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Article: Testicular histopathology associated with disruption of the Sertoli cell cytoskeleton.

Johnson, Kamin J

2015 Volume 4, Issue 2, Page(s) e979106

Abstract: Testicular histological alterations following Sertoli cell cytoskeleton disruption are numerous. The Sertoli cell cytoskeleton is comprised of intermediate filaments, microtubules, microfilaments and their direct interacting proteins and performs ... ...

Abstract	Testicular histological alterations following Sertoli cell cytoskeleton disruption are numerous. The Sertoli cell cytoskeleton is comprised of intermediate filaments, microtubules, microfilaments and their direct interacting proteins and performs essential functions including structural support of the seminiferous epithelium, apicobasal movement of elongate spermatids, and release of elongate spermatids from the seminiferous epithelium during spermiation. This review summarizes the histological changes occurring after disruption of the Sertoli cell cytoskeleton, including the signature lesion of seminiferous epithelium sloughing. By presenting examples of histological changes after exposure to toxins or toxicants directly affecting the Sertoli cell cytoskeleton or genetic manipulations of this cytoskeleton, the toxicologist observing similar histological changes associated with exposure to novel compounds can use this information to generate hypotheses about a potential mode of action.
Language	English
Publishing date	2015-02-19
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	2629571-4
ISSN	2156-5562 ; 2156-5554
ISSN (online)	2156-5562
ISSN	2156-5554
DOI	10.4161/21565562.2014.979106
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Article ; Online: A Rat Liver Transcriptomic Point of Departure Predicts a Prospective Liver or Non-liver Apical Point of Departure.

Johnson, Kamin J / Auerbach, Scott S / Costa, Eduardo

Toxicological sciences : an official journal of the Society of Toxicology

2020 Volume 176, Issue 1, Page(s) 86–102

Abstract: Identifying a toxicity point of departure (POD) is a required step in human health risk characterization of crop protection molecules, and this POD has historically been derived from apical endpoints across a battery of animal-based toxicology studies. ... ...

Abstract	Identifying a toxicity point of departure (POD) is a required step in human health risk characterization of crop protection molecules, and this POD has historically been derived from apical endpoints across a battery of animal-based toxicology studies. Using rat transcriptome and apical data for 79 molecules obtained from Open TG-GATES (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System) (632 datasets), the hypothesis was tested that a short-term exposure, transcriptome-based liver biological effect POD (BEPOD) could estimate a longer-term exposure "systemic" apical endpoint POD. Apical endpoints considered were body weight, clinical observation, kidney weight and histopathology and liver weight and histopathology. A BMDExpress algorithm using Gene Ontology Biological Process gene sets was optimized to derive a liver BEPOD most predictive of a systemic apical POD. Liver BEPODs were stable from 3 h to 29 days of exposure; the median fold difference of the 29-day BEPOD to BEPODs from earlier time points was approximately 1 (range: 0.7-1.1). Strong positive correlation (Pearson R = 0.86) and predictive accuracy (root mean square difference = 0.41) were observed between a concurrent (29 days) liver BEPOD and the systemic apical POD. Similar Pearson R and root mean square difference values were observed for comparisons between a 29-day systemic apical POD and liver BEPODs derived from 3 h to 15 days of exposure. These data across 79 molecules suggest that a longer-term exposure study apical POD from liver and non-liver compartments can be estimated using a liver BEPOD derived from an acute or subacute exposure study.
MeSH term(s)	Animals ; Benchmarking ; Computational Biology ; Dose-Response Relationship, Drug ; Genomics ; Liver/drug effects ; Prospective Studies ; Rats ; Risk Assessment ; Toxicogenetics ; Transcriptome/drug effects
Language	English
Publishing date	2020-05-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfaa062
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Article ; Online: A microRNA or messenger RNA point of departure estimates an apical endpoint point of departure in a rat developmental toxicity model.

