Physiological Role of the Aryl Hydrocarbon Receptor in Mouse Ovary Development

Benedict, Jamie C.; Lin, Tien Min; Loeffler, Ivonne; Peterson, Richard E.; Flaws, Jodi A.

doi:10.1093/toxsci/56.2.382

Cited by 187 publications

(147 citation statements)

References 23 publications

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“…Importantly, some of the phenotypes observed in the Ah -/-mice are similar to those reported in TCDD-treated animals, suggesting that the endogenous AHR responds to endogenous signals. Notably, Ah -/-mice exhibit defects in reproduction and ovary development, and these defects are also observed in wild type mice treated with TCDD [17][18][19][20]. Collectively, these findings support the hypothesis that a reduction in the level of endogenous AHR protein may reduce responsiveness to endogenous signaling molecules and possibly contribute to the biological effects mediated by TCDD.…”

Section: Introductionsupporting

confidence: 67%

Specific blockage of ligand-induced degradation of the Ah receptor by proteasome but not calpain inhibitors in cell culture lines from different species

Pollenz

2007

Biochemical Pharmacology

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To firmly establish the pathway involved in ligand-induced degradation of the AHR, cell lines derived from mouse rat or human tissues were exposed to inhibitors specific to the proteasome or calpain proteases and exposed to TCDD. The level of endogenous AHR and CYP1A1 protein was then evaluated by quantitative Western blotting. Treatment of cells with the calpain inhibitors: calpeptin, calpain inhibitor III, or PD150606 either individually or in combinations up to 75μM did not reduce TCDD-induced degradation of the AHR, the induction of endogenous CYP1A1 or the nuclear accumulation of the AHR. The activity of the inhibitors was verified with an in vivo calpain assay. In contrast, exposure of cells to the specific proteasome inhibitors: epoxomicin (1-5μM), proteasome inhibitor I (5-10μM) or lactacystin (5-15μM) completely inhibited TCDD-induced degradation of the AHR. Inhibition of AHR degradation with these compounds did not reduce the induction of endogenous CYP1A1. In addition, exposure of the Hepa-1 line to the various proteasome inhibitors caused an accumulation of the AHR in the nucleus in the absence of TCDD exposure. Finally, Western blot analysis of the DNA bound AHR showed that its molecular mass was unchanged in comparison to the unliganded (cytoplasmic) AHR. Thus, these studies conclusively implicate the proteasome and not calpain proteases in the ligand-induced degradation of the mouse, rat and human AHR and suggest that the pharmacological use of proteasome inhibitors may impact the time course and magnitude of gene regulatory events mediated through the AHR.

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Section: Introductionsupporting

confidence: 67%

Specific blockage of ligand-induced degradation of the Ah receptor by proteasome but not calpain inhibitors in cell culture lines from different species

Pollenz

2007

Biochemical Pharmacology

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“…The ovariectomized animal was the most commonly used model, but no ovary remained to be analyzed in this model, and it can only be used to study effects of ovarian loss on other tissues or systems. Some genetically modified mouse models have been reported, such as follitropin receptor knockout (FORKO) mouse and dioxin/aryl hydrocarbon receptor (AhR) knockout mouse (Dierich et al, 1998;Benedict et al, 2000). The reproductive systems in these models have been affected at early developmental stage, and normal reproductive systems have never formed.…”

Section: Discussionmentioning

confidence: 99%

Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide

Jiang

Zhao

et al. 2013

J. Zhejiang Univ. Sci. B

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Busulfan/cyclophosphamide (Bu/Cy) conditioning regimen has been widely used to treat cancer patients, while their effects on major internal organs in females are not fully understood. We treated female mice with Bu/Cy, and examined the histopathology of major internal organs on Day 30 after the treatment. The results show that Bu/Cy treatment affected the ovaries most extensively, while it had less effect on the spleen, lungs, and kidneys, and no effect on the heart, liver, stomach, and pancreas. To better understand the effect of Bu/Cy on the ovaries, we counted follicles, and determined the levels of ovarian steroids. The Bu/Cy-treated mice showed a reduction of primordial and primary follicles (P<0.01) on Day 30 and a marked loss of follicles at all developmental stages (P<0.01) on Day 60. Plasma levels of estradiol and progesterone in Bu/Cy-treated mice decreased by 43.9% and 61.4%, respectively. Thus, there was a gradual process of follicle loss and low estradiol in Bu/Cy-treated mice; this is a profile similar to what is found in women with premature ovarian failure (POF). The Bu/Cy-treated mice may serve as a useful animal model to study the dynamics of follicle loss in women undergoing POF.

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“…Results from a variety of laboratories over the past decade have revealed that the AHR has key roles in the development of cardiovascular, reproductive, and neural systems as well as in hematopoiesis and regulation of immune responses (Benedict, Lin, Loeffler, Peterson, & Flaws, 2000; Esser & Rannug, 2015; Gasiewicz, Singh, & Bennett, 2014; Kimura, Ding, & Tohyama, 2016; Lahvis et al., 2005; Quintana & Sherr, 2013; Singh et al., 2014; Stockinger, Di Meglio, Gialitakis, & Duarte, 2014). Some of these functions may involve natural or endogenous ligands such as metabolites generated by the microbiome, tryptophan metabolites, or lipid‐derived molecules (Bessede et al., 2014; Hubbard, Murray, & Perdew, 2015; McMillan & Bradfield, 2007; Moura‐Alves et al., 2014).…”

Section: Ahr Pathwaymentioning

confidence: 99%

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

Whitehead

Clark

Reid

et al. 2017

Evolutionary Applications

129

102

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For most species, evolutionary adaptation is not expected to be sufficiently rapid to buffer the effects of human‐mediated environmental changes, including environmental pollution. Here we review how key features of populations, the characteristics of environmental pollution, and the genetic architecture underlying adaptive traits, may interact to shape the likelihood of evolutionary rescue from pollution. Large populations of Atlantic killifish (Fundulus heteroclitus) persist in some of the most contaminated estuaries of the United States, and killifish studies have provided some of the first insights into the types of genomic changes that enable rapid evolutionary rescue from complexly degraded environments. We describe how selection by industrial pollutants and other stressors has acted on multiple populations of killifish and posit that extreme nucleotide diversity uniquely positions this species for successful evolutionary adaptation. Mechanistic studies have identified some of the genetic underpinnings of adaptation to a well‐studied class of toxic pollutants; however, multiple genetic regions under selection in wild populations seem to reflect more complex responses to diverse native stressors and/or compensatory responses to primary adaptation. The discovery of these pollution‐adapted killifish populations suggests that the evolutionary influence of anthropogenic stressors as selective agents occurs widely. Yet adaptation to chemical pollution in terrestrial and aquatic vertebrate wildlife may rarely be a successful “solution to pollution” because potentially adaptive phenotypes may be complex and incur fitness costs, and therefore be unlikely to evolve quickly enough, especially in species with small population sizes.

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Physiological Role of the Aryl Hydrocarbon Receptor in Mouse Ovary Development

Cited by 187 publications

References 23 publications

Specific blockage of ligand-induced degradation of the Ah receptor by proteasome but not calpain inhibitors in cell culture lines from different species

Specific blockage of ligand-induced degradation of the Ah receptor by proteasome but not calpain inhibitors in cell culture lines from different species

Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

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