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Biomedical subjects

L C Erway

Publications and source records attributed to L C Erway.

At least 37 records · Page 2Linked to original sources
PubMed1996

Genetics of age-related hearing loss in mice. III. Susceptibility of inbred and F1 hybrid strains to noise-induced hearing loss.

Some humans and mice are genetically predisposed to age-related hearing loss (AHL), and others are variously susceptible to noise-induced hearing loss (NIHL). The inbred C57BL/6J (B6) mice exhibit AHL at an early age, whereas the inbred CBA/CaJ (CB) mice do not. The B6 mice are much more susceptible to NIHL than are the CB mice (Shone et al., 1991; Li, 1992a). The B6 mice possess an Ahl gene which maps to chromosome 10 (Erway et al., 1995). This study was designed, using these two inbred strains plus two F1 hybrid strains of mice, to begin to test the hypothesis that the Ahl genotypes may influence the susceptibility to NIHL. These strains of mice (with putative genotypes) are: inbred CB (+/+) and B6 (Ahl/Ahl); hybrid CBB6F1 (+/Ahl) and B6D2F1 (Ahl/Ahl; D2 represents inbred DBA/2J). Twenty-four mice of each of these four strains were exposed to noise (110 dB for 0, 1 or 2 h) and tested for auditory-evoked brainstem response (ABR) thresholds. The CB and CBB6F1 strains of mice did not differ significantly from each other, exhibiting mostly temporary threshold shifts. The B6 and B6D2F1 strains of mice did not differ significantly from each other, but did exhibit permanent threshold shifts. These results support the hypothesis that genetic predisposition to AHL may be revealed at a younger age by NIHL. This suggests that it may be possible to use the NIHL to distinguish segregating genotypes (+/Ahl vs. Ahl/Ahl) among backcross progeny and thereby to identify and map single genes for AHL.

Acoustic Stimulation↗
PubMed1996

Thyroid hormone receptor beta is essential for development of auditory function.

Congenital thyroid disorders are often associated with profound deafness, indicating a requirement for thyroid hormone (T3) and its receptors in the development of hearing. Two T3 receptor genes, Tr alpha and Tr beta are differentially expressed, although in overlapping patterns, during development. Thus, the extent to which they mediate unique or redundant functions is unclear. We demonstrate that Tr beta-deficient (Thrb-/-) mice exhibit a permanent deficit in auditory function across a wide range of frequencies, although they show no other overt neurological defects. The auditory-evoked brainstem response (ABR) in Thrb-/- mice, although greatly diminished, displayed normal waveforms, which suggested that the primary defect resides in the cochlea. Although hypothyroidism causes cochlear malformation, there was no evidence of this in Thrb-/- mice. These findings suggest that Tr beta controls the maturation of auditory function but not morphogenesis of the cochlea. Thrb-/- mice provide a model for the human endocrine disorder of resistance to thyroid hormone (RTH), which is typically associated with dominant mutations in Tr beta. However, deafness is generally absent in RTH, indicating that dominant and recessive mutations in Tr beta have different consequences on the auditory system. Our results identify Tr beta as an essential transcription factor for auditory development and indicate that distinct Tr genes serve certain unique functions.

Animals↗
PubMed1995

Mouse model for Usher syndrome: linkage mapping suggests homology to Usher type I reported at human chromosome 11p15.

Usher syndrome is a group of diseases with autosomal recessive inheritance, congenital hearing loss, and the development of retinitis pigmentosa, a progressive retinal degeneration characterized by night blindness and visual field loss over several decades. The causes of Usher syndrome are unknown and no animal models have been available for study. Four human gene sites have been reported, suggesting at least four separate forms of Usher syndrome. We report a mouse model of type I Usher syndrome, rd5, whose linkage on mouse chromosome 7 to Hbb and tub has homology to human Usher I reported on human chromosome 11p15. The electroretinogram in homozygous rd5/rd5 mouse is never normal with reduced amplitudes that extinguish by 6 months. Auditory-evoked response testing demonstrates increased hearing thresholds more than control at 3 weeks of about 30 decibels (dB) that worsen to about 45 dB by 6 months.

Animals↗
PubMed1995

Syngeneic bone marrow transplantation reduces the hearing loss associated with murine mucopolysaccharidosis type VII.

MPS VII mice are deficient in beta-glucuronidase and share many clinical, biochemical, and pathologic characteristics with human mucopolysaccharidosis type VII (MPS VII). We have shown that syngeneic bone marrow transplantation (BMT) prolongs survival and reduces lysosomal storage in many organs of the MPS VII mouse. In this report, we quantify the hearing loss and determine the impact of syngeneic BMT on the development of deafness and the associated pathology in the MPS VII mouse. Eleven weeks after syngeneic BMT performed at birth, treated MPS VII mice had normal auditory-evoked brainstem responses (ABR), whereas untreated MPS VII mice had ABR thresholds 43 dB higher than normal. Treated MPS VII mice had beta-glucuronidase-positive cells in the temporal bone and in the subepithelial connective tissue of the external auditory canal. There was less thickening of the tympanic membrane and middle ear mucosa and decreased distortion of the ossicles and the cochlear bone. Although transplanted MPS VII mice had increased ABR thresholds by 33 weeks of age, four of the six had thresholds 12 to 32 dB lower than untreated mutants. These data indicate that syngeneic BMT in newborn MPS VII mice prevents early hearing loss and, in some animals, results in long-term improved auditory function.