Johnson, Kamin J / Costa, Eduardo / Marshall, Valerie / Sriram, Shreedharan / Venkatraman, Anand / Stebbins, Kenneth / LaRocca, Jessica

Birth defects research

2022 Volume 114, Issue 11, Page(s) 559–576

Abstract: Traditional developmental toxicity testing practice examines fetal apical endpoints to identify a point of departure (POD) for risk assessment. A potential new testing paradigm involves deriving a POD from a comprehensive analysis of molecular-level ... ...

Abstract	Traditional developmental toxicity testing practice examines fetal apical endpoints to identify a point of departure (POD) for risk assessment. A potential new testing paradigm involves deriving a POD from a comprehensive analysis of molecular-level change. Here, the rat ketoconazole endocrine-mediated developmental toxicity model was used to test the hypothesis that maternal epigenomic (miRNA) and transcriptomic (mRNA) PODs are similar to fetal apical endpoint PODs. Sprague-Dawley rats were exposed from gestation day (GD) 6-21 to 0, 0.063, 0.2, 0.63, 2, 6.3, 20, or 40 mg/kg/day ketoconazole. Dam systemic, liver, and placenta PODs, along with GD 21 fetal resorption, body weight, and skeletal apical PODs were derived using BMDS software. GD 21 dam liver and placenta miRNA and mRNA PODs were obtained using three methods: a novel individual molecule POD accumulation method, a first mode method, and a gene set method. Dam apical POD values ranged from 2.0 to 38.6 mg/kg/day; the lowest value was for placenta histopathology. Fetal apical POD values were 10.9-20.3 mg/kg/day; the lowest value was for fetal resorption. Dam liver miRNA and mRNA POD values were 0.34-0.69 mg/kg/day, and placenta miRNA and mRNA POD values were 2.53-6.83 mg/kg/day. Epigenomic and transcriptomic POD values were similar across liver and placenta. Deriving a molecular POD from dam liver or placenta was protective of a fetal apical POD. These data support the conclusion that a molecular POD can be used to estimate, or be protective of, a developmental toxicity apical POD.
MeSH term(s)	Animals ; Female ; Fetal Resorption ; Humans ; Ketoconazole ; MicroRNAs/genetics ; Pregnancy ; RNA, Messenger/genetics ; Rats ; Rats, Sprague-Dawley
Chemical Substances	MicroRNAs ; RNA, Messenger ; Ketoconazole (R9400W927I)
Language	English
Publishing date	2022-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2104792-3
ISSN	2472-1727
ISSN (online)	2472-1727
DOI	10.1002/bdr2.2046
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Article ; Online: Short-term toxicogenomics as an alternative approach to chronic in vivo studies for derivation of points of departure: A case study in the rat with a triazole fungicide.

LaRocca, Jessica / Costa, Eduardo / Sriram, Shreedharan / Hannas, Bethany R / Johnson, Kamin J

Regulatory toxicology and pharmacology : RTP

2020 Volume 113, Page(s) 104655

Abstract: The derivation of an apical endpoint point of departure (POD) from animal-intensive testing programs has been the traditional cornerstone of human health risk assessment. Replacement of in vivo chronic studies with novel approaches, such as ... ...

