The Teratogenic Sensitivity to 2,3,7,8-Tetrachlorodibenzo-<i>p</i>-dioxin Is Modified by a Locus on Mouse Chromosome 3

Thomae, Tami L.; Stevens, Emily A.; Liss, Adam L.; Drinkwater, Norman R.; Bradfield, Christopher A.

doi:10.1124/mol.105.019760

Cited by 13 publications

(11 citation statements)

References 35 publications

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“…Both the hamster and rat fetuses exhibited cleft palate at the 18 g/kg dose, a response, which has only been previously reported in rats and mice (Peterson et al, 1993). Fetal hamsters also had teratogenic responses in the kidney consisting of congestion and hydronephrosis, a common response in fetal mice gestationally exposed to TCDD (Abbott et al, 1987;Couture et al, 1990b;Peterson et al, 1993;Thomae et al, 2005). Fetal rats displayed a dose-dependent increase in intestinal hemorrhaging which has also been previously reported (Olson and McGarrigle, 1992;Olson et al, 1990;Sparschu et al, 1971).…”

Section: Discussionmentioning

confidence: 55%

Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig

2007

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Section: Discussionmentioning

confidence: 55%

Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig

2007

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“…Keller, Huang, et al (2007) also found that C57BL/6J congenic mice exhibited TCDD-induced changes in mandible morphology. Effects of TCDD therefore appear to be trait specific, as noted previously (Thomae et al 2006;Simanainen et al 2003;Poland and Glover 1980). Despite TCDD's clear effect on mandible shape over multiple strains, differences in mandible size were detectable only in C3H/HeJ male mice.…”

Section: Tcdd Effects On Mandible Size and Shapementioning

confidence: 76%

“…For example, non-Ahr loci are known to alter the sensitivity to TCDD-induced cleft palate (Thomae et al 2006), hepatic porphyria (Robinson et al 2002), and mouse molar size (Keller, Allen, et al 2007). Furthermore, we recently completed studies on TCDD's effect on molar development in five different inbred mouse strains that, based on their functionally similar Ahr b alleles, would be expected to exhibit similar sensitivity to TCDD.…”

mentioning

confidence: 99%

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

et al. 2008

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The contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant and teratogen that has been shown to alter craniofacial development. Differences in sensitivity to TCDD are attributed primarily to differences in alleles at the Ahr locus coding for the aryl-hydrocarbon receptor (AHR) that binds TCDD and mediates its effects by altering gene expression. The authors used geometric morphometric methods to evaluate differences in the effects of small in utero exposures of TCDD on adult mandible size and shape in five different inbred mouse strains with the same Ahr alleles. Because of the known effects of this toxicant on bone and craniofacial structures, the authors hypothesized that TCDD would decrease mandible size and alter mandible shape, but that the effects of TCDD exposure would differ among the inbred strains. The authors found that TCDD did alter mandible size and shape, but these effects were limited to specific strains and also differed between the sexes. The relative sensitivity to TCDD's effects on mandibles did not correspond with the previously reported sensitivity to TCDD's effects on molars. The authors hypothesize that beyond Ahr-related effects, variation in response to TCDD reflects differences in the genetic architecture controlling the trait being evaluated, thus explaining the species, strain, and trait specificity of TCDD.

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“…We found that the c57Bl/6 mouse strain (Ahb-1) was most sensitive to ototoxic effects due to a low dosage (30 μg/kg) TCDD prenatal exposure and the CBA mouse (Ahb-2) was not impaired. Similarly, when Thomae et al (2006) administered a higher dose of TCDD at embryonic day 9, nearly 100% of the c57Bl/6 offspring exhibited cleft palate, while a similar exposure in CBA mice only resulted in cleft palate in 8% of the offspring. Their finding lead to the conclusion that there must be an additional genetic basis for strain-dependent dioxin sensitivity, as both stains carried the high-affinity b allele.…”

Section: Discussionmentioning

confidence: 98%

“…Their finding lead to the conclusion that there must be an additional genetic basis for strain-dependent dioxin sensitivity, as both stains carried the high-affinity b allele. In pursuit of this unidentified locus, c57Bl/6 and CBA mice were crossed and linkage analysis on cleft palate incidence was performed to assess dioxin-induced teratogenic effects and found one locus segregating with dioxin-induced cleft palate (designated as cmt1) located on chromosome 3 (Thomae et al 2006). Presumably, this locus is also required for ototoxic effects due to a lower dosage of TCDD.…”

Section: Discussionmentioning

confidence: 99%

Prenatal low dosage dioxin (TCDD) exposure impairs cochlear function resulting in auditory neuropathy

Safe

Luebke

2016

Hearing Research

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2,3,7,8-tetrachorodibenzo-p-dioxin (TCDD), a ubiquitous and persistent environmental contaminant, is a potent teratogen. Whereas developmental TCDD toxicity is mediated by the aryl hydrocarbon receptor (AhR), the normal function of the AhR is poorly understood. We tested whether dioxin exposure during a critical period of hair cell development disrupts cochlear function in three mouse strains, (C57BL6, BalbC, and CBA) that contain high affinity AhR-b alleles. C57BL/6, BalbC, and CBA dams were exposed to 500 ng/kg TCDD or olive oil (vehicle) on embryonic day 12 by gavage. Cochlear function was analyzed at 1.5 months of age by measuring 1) auditory brainstem response (ABRs) to tone pips from 5.6 to 30 kHz, and 2) distortion-product otoacoustic emissions (DPOAEs) evoked by primaries with f2 at the same frequency values. Cochlear threshold sensitivity following TCDD exposure was significantly elevated in both female and male mice in the C57BL/6 strain, carrying the Ahb-1 allele, but not significantly elevated in the BalbC or CBA strains, carrying the Ahb-2 allele. These ABR threshold deficits in mice carrying the Ahb-1 allele parallels the cleft palate incidence to higher TCDD exposures, suggesting that ABR testing could serve as a sensitive indicator of TCDD toxicity in at-risk children. Moreover, DPOAEs were not affected following TCDD exposure in any of the mouse strains, suggesting that following TCDD exposure mice with the Ahb-1 allele exhibit a mild auditory neuropathy. The causes of many auditory neuropathies are unknown, yet a developmental exposure to dioxin may be a risk factor for this condition.

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The Teratogenic Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Is Modified by a Locus on Mouse Chromosome 3

Cited by 13 publications

References 35 publications

Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig

Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig

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

Prenatal low dosage dioxin (TCDD) exposure impairs cochlear function resulting in auditory neuropathy

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