Animals↗
PubMed1995

Genetics of age-related hearing loss in mice. II. Strain differences and effects of caloric restriction on cochlear pathology and evoked response thresholds.

The effects of genotype and diet on age-related hearing loss were evaluated using auditory brainstem response (ABR) thresholds and post-mortem cochlear histopathology in 5 inbred mouse strains, CBA/H-T6J (CH), DBA/2J (D2), C57BL/6J (B6), BALB/cByJ (BY) and WB/ReJ (WB), and their 10 F1 hybrid strains. The mice had been maintained since weaning on either a high-energy (HE) control diet or low-energy (LE) calorically restricted diet. ABR thresholds were obtained when the mice were 23 months old; the mice were allowed to age until they died from natural causes prior to obtaining the histological material. The severity of post-mortem cochlear pathology in mice maintained with the HE diet supports our earlier genetic model which postulated that B6, BY, and WB strains each possessed a different recessive allele causing age-related hearing loss, D2 mice possessed all 3 genes, and CH mice possessed none. The histopathology indicates that the genes act at the cochlear level. Dietary restriction resulted in increased longevity in a number of strains, but age-related changes in cochlear pathology were not ameliorated in any of these; indeed, in some strains long-lived LE mice exhibited severe cochlear degeneration. In strains for which longevity was not extended by caloric restriction, only B6 mice exhibited an ameliorative effect of the LE diet on cochlear pathology. ABRs in 23-month-olds indicated a slowing of age-related hearing loss in LE mice of 3 F1 hybrid strains.

Analysis of Variance↗
PubMed1993

Genetics of age-related hearing loss in mice: I. Inbred and F1 hybrid strains.

The auditory-evoked brainstem response (ABR) was used to assess hearing loss in five inbred strains of mice and all ten combinations of F1 hybrids. The inbred strains are CBA/H-T6J (CH), DBA/2J (D2), C57BL/6J (B6), BALB/cByJ (BY) and WB/ReJ (WB). The F1 hybrids are CHD2, CHB6, CHBY, CHWB, D2B6, D2BY, D2WB, B6BY, B6WB, and BYWB. At middle age (12, 16 months), mice were tested with click stimuli. At a relatively old age (23 months, near inbreds' median life span), they were tested with both click and tone-pip stimuli. The CH mice and their four F1 hybrid strains exhibit lower thresholds than the other strains, with the F1 strains being most sensitive (i.e., hybrid vigor). The D2 inbred and the three D2 F1 hybrids (excluding CHD2) exhibit the earliest and most severe hearing losses. The B6, BY and WB inbred strains exhibit severe hearing losses between 16 and 23 months of age; however, the B6BY, B6WB and BYWB F1 hybrids have significantly lower thresholds than their parental strains (genetic complementation). These data support a genetic model for recessive alleles at three different loci which contribute to age-related hearing loss. The CH mice have none of the recessive alleles, and the D2 mice are homozygous recessive for all three; the B6, BY and WB inbred strains are homozygous recessive respectively for one of the three loci.

Acoustic Stimulation↗
PubMed1986

Intestinal metallothionein in lethal-milk mice with systemic zinc deficiency.

Lethal-milk (C57BL/6J-lm) mice over 12 months of age exhibit clinical signs of systemic Zn deficiency. Such lm mice have increased concentrations of metallothionein (MT) in the intestinal mucosa. Various concentrations of Cd or Zn were added to the drinking water. MT was assayed using the Cd-saturation/hemolysate method and for sulfhydryl concentration (MT has 33% cysteine residues) with Ellman's reagent. As assayed by both methods, mucosa from untreated lm mice contained approximately twice as much MT as did the C57BL/6J-(+lm/+lm) (B6) controls. Treatment with 150 and 500 ppm Zn removed the genotypic differences observed for the untreated and Cd-treated mice. These results are consistent with the lm mutation affecting Zn metabolism through impaired MT metabolism as measured for the intestinal mucosa. These studies do not eliminate the possibility that the liver may also contribute.

Animals↗
PubMed1986

Genes, manganese, and zinc in formation of otoconia: labeling, recovery, and maternal effects.

