Genetic Differences in Sensitivity to Alterations of Mandible Structure Caused by the Teratogen 2,3,7,8-Tetrachlorodibenzo-<i>p</i>-Dioxin

Keller, James M.; Zelditch, Miriam Leah; Huet-Hudson, Yvette M.; Leamy, Larry J.

doi:10.1177/0192623308327409

Cited by 12 publications

(7 citation statements)

References 24 publications

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“…Additional studies performed in zebrafish reported that TCDD-induced craniofacial defects are mediated by AHR signaling. However, the defects are uniquely found in the lower jaw, affecting the structure of the mandible and the development of the Meckel's cartilage (Keller et al, 2008;Planchart and Mattingly, 2010), highlighting possible evolutionary divergences between zebrafish and mammals.…”

Section: Discussionmentioning

confidence: 99%

Pax3 and Pax7 Play Essential Safeguard Functions against Environmental Stress-Induced Birth Defects

Zalc¹,

Rattenbach²,

Aurade³

et al. 2015

Developmental Cell

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Exposure to environmental teratogenic pollutant leads to severe birth defects. However, the biological events underlying these developmental abnormalities remain undefined. Here, we report a molecular link between an environmental stress response pathway and key developmental genes during craniofacial development. Strikingly, mutant mice with impaired Pax3/7 function display severe craniofacial defects. We show that these are associated with an upregulation of the signaling pathway mediated by the Aryl hydrocarbon receptor (AHR), the receptor to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), revealing a genetic interaction between Pax3 and AHR signaling. Activation of AHR signaling in Pax3-deficient embryos drives facial mesenchymal cells out of the cell cycle through the upregulation of p21 expression. Accordingly, inhibiting AHR activity rescues the cycling status of these cells and the facial closure of Pax3/7 mutants. Together, our findings demonstrate that the regulation of AHR signaling by Pax3/7 is required to protect against TCDD/AHR-mediated teratogenesis during craniofacial development.

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Section: Discussionmentioning

confidence: 99%

Pax3 and Pax7 Play Essential Safeguard Functions against Environmental Stress-Induced Birth Defects

Zalc¹,

Rattenbach²,

Aurade³

et al. 2015

Developmental Cell

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“…Phenotypes and alleles of developmental genes can be influenced by genetic background [ 104 , 105 ]. An interesting and highly relevant example is the fact that different inbred strains of mice display differential response to AhR-mediated effects on mandible development [ 106 ]. The morphs studied here all (except AC) exist in sympatry in Lake Thingvallavatn.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of the aryl hydrocarbon receptor pathway associates with craniofacial polymorphism in sympatric Arctic charr

Ahi

Steinhäuser

Pálsson

et al. 2015

EvoDevo

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BackgroundThe developmental basis of craniofacial morphology hinges on interactions of numerous signalling systems. Extensive craniofacial variation in the polymorphic Arctic charr, a member of the salmonid family, from Lake Thingvallavatn (Iceland), offers opportunities to find and study such signalling pathways and their key regulators, thereby shedding light on the developmental pathways, and the genetics of trophic divergence.ResultsTo identify genes involved in the craniofacial differences between benthic and limnetic Arctic charr, we used transcriptome data from different morphs, spanning early development, together with data on craniofacial expression patterns and skeletogenesis in model vertebrate species. Out of 20 genes identified, 7 showed lower gene expression in benthic than in limnetic charr morphs. We had previously identified a conserved gene network involved in extracellular matrix (ECM) organization and skeletogenesis, showing higher expression in developing craniofacial elements of benthic than in limnetic Arctic charr morphs. The present study adds a second set of genes constituting an expanded gene network with strong, benthic–limnetic differential expression. To identify putative upstream regulators, we performed knowledge-based motif enrichment analyses on the regulatory sequences of the identified genes which yielded potential binding sites for a set of known transcription factors (TFs). Of the 8 TFs that we examined using qPCR, two (Ahr2b and Ap2) were found to be differentially expressed between benthic and limnetic charr. Expression analysis of several known AhR targets indicated higher activity of the AhR pathway during craniofacial development in benthic charr morphotypes.ConclusionThese results suggest a key role of the aryl hydrocarbon receptor (AhR) pathway in the observed craniofacial differences between distinct charr morphotypes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13227-015-0022-6) contains supplementary material, which is available to authorized users.