Abstract	The derivation of an apical endpoint point of departure (POD) from animal-intensive testing programs has been the traditional cornerstone of human health risk assessment. Replacement of in vivo chronic studies with novel approaches, such as toxicogenomics, holds promise for future alternative testing paradigms that significantly reduce animal testing. We hypothesized that a toxicogenomic POD following a 14 day exposure in the rat would approximate the most sensitive apical endpoint POD derived from a battery of chronic, carcinogenicity, reproduction and endocrine guideline toxicity studies. To test this hypothesis, we utilized myclobutanil, a triazole fungicide, as a model compound. In the 14 day study, male rats were administered 0 (vehicle), 30, 150, or 400 mg/kg/day myclobutanil via oral gavage. Endpoints evaluated included traditional apical, hormone, and liver and testis transcriptomic (whole genome RNA sequencing) data. From the transcriptomic data, liver and testis biological effect POD (BEPOD) values were derived. Myclobutanil exposure for 14 days resulted in increased liver weight, altered serum hormones, liver histopathology, and differential gene expression in liver and testis. The liver and testis BEPODs from the short-term study were 22.2 and 25.4 mg/kg/day, respectively. These BEPODs were approximately an order of magnitude higher than the most sensitive apical POD identified from the two year cancer bioassay based on testis atrophy (1.4 mg/kg/day). This study demonstrates the promise of using a short-term study BEPOD to derive a POD for human health risk assessment while substantially reducing animal testing.
MeSH term(s)	Administration, Oral ; Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Fungicides, Industrial/administration & dosage ; Fungicides, Industrial/toxicity ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Male ; Nitriles/administration & dosage ; Nitriles/toxicity ; No-Observed-Adverse-Effect Level ; Organ Size/drug effects ; Rats ; Rats, Sprague-Dawley ; Testis/drug effects ; Testis/metabolism ; Testis/pathology ; Time Factors ; Toxicity Tests, Subacute ; Toxicogenetics ; Triazoles/administration & dosage ; Triazoles/toxicity
Chemical Substances	Fungicides, Industrial ; Nitriles ; Triazoles ; systhane (B6T1JTM6KZ)
Language	English
Publishing date	2020-04-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	604672-1
ISSN	1096-0295 ; 0273-2300
ISSN (online)	1096-0295
ISSN	0273-2300
DOI	10.1016/j.yrtph.2020.104655
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Article ; Online: Dioxin male rat reproductive toxicity mode of action and relative potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzofuran characterized by fetal pituitary and testis transcriptome profiling.

Johnson, Kamin J / Passage, Julie / Lin, Hui / Sriram, Shreedharan / Budinsky, Robert A

Reproductive toxicology (Elmsford, N.Y.)

2020 Volume 93, Page(s) 146–162

Abstract: Fetal rat exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reduces epididymal sperm number involving altered pituitary-testicular hormonal signaling as the proposed mode-of-action (MOA). To evaluate this MOA and compare TCDD to 2,3,7,8- ... ...

Abstract	Fetal rat exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reduces epididymal sperm number involving altered pituitary-testicular hormonal signaling as the proposed mode-of-action (MOA). To evaluate this MOA and compare TCDD to 2,3,7,8-tetrachlorodibenzofuran (TCDF), an in utero rat exposure and study was conducted. Endpoints included congener tissue levels and transcriptomes of maternal liver and fetal liver, testis, and pituitary. Decreased gonadotropin subunit mRNAs levels (Lhb and Fshb) and enriched signaling pathways including GNRH Signaling and Calcium Signaling were observed in fetal pituitary after TCDD (but not TCDF) exposure. TCDD (but not TCDF) decreased fetal testis cholesterologenic and steroidogenic pathway genes. TCDD tissue concentrations in dam liver, dam adipose, and whole fetus were approximately 3- to 6-fold higher than TCDF. These results support a MOA for dioxin-induced rat male reproductive toxicity involving key events in both the fetal pituitary (e.g., reduced gonadotropin production) and fetal testis (e.g., reduced Leydig cell cholesterologenesis and steroidogenesis).
MeSH term(s)	Animals ; Benzofurans/toxicity ; Female ; Fetus/drug effects ; Fetus/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Developmental/drug effects ; Liver/drug effects ; Liver/metabolism ; Male ; Pituitary Gland/drug effects ; Pituitary Gland/metabolism ; Polychlorinated Dibenzodioxins/toxicity ; Pregnancy ; Rats, Sprague-Dawley ; Testis/drug effects ; Testis/metabolism
Chemical Substances	Benzofurans ; Polychlorinated Dibenzodioxins ; 2,3,7,8-tetrachlorodibenzofuran (XZJ41GQI5D)
Language	English
Publishing date	2020-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639342-1
ISSN	1873-1708 ; 0890-6238
ISSN (online)	1873-1708
ISSN	0890-6238
DOI	10.1016/j.reprotox.2020.02.008
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Article ; Online: Development of a human liver microphysiological co-culture system for higher throughput chemical safety assessment.