Published studies indicate that genes and dietary manganese deficiency cause vestibular defects and ataxic behaviors. Manganese deficiency during development causes otoconial defects in mice, rats, guinea pigs, and chicks. Mutant genes cause otoconial defects in mice, mink, and poultry. Manganese supplementation prevents the otoconial defects in some mutant mice and mink. Manganese is essential, before crystallization of the otoconia, for synthesis of mucopolysaccharides and otoconial matrix. Such defects can be induced, after otoconia are crystallized during fetal development, by dietary zinc deficiency and sulfonamide treatment (inhibits carbonic anhydrase, a zinc-requiring enzyme). Manganese and/or zinc supplementation ameliorates otoconial defects in pallid and lethal-milk (zinc-deficient) mice. Studies herein show that: Developing otoconia can be quantitatively labeled with 45 Ca. This may provide a means for studying calcium metabolism in otoconia over a prolonged period of time and for determining the possible effects of diet, drugs, and other factors on otoconia. Otoconial defects, induced after otoconia form in the fetus, were observed in newborn mice, but disappeared by two days after birth. Conditions of the inner ear may contribute to the calcification of otoconia. Manganese and zinc supplementation of pallid mice via acidified drinking water is more effective than dietary supplementation in preventing otoconial defects. The effectiveness of zinc but not of manganese is related to maternal genotype (+/pa vs. pa/pa). The effect of supplementation of the dams with zinc but not with manganese increases over successive litters. These studies indicate the potential for interaction of genes and trace minerals on otoconial formation and maintenance.

Animals↗
PubMed1979

Effects of genetic vestibular defects on behavior related to spatial orientation and emotionality.

A large battery of behavioral tests was administered to normal mice and to mice with varying degrees of otoconial agenesis due to genes affecting vestibular development. Many significant differences were found, but a factor analysis revealed that the variance on the 11 best tests could be accounted for in terms of two underlying variables. Factor I, the more important of the two, was associated with activity, habituation, and spontaneous alternation. Factor II appeared to represent a fear of new stimuli or situations. In both cases factor scores were highly related to the degree of otoconial deficiency. One subgroup of mice with severe otoconial agenesis displayed hyperactivity and a total absence of either habituation or spontaneous alternation. In these animals, brain and body development were stunted, and the reactions to amphetamine and physostigmine were opposite to those seen in normal mice. The results support the idea that the static organs contribute importantly to spatial orientation and suggest that early-onset vestibular defects can result in profound alterations of emotionality.

Acetylcholine↗
PubMed1975

The effects of cosmic particle radiation on pocket mice aboard Apollo XVII: X. Results of ear examination.

In the five pocket mice flown on Apollo XVII, no evidence was found that the inner ear had been damaged, though poor fixation precluded detailed study. On the other hand, the middle ear cavity was involved in all the mice, hemorrhage having occurrred in response to excursions in pressure within the canister that housed the mice during their flight. The same occurred in flight control mice which had been subjected to pressure excursions of much the same magnitude. A greater degree of exudation into air cells and greater leukotaxis were noted in the flight animals than in the control animals. There was no increase in leukocyte population along the paths of the 23 cosmic ray particles registered in the subscalp dosimeters that traversed the middle ear cavities of the flight mice. The increased exudation and the greater response by leukocytes in the flight mice may have been causally related to the lesions found in their olfactory mucosa but there were no data in support of this possibility.

Animals↗
PubMedDate not supplied

Preliminary findings of a reduction of otoconia in the inner ear of adult rats prenatally exposed to phenytoin.

Pregnant Sprague-Dawley CD rats were administered phenytoin by gavage on days 7-18 of gestation in doses of 0 or 200 mg/kg. Following completion of a series of behavioral tests (20), progeny (18 months of age) were examined for otoconia in the vestibular labyrinth of the inner ear. None of the controls (N = 22) had reduced otoconia, while 23.3% of phenytoin-treated offspring (N = 43) had reductions. None of the controls, but 44.2% of phenytoin-treated offspring exhibited abnormal circling behavior during systematic examinations conducted in dry and swimming environments. Of the phenytoin-treated offspring exhibiting circling, 21.0% had reduced otoconia in either the utricle or saccule of one ear, while 25.0% of phenytoin-treated offspring not circling exhibited similar reductions. Conversely, 79% of phenytoin-treated offspring exhibiting circling did not exhibit any otoconial reductions. Thus, otoconial reduction cannot account for the majority of the cases of circling. The 21% vs. 25% otoconial reduction difference was not significant, however, when ratings of the magnitude of reduction were analyzed, circling offspring had significantly lower scores in their utricles than those not circling. More specifically, otoconial reduction in the right utricle and circling behavior were significantly related, although the number of concordant cases was small. Otoconial ratings did not differ for saccules. No differences in regional brain weights were found at the time of otoconial examination (560 days). The evidence provide preliminary support for the idea that prenatal exposure to phenytoin induces a reduction in otoconial crystals of the vestibular labyrinth in some of the exposed offspring, but it cannot account for most of the behavioral effects that have been observed in these offspring.

Animals↗