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1.
Chem Biol Interact ; 394: 110952, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38570061

RESUMEN

High throughput transcriptomics (HTTr) profiling has the potential to rapidly and comprehensively identify molecular targets of environmental chemicals that can be linked to adverse outcomes. We describe here the construction and characterization of a 50-gene expression biomarker designed to identify estrogen receptor (ER) active chemicals in HTTr datasets. Using microarray comparisons, the genes in the biomarker were identified as those that exhibited consistent directional changes when ER was activated (4 ER agonists; 4 ESR1 gene constitutively active mutants) and opposite directional changes when ER was suppressed (4 antagonist treatments; 4 ESR1 knockdown experiments). The biomarker was evaluated as a predictive tool using the Running Fisher algorithm by comparison to annotated gene expression microarray datasets including those evaluating the transcriptional effects of hormones and chemicals in MCF-7 cells. Depending on the reference dataset used, the biomarker had a predictive accuracy for activation of up to 96%. To demonstrate applicability for HTTr data analysis, the biomarker was used to identify ER activators in a set of 15 chemicals that are considered potential bisphenol A (BPA) alternatives examined at up to 10 concentrations in MCF-7 cells and analyzed by full-genome TempO-Seq. Using benchmark dose (BMD) modeling, the biomarker genes stratified the ER potency of BPA alternatives consistent with previous studies. These results demonstrate that the ER biomarker can be used to accurately identify ER activators in transcript profile data derived from MCF-7 cells.


Asunto(s)
Compuestos de Bencidrilo , Fenoles , Receptores de Estrógenos , Humanos , Células MCF-7 , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/genética , Compuestos de Bencidrilo/toxicidad , Fenoles/farmacología , Fenoles/toxicidad , Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos , Biomarcadores/metabolismo , Moduladores de los Receptores de Estrógeno/farmacología
2.
Front Toxicol ; 5: 1194895, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37288009

RESUMEN

The growing number of chemicals in the current consumer and industrial markets presents a major challenge for regulatory programs faced with the need to assess the potential risks they pose to human and ecological health. The increasing demand for hazard and risk assessment of chemicals currently exceeds the capacity to produce the toxicity data necessary for regulatory decision making, and the applied data is commonly generated using traditional approaches with animal models that have limited context in terms of human relevance. This scenario provides the opportunity to implement novel, more efficient strategies for risk assessment purposes. This study aims to increase confidence in the implementation of new approach methods in a risk assessment context by using a parallel analysis to identify data gaps in current experimental designs, reveal the limitations of common approaches deriving transcriptomic points of departure, and demonstrate the strengths in using high-throughput transcriptomics (HTTr) to derive practical endpoints. A uniform workflow was applied across six curated gene expression datasets from concentration-response studies containing 117 diverse chemicals, three cell types, and a range of exposure durations, to determine tPODs based on gene expression profiles. After benchmark concentration modeling, a range of approaches was used to determine consistent and reliable tPODs. High-throughput toxicokinetics were employed to translate in vitro tPODs (µM) to human-relevant administered equivalent doses (AEDs, mg/kg-bw/day). The tPODs from most chemicals had AEDs that were lower (i.e., more conservative) than apical PODs in the US EPA CompTox chemical dashboard, suggesting in vitro tPODs would be protective of potential effects on human health. An assessment of multiple data points for single chemicals revealed that longer exposure duration and varied cell culture systems (e.g., 3D vs. 2D) lead to a decreased tPOD value that indicated increased chemical potency. Seven chemicals were flagged as outliers when comparing the ratio of tPOD to traditional POD, thus indicating they require further assessment to better understand their hazard potential. Our findings build confidence in the use of tPODs but also reveal data gaps that must be addressed prior to their adoption to support risk assessment applications.

