T-screen may directly predict this THR-mediated in vivo adverse effect.

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Characterization of Xenobiotic-Induced Hepatocellular Enzyme Induction in Rats

Cited by 35 publications

References 30 publications

Quantitative Histological Assessment of Xenobiotic-Induced Liver Enzyme Induction and Pituitary-Thyroid Axis Stimulation in Rats Using Whole-Slide Automated Image Analysis

Quantitative Histological Assessment of Xenobiotic-Induced Liver Enzyme Induction and Pituitary-Thyroid Axis Stimulation in Rats Using Whole-Slide Automated Image Analysis

Relationship between urinary triclosan and paraben concentrations and serum thyroid measures in NHANES 2007–2008

In vitro pituitary and thyroid cell proliferation assays and their relevance as alternatives to animal testing

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