Ip, Blanche C / Madnick, Samantha J / Zheng, Sophia / van Tongeren, Tessa C A / Hall, Susan J / Li, Hui / Martin, Suzanne / Spriggs, Sandrine / Carmichael, Paul / Chen, Wei / Ames, David / Breitweiser, Lori A / Pence, Heather E / Bowling, Andrew J / Johnson, Kamin J / Cubberley, Richard / Morgan, Jeffrey R / Boekelheide, Kim

Toxicological sciences : an official journal of the Society of Toxicology

2024

Abstract: Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites and exhibit altered toxicity compared to their parent compounds. This paper describes a two-chamber liver-organ co-culture model in a higher-throughput ... ...

Abstract	Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites and exhibit altered toxicity compared to their parent compounds. This paper describes a two-chamber liver-organ co-culture model in a higher-throughput 96-well format for the determination of toxicity on target tissues in the presence of physiologically relevant human liver metabolism. This two-chamber system is a hydrogel formed within each well consisting of a central well (target tissue) and an outer ring-shaped trough (human liver tissue). The target tissue chamber can be configured to accommodate a three-dimensional (3D) spheroid-shaped microtissue, or a two-dimensional (2D) cell mono-layer. Culture medium and compounds freely diffuse between the two chambers. Human differentiated HepaRGTM liver cells are used to form the 3D human liver microtissues, which displayed robust protein expression of liver biomarkers (albumin, asialoglycoprotein receptor, Phase I cytochrome P450 (CYP3A4) enzyme, multidrug resistance-associated protein 2 transporter, and glycogen), and exhibited Phase I/II enzyme activities over the course of 17 days. Histological and ultrastructural analyses confirmed that the HepaRG microtissues presented a differentiated hepatocyte phenotype, including abundant mitochondria, endoplasmic reticulum and bile canaliculi. Liver microtissue zonation characteristics could be easily modulated by maturation in different media supplements. Furthermore, our proof-of-concept study demonstrated the efficacy of this co-culture model in evaluating testosterone-mediated androgen receptor responses in the presence of human liver metabolism. This liver-organ co-culture system provides a practical, higher-throughput testing platform for metabolism-dependent bioactivity assessment of drugs/chemicals, to better recapitulate the biological effects and potential toxicity of human exposures.
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfae018
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Article ; Online: A Transformative Vision for an Omics-Based Regulatory Chemical Testing Paradigm.

Johnson, Kamin J / Auerbach, Scott S / Stevens, Tina / Barton-Maclaren, Tara S / Costa, Eduardo / Currie, Richard A / Dalmas Wilk, Deidre / Haq, Saddef / Rager, Julia E / Reardon, Anthony J F / Wehmas, Leah / Williams, Andrew / O'Brien, Jason / Yauk, Carole / LaRocca, Jessica L / Pettit, Syril

Toxicological sciences : an official journal of the Society of Toxicology

2022 Volume 190, Issue 2, Page(s) 127–132

Abstract: Use of molecular data in human and ecological health risk assessments of industrial chemicals and agrochemicals has been anticipated by the scientific community for many years; however, these data are rarely used for risk assessment. Here, a logic ... ...