3.
Toxicol Sci ; 191(2): 266-275, 2023 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-36534918

RESUMEN

Since initial regulatory action in 2010 in Canada, bisphenol A (BPA) has been progressively replaced by structurally related alternative chemicals. Unfortunately, many of these chemicals are data-poor, limiting toxicological risk assessment. We used high-throughput transcriptomics to evaluate potential hazards and compare potencies of BPA and 15 BPA alternative chemicals in cultured breast cancer cells. MCF-7 cells were exposed to BPA and 15 alternative chemicals (0.0005-100 µM) for 48 h. TempO-Seq (BioSpyder Inc) was used to examine global transcriptomic changes and estrogen receptor alpha (ERα)-associated transcriptional changes. Benchmark concentration (BMC) analysis was conducted to identify 2 global transcriptomic points of departure: (1) the lowest pathway median gene BMC and (2) the 25th lowest rank-ordered gene BMC. ERα activation was evaluated using a published transcriptomic biomarker and an ERα-specific transcriptomic point of departure was derived. Genes fitting BMC models were subjected to upstream regulator and canonical pathway analysis in Ingenuity Pathway Analysis. Biomarker analysis identified BPA and 8 alternative chemicals as ERα active. Global and ERα transcriptomic points of departure produced highly similar potency rankings with bisphenol AF as the most potent chemical tested, followed by BPA and bisphenol C. Further, BPA and transcriptionally active alternative chemicals enriched similar gene sets associated with increased cell division and cancer-related processes. These data provide support for future read-across applications of transcriptomic profiling for risk assessment of data-poor chemicals and suggest that several BPA alternative chemicals may cause hazards at similar concentrations to BPA.


Asunto(s)
Compuestos de Bencidrilo , Receptor alfa de Estrógeno , Transcriptoma , Humanos , Compuestos de Bencidrilo/toxicidad , Receptor alfa de Estrógeno/metabolismo , Estrona , Perfilación de la Expresión Génica , Células MCF-7 , Estrógenos/efectos adversos , Estrógenos/farmacología
4.
Am J Physiol Endocrinol Metab ; 322(5): E383-E413, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35156417

RESUMEN

Persistent organic pollutants (POPs) are a diverse family of contaminants that show widespread global dispersion and bioaccumulation. Humans are continuously exposed to POPs through diet, air particles, and household and commercial products; POPs are consistently detected in human tissues, including the pancreas. Epidemiological studies show a modest but consistent correlation between exposure to POPs and increased diabetes risk. The goal of this review is to provide an overview of epidemiological evidence and an in-depth evaluation of the in vivo and in vitro evidence that POPs cause ß-cell toxicity. We review evidence for six classes of POPs: dioxins, polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), organophosphate pesticides (OPPs), flame retardants, and per- and polyfluoroalkyl substances (PFAS). The available data provide convincing evidence implicating POPs as a contributing factor driving impaired glucose homeostasis, ß-cell dysfunction, and altered metabolic and oxidative stress pathways in islets. These findings support epidemiological data showing that POPs increase diabetes risk and emphasize the need to consider the endocrine pancreas in toxicity assessments. Our review also highlights significant gaps in the literature assessing islet-specific endpoints after both in vivo and in vitro POP exposure. In addition, most rodent studies do not consider the impact of biological sex or secondary metabolic stressors in mediating the effects of POPs on glucose homeostasis and ß-cell function. We discuss key gaps and limitations that should be assessed in future studies.


Asunto(s)
Contaminantes Ambientales , Hidrocarburos Clorados , Plaguicidas , Bifenilos Policlorados , Contaminantes Ambientales/toxicidad , Glucosa , Hidrocarburos Clorados/análisis , Hidrocarburos Clorados/toxicidad , Contaminantes Orgánicos Persistentes , Plaguicidas/análisis , Plaguicidas/toxicidad , Bifenilos Policlorados/análisis , Bifenilos Policlorados/toxicidad
5.
Endocrinology ; 162(6)2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33693622

