Comparative analysis of transcriptomic points-of-departure (tPODs) and apical responses in embryo-larval fathead minnows exposed to fluoxetine

Alcaraz, Alper James; Baraniuk, Shaina; Mikulášek, Kamil; Park, Bradley; Lane, Taylor; Burbridge, Connor; Ewald, Jessica; Potěšil, David; Xia, Jianguo; Zdráhal, Zbyněk; Schneider, David J.; Crump, Doug; Basu, Niladri; Hogan, Natacha S.; Brinkmann, Markus; Hecker, Markus

doi:10.1016/j.envpol.2021.118667

Cited by 14 publications

(11 citation statements)

References 67 publications

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“…This divergence in transcriptomic responses is not surprising given that the initial transcriptomic response following methylmercury exposure is likely compensatory and includes genes and pathways that give insight into a chemical's mechanism of action, whereas the later ones (with increasing exposure levels) reflect cellular adversity. Similar patterns are being observed across the tPOD literature including recent data on fish (Alcaraz et al, 2021, 2022; Pagé‐Larivière et al, 2019).…”

Section: Resultssupporting

confidence: 82%

“…In all cases, our calculated tPOD and pathway BMD values were lower than concentrations derived from in vitro cytotoxicity studies, and generally within a 10-fold range of values below the in vivo LC50s (Figure 3). In addition, we were able to compare our findings with a previous study reporting tPODs from embryo-larval fathead minnows exposed to fluoxetine (Alcaraz et al, 2022). The tPODs and pathway BMDs in our study were approximately 12-to 14-fold and approximately 15-to 27-fold higher, respectively, than values derived from that study on fathead minnows (i.e., 7.5 and 5.7 ppb, respectively).…”

Section: Benchmarking In Vitro Tpod and Pathway Bmd Valuessupporting

confidence: 57%

“…For example, tPODs derived from rainbow trout embryos exposed to ethinylestradiol were in the same order of magnitude as empirically derived BMDs for apical endpoints (Alcaraz et al, 2021). A fluoxetine study derived tPODs from embryo–larval fathead minnows that were similar to apical BMDs in chronically exposed fish (Alcaraz et al, 2022). Finally, based on a literature review, researchers at Environment and Climate Change Canada calculated that tPODs derived from fish exposed to notable endocrine‐ disrupting chemicals (bisphenol A, ethinylestradiol, diethylstilbestrol) for short periods correlated well with lowest‐observed‐effect concentration values from chronic animal studies (Pagé‐Larivière et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic Points of Departure Calculated from Rainbow Trout Gill, Liver, and Gut Cell Lines Exposed to Methylmercury and Fluoxetine

Mittal

Ewald

Basu

2022

Enviro Toxic and Chemistry

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Ethical and resource limitation concerns are pushing chemicals management to develop alternatives to animal testing strategies. The objective of our study was to determine whether transcriptomic point of departure (tPOD) values could be derived from studies that followed Organisation for Economic Co‐operation and Development (OECD) Test No. 249 (rainbow trout gill cell line), as well as from studies on trout liver and gut cells. Gill, liver, and gut cell lines were exposed to methylmercury and fluoxetine. Concentrations causing 50% cytotoxicity (LC50) were derived, the whole transcriptome was sequenced, and gene tPOD and pathway benchmark dose (BMD) values were derived from transcriptomic dose–response analysis. Differences in LC50 and transcriptomic responses across the cell lines were noted. For methylmercury, the tPODmode values were 14.5, 20.5, and 17.8 ppb for the gill, liver, and gut cells, respectively. The most sensitive pathway (pathway BMDs in parentheses) was ferroptosis in the gill (3.1 ppb) and liver (3.5 ppb), and glutathione metabolism in the gut (6.6 ppb). For fluoxetine, the tPODmode values were 109.4, 108.4, and 97.4 ppb for the gill, liver, and gut cells, respectively. The most sensitive pathway was neurotrophin signaling in the gill (147 ppb) and dopaminergic signaling in the gut (86.3 ppb). For both chemicals, the gene tPOD and pathway BMD values were lower than cytotoxic concentrations in vitro, and within 10‐fold below the in vivo LC50s. By bringing together transcriptomics and dose–response analysis with an OECD test method in three cell lines, the results help to establish an in vitro method yielding tPOD values that are hypothesized to be protective of in vivo concentrations associated with adverse outcomes, and also give insights into mechanisms of action. Environ Toxicol Chem 2022;41:1982–1992. © 2022 SETAC

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Section: Resultssupporting

confidence: 82%

Section: Benchmarking In Vitro Tpod and Pathway Bmd Valuessupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

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Transcriptomic Points of Departure Calculated from Rainbow Trout Gill, Liver, and Gut Cell Lines Exposed to Methylmercury and Fluoxetine

Mittal

Ewald

Basu

2022

Enviro Toxic and Chemistry

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“…In fish, transcriptomic points of departure (tPODs) detection were recently presented as a possible approach for quantitative hazard assessment based on transcriptomics. 51 Such an approach could in principle also be considered for other test organisms, such as L. minor . With the functional annotation of the L. minor genome, our work provides an important prerequisite for such future studies.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Short-Term Test for Toxicogenomic Analysis of Ecotoxic Modes of Action in Lemna minor

Loll

Reinwald

Ayobahan

et al. 2022

Environ. Sci. Technol.