Abstract	Use of molecular data in human and ecological health risk assessments of industrial chemicals and agrochemicals has been anticipated by the scientific community for many years; however, these data are rarely used for risk assessment. Here, a logic framework is proposed to explore the feasibility and future development of transcriptomic methods to refine and replace the current apical endpoint-based regulatory toxicity testing paradigm. Four foundational principles are outlined and discussed that would need to be accepted by stakeholders prior to this transformative vision being realized. Well-supported by current knowledge, the first principle is that transcriptomics is a reliable tool for detecting alterations in gene expression that result from endogenous or exogenous influences on the test organism. The second principle states that alterations in gene expression are indicators of adverse or adaptive biological responses to stressors in an organism. Principle 3 is that transcriptomics can be employed to establish a benchmark dose-based point of departure (POD) from short-term, in vivo studies at a dose level below which a concerted molecular change (CMC) is not expected. Finally, Principle 4 states that the use of a transcriptomic POD (set at the CMC dose level) will support a human health-protective risk assessment. If all four principles are substantiated, this vision is expected to transform aspects of the industrial chemical and agrochemical risk assessment process that are focused on establishing safe exposure levels for mammals across numerous toxicological contexts resulting in a significant reduction in animal use while providing equal or greater protection of human health. Importantly, these principles and approaches are also generally applicable for ecological safety assessment.
MeSH term(s)	Animals ; Humans ; Risk Assessment/methods ; Toxicity Tests ; Transcriptome ; Benchmarking ; Mammals
Language	English
Publishing date	2022-09-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfac097
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Article ; Online: Development of a human liver microphysiological coculture system for higher throughput chemical safety assessment

Ip, Blanche C. / Madnick, Samantha J. / Zheng, Sophia / van Tongeren, Tessa C.A. / Hall, Susan J. / Li, Hui / Martin, Suzanne / Spriggs, Sandrine / Carmichael, Paul / Chen, Wei / Ames, David / Breitweiser, Lori A. / Pence, Heather E. / Bowling, Andrew J. / Johnson, Kamin J. / Cubberley, Richard / Morgan, Jeffrey R. / Boekelheide, Kim

Toxicological sciences (2024) ; ISSN: 1096-6080

2024

Abstract: Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher- ... ...

Abstract	Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher-throughput 96-well format for the determination of toxicity on target tissues in the presence of physiologically relevant human liver metabolism. This 2-chamber system is a hydrogel formed within each well consisting of a central well (target tissue) and an outer ring-shaped trough (human liver tissue). The target tissue chamber can be configured to accommodate a three-dimensional (3D) spheroid-shaped microtissue, or a 2-dimensional (2D) cell monolayer. Culture medium and compounds freely diffuse between the 2 chambers. Human-differentiated HepaRG liver cells are used to form the 3D human liver microtissues, which displayed robust protein expression of liver biomarkers (albumin, asialoglycoprotein receptor, Phase I cytochrome P450 [CYP3A4] enzyme, multidrug resistance-associated protein 2 transporter, and glycogen), and exhibited Phase I/II enzyme activities over the course of 17 days. Histological and ultrastructural analyses confirmed that the HepaRG microtissues presented a differentiated hepatocyte phenotype, including abundant mitochondria, endoplasmic reticulum, and bile canaliculi. Liver microtissue zonation characteristics could be easily modulated by maturation in different media supplements. Furthermore, our proof-of-concept study demonstrated the efficacy of this coculture model in evaluating testosterone-mediated androgen receptor responses in the presence of human liver metabolism. This liver-organ coculture system provides a practical, higher-throughput testing platform for metabolism-dependent bioactivity assessment of drugs/chemicals to better recapitulate the biological effects and potential toxicity of human exposures.
Keywords	Life Science
Subject code	500
Language	English
Publishing country	nl
Document type	Article ; Online
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Article ; Online: Of mice and men (and rats): phthalate-induced fetal testis endocrine disruption is species-dependent.

Johnson, Kamin J / Heger, Nicholas E / Boekelheide, Kim

Toxicological sciences : an official journal of the Society of Toxicology

2012 Volume 129, Issue 2, Page(s) 235–248

Abstract: For over 15 years, reproductive toxicologists have explored the physiological outcomes and mechanism of fetal phthalate exposure to determine the risk posed to human male reproductive health. This review examines the fetal male reproductive system ... ...