RESUMEN

CONTEXT: Human studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka "dioxin"), and increased diabetes risk. We previously showed that a single high-dose TCDD exposure (20 µg/kg) decreased plasma insulin levels in male and female mice in vivo, but effects on glucose homeostasis were sex-dependent. OBJECTIVE: The current study assessed whether prolonged exposure to a physiologically relevant low-dose of TCDD impacts glucose homeostasis and/or the islet phenotype in a sex-dependent manner in chow-fed or high-fat diet (HFD)-fed mice. METHODS: Male and female mice were exposed to 20 ng/kg/d TCDD 2×/week for 12 weeks and simultaneously fed standard chow or a 45% HFD. Glucose homeostasis was assessed by glucose and insulin tolerance tests, and glucose-induced plasma insulin levels were measured in vivo. Histological analysis was performed on pancreas from male and female mice, and islets were isolated from females for TempO-Seq transcriptomic analysis. RESULTS: Low-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in females. TCDD caused a modest increase in islet area in males but reduced the percent beta cell area within islets in females. TempO-Seq analysis suggested abnormal changes to endocrine and metabolic pathways in female TCDDHFD islets. CONCLUSION: Our data suggest that prolonged low-dose TCDD exposure has minimal effects on glucose homeostasis and islet morphology in chow-fed male and female mice but promotes maladaptive metabolic responses in HFD-fed females.


Asunto(s)
Adaptación Fisiológica/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Dioxinas/farmacología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Metabolismo Energético/efectos de los fármacos , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/farmacología , Femenino , Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Dibenzodioxinas Policloradas/farmacología , Caracteres Sexuales , Factores de Tiempo
6.
Mol Metab ; 42: 101104, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33075544

RESUMEN

OBJECTIVE: Exposure to persistent organic pollutants is consistently associated with increased diabetes risk in humans. We investigated the short- and long-term impact of transient low-dose dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) exposure during pregnancy and lactation on glucose homeostasis and beta cell function in female mice, including their response to a metabolic stressor later in life. METHODS: Female mice were injected with either corn oil (CO; vehicle control) or 20 ng/kg/d TCDD 2x/week throughout mating, pregnancy and lactation, and then tracked for 6-10 weeks after chemical exposure stopped. A subset of CO- and TCDD-exposed dams was then transferred to a 45% high-fat diet (HFD) or remained on a standard chow diet for an additional 11 weeks to assess the long-term effects of TCDD on adaptability to a metabolic stressor. To summarize, female mice were transiently exposed to TCDD and then subsequently tracked beyond when TCDD had been excreted to identify lasting metabolic effects of TCDD exposure. RESULTS: TCDD-exposed dams were hypoglycemic at birth but otherwise had normal glucose homeostasis during and post-TCDD exposure. However, TCDD-exposed dams on a chow diet were modestly heavier than controls starting 5 weeks after the last TCDD injection, and their weight gain accelerated after transitioning to a HFD. TCDD-exposed dams also had an accelerated onset of hyperglycemia, impaired glucose-induced plasma insulin levels, reduced islet size, increased MAFA-ve beta cells, and increased proinsulin accumulation following HFD feeding compared to controls. Overall, our study demonstrates that low-dose TCDD exposure during pregnancy has minimal effects on metabolism during the period of active exposure, but has detrimental long-term effects on metabolic adaptability to HFD feeding. CONCLUSIONS: Our study suggests that transient low-dose TCDD exposure in female mice impairs metabolic adaptability to HFD feeding, demonstrating that dioxin exposure may be a contributing factor to obesity and diabetes pathogenesis in females.


Asunto(s)
Dioxinas/efectos adversos , Obesidad/metabolismo , Animales , Diabetes Mellitus , Dieta Alta en Grasa , Dioxinas/metabolismo , Dioxinas/farmacología , Susceptibilidad a Enfermedades/inducido químicamente , Femenino , Glucosa/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/fisiología , Lactancia/efectos de los fármacos , Lactancia/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Embarazo
7.
Sci Rep ; 10(1): 1448, 2020 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-31996693