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“…If L–E rats have a longer and/or later period of facial growth by comparison, during adulthood their faces may remain more susceptible to environmental stressors [53] , [54] , [55] , which can alter natural between-strain differences in cranial shape [56] . Furthermore, although the H/W and L–E rats have different AhR alleles, five inbred strains of mice that possess the same AhR alleles have shown different TCDD-induced changes in mandibular size and shape [15] . These findings suggest that between-strain differences in TCDD responses may involve genes beyond the AhR locus, such as those that control the genetic architecture of a particular trait [15] .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, although the H/W and L–E rats have different AhR alleles, five inbred strains of mice that possess the same AhR alleles have shown different TCDD-induced changes in mandibular size and shape [15] . These findings suggest that between-strain differences in TCDD responses may involve genes beyond the AhR locus, such as those that control the genetic architecture of a particular trait [15] . Consistent with these findings, our results suggest that genetically programmed differences in growth potential may modulate TCDD toxicity in different rat stains.…”

Section: Discussionmentioning

confidence: 99%

“…In the postcranial skeleton, TCDD exposure has been associated with significant alterations in bone mineral density, biomechanical strength, and bone geometry among different rat strains and at dose levels of relevance to human and wildlife exposure situations [10] , [11] , [12] , [13] . In the skull, dioxin-induced changes in the size and shape of the mandible of exposed mice have been identified using geometric morphometric techniques [14] , [15] . Teeth also exhibit dioxin sensitivity, as low levels of in utero/lactational exposure and high levels of adult exposure have shown numerous effects on eruption, size, structure, and caries susceptibility [16] , [17] , [18] , [19] .…”

Section: Introductionmentioning

confidence: 99%

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Craniofacial form is altered by chronic adult exposure to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) in Han/Wistar and Long–Evans rats with different aryl hydrocarbon receptor (AhR) structures

et al. 2015

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Mammalian bone has shown a variety of responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in experimental and wildlife studies. Although many responses have been well characterized in the postcranial skeleton, dioxin-induced effects on the cranium are largely unknown. In this study, we investigated the effects of chronic adult exposure to TCDD on cranial size and shape in dioxin-resistant Han/Wistar (H/W) and dioxin-sensitive Long–Evans (L–E) rat strains. Three-dimensional landmark configurations for the face, vault, and base of the cranium were recorded and analyzed using geometric morphometrics (GM) and dose–response modeling. The strongest effects were shown by L–E and H/W rats with daily exposures of 100 and 1000 ng TCDD/kg bw/day, respectively, resulting in significant reductions in centroid size (CS) in all three cranial modules for both strains except for the vault in H/W rats. Consistent with previous evidence of intraspecific variation in TCDD resistance, the benchmark doses (CEDs) for cranial size reduction in L–E rats were roughly 10-fold lower than those for H/W rats. For both strains, the face showed the greatest size reduction from the highest doses of TCDD (i.e., 3.6 and 6.3% decreases in H/W and L–E rats, respectively), most likely related to dose-dependent reductions in limb bone size and body weight gain. However, intrinsic morphological differences between strains were also observed: although the control groups of H/W and L–E rats had vaults and bases of comparable size, the face was 6.4% larger in L–E rats. Thus, although H/W rats possess an altered aryl hydrocarbon receptor (AhR) that appears to mediate and provides some resistance to TCDD exposure, their smaller reductions in facial size may also relate to strain-specific patterns of cranial development and growth. Future research will be aimed at understanding how ontogenetic factors may modulate toxic effects of prenatal and lactational exposure on the mammalian skeleton.

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Genetic Differences in Sensitivity to Alterations of Mandible Structure Caused by the Teratogen 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

Cited by 12 publications

References 24 publications

Pax3 and Pax7 Play Essential Safeguard Functions against Environmental Stress-Induced Birth Defects

Pax3 and Pax7 Play Essential Safeguard Functions against Environmental Stress-Induced Birth Defects

Differential expression of the aryl hydrocarbon receptor pathway associates with craniofacial polymorphism in sympatric Arctic charr

Craniofacial form is altered by chronic adult exposure to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) in Han/Wistar and Long–Evans rats with different aryl hydrocarbon receptor (AhR) structures

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