Abstract	For over 15 years, reproductive toxicologists have explored the physiological outcomes and mechanism of fetal phthalate exposure to determine the risk posed to human male reproductive health. This review examines the fetal male reproductive system response to phthalate exposure across species including rat, mouse, and human, with emphasis on the testis. In the rat, in utero phthalate exposure causes male reproductive tract malformations, in large part, by targeting the testis and inhibiting fetal Leydig cell hormone production. Despite mouse phthalate pharmacokinetics being similar to the rat, inhibition of fetal Leydig cell hormone synthesis is not observed in the mouse. The species-specific differences in testicular response following in utero phthalate exposure and the discordant reaction of the rodent fetal testis when exposed to phthalates ex vivo versus in vivo have made determining risk to humans difficult, yet critically important. The recent use of fetal testis xenotransplants to study phthalate toxicity suggests that the human fetal testis responds like the mouse fetal testis; it appears refractory to phthalate-induced inhibition of testosterone production. Although this result is unfulfilling from the perspective of identifying environmental contributions to human reproductive maldevelopment, it has important implications for phthalate risk assessment.
MeSH term(s)	Animals ; Cell Line ; Endocrine Disruptors/toxicity ; Humans ; Male ; Mice ; Phthalic Acids/toxicity ; Rats ; Species Specificity ; Steroids/biosynthesis ; Testis/drug effects ; Testis/embryology ; Testis/pathology
Chemical Substances	Endocrine Disruptors ; Phthalic Acids ; Steroids
Language	English
Publishing date	2012-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfs206
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Article ; Online: A rat subchronic study transcriptional point of departure estimates a carcinogenicity study apical point of departure.

Bianchi, Enrica / Costa, Eduardo / Yan, Zhongyu June / Murphy, Lynea / Howell, Jessica / Anderson, Donna / Mukerji, Push / Venkatraman, Anand / Terry, Claire / Johnson, Kamin J

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

2020 Volume 147, Page(s) 111869

Abstract: Considerations of human relevance and animal use are driving research to identify new approaches to inform risk assessment of chemicals and replace guideline-based rodent carcinogenicity tests. Here, the hypothesis was tested across four agrochemicals ... ...

Abstract	Considerations of human relevance and animal use are driving research to identify new approaches to inform risk assessment of chemicals and replace guideline-based rodent carcinogenicity tests. Here, the hypothesis was tested across four agrochemicals that 1) a rat 90-day transcriptome-based BEPOD is protective of a rat carcinogenicity study and 2) a subchronic liver or kidney BEPOD would approximate a cancer bioassay apical POD derived from other organs and a rat subchronic BEPOD would approximate a mouse cancer bioassay apical POD. Using RNA sequencing and BMDExpress software, liver and/or kidney BEPOD values were generated in male rats exposed for 90 days to either Triclopyr Acid, Pronamide, Sulfoxaflor, or Fenpicoxamid. BEPOD values were compared to benchmark dose-derived apical POD values generated from rat 90-day and rodent carcinogenicity studies. Across all four agrochemicals, findings showed that a rat 90-day study BEPOD approximated the most sensitive apical POD (within 10-fold) generated from the 90-day rat study and long-term rodent carcinogenicity studies. This study supports the conclusion that a subchronic transcriptome-based BEPOD could be utilized to estimate an apical POD within a risk-based approach of chronic toxicity and carcinogenicity agrochemical assessment, abrogating the need for time- and resource-intensive rodent carcinogenicity studies and minimizing animal testing.
MeSH term(s)	Agrochemicals/toxicity ; Animals ; Carcinogenicity Tests ; Chemical and Drug Induced Liver Injury/pathology ; Dose-Response Relationship, Drug ; Gene Expression Regulation/drug effects ; Kidney Diseases/chemically induced ; Rats ; Toxicogenetics ; Transcription, Genetic/drug effects
Chemical Substances	Agrochemicals
Language	English
Publishing date	2020-11-18
Publishing country	England
Document type	Journal Article
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2020.111869
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