RESUMEN

Epidemiological studies have consistently shown an association between exposure to environmental pollutants and diabetes risk in humans. We have previously shown that direct exposure of mouse and human islets (endocrine pancreas) to the highly persistent pollutant TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) causes reduced insulin secretion ex vivo. Furthermore, a single high-dose of TCDD (200 µg/kg) suppressed both fasting and glucose-induced plasma insulin levels and promoted beta-cell apoptosis after 7 days in male mice. The current study investigated the longer-term effects of a single high-dose TCDD injection (20 µg/kg) on glucose metabolism and beta cell function in male and female C57Bl/6 mice. TCDD-exposed males displayed modest fasting hypoglycemia for ~4 weeks post-injection, reduced fasting insulin levels for up to 6 weeks, increased insulin sensitivity, decreased beta cell area, and increased delta cell area. TCDD-exposed females also had long-term suppressed basal plasma insulin levels, and abnormal insulin secretion for up to 6 weeks. Unlike males, TCDD did not impact insulin sensitivity or islet composition in females, but did cause transient glucose intolerance 4 weeks post-exposure. Our results show that a single exposure to dioxin can suppress basal insulin levels long-term in both sexes, but effects on glucose homeostasis are sex-dependent.


Asunto(s)
Diabetes Mellitus/epidemiología , Contaminantes Ambientales/efectos adversos , Células Secretoras de Insulina/fisiología , Dibenzodioxinas Policloradas/efectos adversos , Factores Sexuales , Animales , Diabetes Mellitus/etiología , Modelos Animales de Enfermedad , Femenino , Homeostasis , Humanos , Hipoglucemia , Insulina/metabolismo , Secreción de Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Riesgo
8.
Diabetologia ; 63(1): 162-178, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31776611

RESUMEN

AIMS/HYPOTHESIS: Exposure to environmental pollution has been consistently linked to diabetes incidence in humans, but the potential causative mechanisms remain unclear. Given the critical role of regulated insulin secretion in maintaining glucose homeostasis, environmental chemicals that reach the endocrine pancreas and cause beta cell injury are of particular concern. We propose that cytochrome P450 (CYP) enzymes, which are involved in metabolising xenobiotics, could serve as a useful biomarker for direct exposure of islets to pollutants. Moreover, functional CYP enzymes in islets could also impact beta cell physiology. The aim of this study was to determine whether CYP1A enzymes are activated in islets following direct or systemic exposure to environmental pollutants. METHODS: Immortalised liver (HepG2) and rodent pancreatic endocrine cell lines (MIN6, ßTC-6, INS1, α-TC1, α-TC3), as well as human islets, were treated in vitro with known CYP1A inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3-MC). In addition, mice were injected with either a single high dose of TCDD or multiple low doses of TCDD in vivo, and islets were isolated 1, 7 or 14 days later. RESULTS: CYP1A enzymes were not activated in any of the immortalised beta or alpha cell lines tested. However, both 3-MC and TCDD potently induced CYP1A1 gene expression and modestly increased CYP1A1 enzyme activity in human islets after 48 h. The induction of CYP1A1 in human islets by TCDD was prevented by cotreatment with a cytokine mixture. After a systemic single high-dose TCDD injection, CYP1A1 enzyme activity was induced in mouse islets ~2-fold, ~40-fold and ~80-fold compared with controls after 1, 7 and 14 days, respectively, in vivo. Multiple low-dose TCDD exposure in vivo also caused significant upregulation of Cyp1a1 in mouse islets. Direct TCDD exposure to human and mouse islets in vitro resulted in suppressed glucose-induced insulin secretion. A single high-dose TCDD injection resulted in lower plasma insulin levels, as well as a pronounced increase in beta cell death. CONCLUSIONS/INTERPRETATION: Transient exposure to TCDD results in long-term upregulation of CYP1A1 enzyme activity in islets. This provides evidence for direct exposure of islets to lipophilic pollutants in vivo and may have implications for islet physiology.


Asunto(s)
Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Contaminantes Ambientales/toxicidad , Animales , Glucemia/efectos de los fármacos , Línea Celular , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Células Hep G2 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Dibenzodioxinas Policloradas/toxicidad , Reacción en Cadena en Tiempo Real de la Polimerasa
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