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In the environmental risk assessment of substances, toxicity to aquatic plants is evaluated using, among other methods, the 7 day Lemna sp. growth inhibition test following the OECD TG 221. So far, the test is not applicable for short-term screening of toxicity, nor does it allow evaluation of toxic modes of action (MoA). The latter is also complicated by the lack of knowledge of gene functions in the test species. Using ecotoxicogenomics, we developed a time-shortened 3 day assay in Lemna minor which allows discrimination of ecotoxic MoA. By examining the changes in gene expression induced by low effect concentrations of the pharmaceutical atorvastatin and the herbicide bentazon at the transcriptome and proteome levels, we were able to identify candidate biomarkers for the respective MoA. We developed a homology-based functional annotation pipeline for the reference genome of L. minor , which allowed overrepresentation analysis of the gene ontologies affected by both test compounds. Genes affected by atorvastatin mainly influenced lipid synthesis and metabolism, whereas the bentazon-responsive genes were mainly involved in light response. Our approach is therefore less time-consuming but sensitive and allows assessment of MoA in L. minor . Using this shortened assay, investigation of expression changes of the identified candidate biomarkers may allow the development of MoA-specific screening approaches in the future.

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Far from Their Origins: A Transcriptomic Investigation on How 2,4‐Di‐tert‐butyl‐6‐(5‐chloro‐2H‐benzotriazol‐2‐yl) Phenol Affects Rainbow Trout Alevins

Eriksson,

Dubiel,

Alcaraz

et al. 2024

Enviro Toxic and Chemistry

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Benzotriazole ultraviolet stabilizers (BUVSs) are a group of widely used chemicals added to a variety of consumer (e.g., plastics) and industrial (e.g., metal coating) goods. Although detected globally as an environmentally persistent pollutant, BUVSs have received relatively little toxicological attention and only recently have been acknowledged to affect development and the endocrine system in vivo. In our previous study, altered behavior, indicative of potential neurotoxicity, was observed among rainbow trout alevins (day 14 posthatching) that were microinjected as embryos with a single environmentally relevant dose of 2,4‐di‐tert‐butyl–6‐(5‐chloro‐2H‐benzotriazol‐2‐yl) phenol (UV‐327). In the present follow‐up study, we performed whole‐transcriptome profiling (RNA sequencing) of newly hatched alevins from the same batch. The primary aim was to identify biomarkers related to behavior and neurology. Dose‐specifically, 1 to 176 differentially expressed genes (DEGs) were identified. In the group presenting altered behavior (273.4 ng g−1), 176 DEGs were identified, yet only a fraction was related to neurological functions, including water, calcium, and potassium homeostasis; acetylcholine transmission and signaling; as well insulin and energy metabolism. The second objective was to estimate the transcriptomic point of departure (tPOD) and assess if point estimate(s) are protective of altered behavior. A tPOD was established at 35 to 94 ng UV‐327 g−1 egg, making this tPOD protective of behavioral alterations. Holistically, these transcriptomic alterations provide a foundation for future research on how BUVSs can influence rainbow trout alevin development, while providing support to the hypothesis that UV‐327 can influence neurogenesis and subsequent behavioral endpoints. The exact structural and functional changes caused by embryonic exposure to UV‐327 remain enigmatic and will require extensive investigation before being deciphered and understood toxicologically. Environ Toxicol Chem 2024;00:1–12. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

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Comparative analysis of transcriptomic points-of-departure (tPODs) and apical responses in embryo-larval fathead minnows exposed to fluoxetine

Cited by 14 publications

References 67 publications

Transcriptomic Points of Departure Calculated from Rainbow Trout Gill, Liver, and Gut Cell Lines Exposed to Methylmercury and Fluoxetine

Transcriptomic Points of Departure Calculated from Rainbow Trout Gill, Liver, and Gut Cell Lines Exposed to Methylmercury and Fluoxetine

Short-Term Test for Toxicogenomic Analysis of Ecotoxic Modes of Action in Lemna minor

Far from Their Origins: A Transcriptomic Investigation on How 2,4‐Di‐tert‐butyl‐6‐(5‐chloro‐2H‐benzotriazol‐2‐yl) Phenol Affects Rainbow Trout Alevins

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