Insulin resistance due to dietary iron overload disrupts inner hair cell ribbon synapse plasticity in male mice

Yu, Fang; Hao, Shuai; Yang, Bo; Zhao, Yue; Zhang, Rui; Zhang, Wenyue; Yang, Jun; Chen, Jie

doi:10.1016/j.neulet.2015.04.049

Cited by 10 publications

(7 citation statements)

References 25 publications

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“…Measurements of iron status were performed as previously described [24,26]. Blood samples of dams (0.5 mL/per animal) were collected on GD 7, 14, and 21 by alternately clipping the toenails for serum level of iron (SI), hematocrit (Hct) and serum ferritin (SF) measured.…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: Low Iron Diet Increases Susceptibility to Noise-Induced Hearing Loss in Young Rats

Hao

Yang

et al. 2016

Nutrients

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We evaluated the role of iron deficiency (ID) without anemia on hearing function and cochlear pathophysiology of young rats before and after noise exposure. We used rats at developmental stages as an animal model to induce ID without anemia by dietary iron restriction. We have established this dietary restriction model in the rat that should enable us to study the effects of iron deficiency in the absence of severe anemia on hearing and ribbon synapses. Hearing function was measured on Postnatal Day (PND) 21 after induction of ID using auditory brainstem response (ABR). Then, the young rats were exposed to loud noise on PND 21. After noise exposure, hearing function was again measured. We observed the morphology of ribbon synapses, hair cells and spiral ganglion cells (SGCs), and assessed the expression of myosin VIIa, vesicular glutamate transporter 3 and prestin in the cochlea. ID without anemia did not elevate ABR threshold shifts, but reduced ABR wave I peak amplitude of young rats. At 70, 80, and 90 dB SPL, amplitudes of wave I (3.11 ± 0.96 µV, 3.52 ± 1.31 µV, and 4.37 ± 1.08 µV, respectively) in pups from the ID group were decreased compared to the control (5.92 ± 1.67 µV, 6.53 ± 1.70 µV, and 6.90 ± 1.76 µV, respectively) (p < 0.05). Moreover, ID without anemia did not impair the morphology hair cells and SGCs, but decreased the number of ribbon synapses. Before noise exposure, the mean number of ribbon synapses per inner hair cell (IHC) was significantly lower in the ID group (8.44 ± 1.21) compared to that seen in the control (13.08 ± 1.36) (p < 0.05). In addition, the numbers of ribbon synapses per IHC of young rats in the control (ID group) were 6.61 ± 1.59, 3.07 ± 0.83, 5.85 ± 1.63 and 12.25 ± 1.97 (3.75 ± 1.45, 2.03 ± 1.08, 3.81 ± 1.70 and 4.01 ± 1.65) at 1, 4, 7 and 14 days after noise exposure, respectively. Moreover, ABR thresholds at 4 and 8 kHz in young rats from the ID group were significantly elevated at 7 and 14 days after noise exposure compared to control (p < 0.05). The average number of young rat SGCs from the ID group were significantly decreased in the basal turn of the cochlea compared to the control (p < 0.05). Therefore, ID without anemia delayed the recovery from noise-induced hearing loss and ribbon synapses damage, increased SGCs loss, and upregulated prestin after noise exposure. Thus, the cochleae in rat pups with ID without anemia were potentially susceptible to loud noise exposure, and this deficit may be attributed to the reduction of ribbon synapses and SGCs.

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Section: Methodsmentioning

confidence: 99%

RETRACTED: Low Iron Diet Increases Susceptibility to Noise-Induced Hearing Loss in Young Rats

Hao

Yang

et al. 2016

Nutrients

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“…Other investigators have measured growth and Hb levels in rodents fed high-iron diets [ 36 – 38 ], including some studies that have used weanling SD rats [ 39 , 40 ]. In general, most studies documented decrements in body weight after high-iron feeding.…”

Section: Discussionmentioning

confidence: 99%

“…A mechanistic explanation for altered growth rates was, however, not provided. A few studies also measured Hb levels after high-iron feeding and showed no changes [ 36 , 40 ] or an increase [ 39 ]. Differences between these previous studies and the current investigation could relate to the diets used, the length of feeding, the specific strain of mouse or rat used, and/or to rodent housing conditions.…”

Section: Discussionmentioning

confidence: 99%

High-Iron Consumption Impairs Growth and Causes Copper-Deficiency Anemia in Weanling Sprague-Dawley Rats

Doguer

Wang

et al. 2016

PLoS ONE

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Iron-copper interactions were described decades ago; however, molecular mechanisms linking the two essential minerals remain largely undefined. Investigations in humans and other mammals noted that copper levels increase in the intestinal mucosa, liver and blood during iron deficiency, tissues all important for iron homeostasis. The current study was undertaken to test the hypothesis that dietary copper influences iron homeostasis during iron deficiency and iron overload. We thus fed weanling, male Sprague-Dawley rats (n = 6-11/group) AIN-93G-based diets containing high (~8800 ppm), adequate (~80) or low (~11) iron in combination with high (~183), adequate (~8) or low (~0.9) copper for 5 weeks. Subsequently, the iron- and copper-related phenotype of the rats was assessed. Rats fed the low-iron diets grew slower than controls, with changes in dietary copper not further influencing growth. Unexpectedly, however, high-iron (HFe) feeding also impaired growth. Furthermore, consumption of the HFe diet caused cardiac hypertrophy, anemia, low serum and tissue copper levels and decreased circulating ceruloplasmin activity. Intriguingly, these physiologic perturbations were prevented by adding extra copper to the HFe diet. Furthermore, higher copper levels in the HFe diet increased serum nonheme iron concentration and transferrin saturation, exacerbated hepatic nonheme iron loading and attenuated splenic nonheme iron accumulation. Moreover, serum erythropoietin levels, and splenic erythroferrone and hepatic hepcidin mRNA levels were altered by the dietary treatments in unanticipated ways, providing insight into how iron and copper influence expression of these hormones. We conclude that high-iron feeding of weanling rats causes systemic copper deficiency, and further, that copper influences the iron-overload phenotype.

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“…Notably, IL6, NFKBIA, NFKB1, NOS3, PTPN1, PIK3R1, and STAT3 (members in the enriched WGCNA module) have been shown to alter insulin resistance (Seo et al, 2016). Researchers have shown that insulin resistance can decrease the number of ribbon synapses and elevate the ABR threshold in an age-related hearing loss model without affecting OHCs, IHCs, and SGNs (Yu et al, 2015).…”

Section: Functional Annotation Of Wgcna and Ppi Enriched Modulesmentioning

confidence: 99%

Systematic Transcriptome Analysis of Noise-Induced Hearing Loss Pathogenesis Suggests Inflammatory Activities and Multiple Susceptible Molecules and Pathways

Wang

Shen

et al. 2020

Front. Genet.

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Noise-induced hearing loss (NIHL) is characterized by damage to cochlear neurons and associated hair cells; however, a systematic evaluation of NIHL pathogenesis is still lacking. Here, we systematically evaluated differentially expressed genes of 22 cochlear samples in an NIHL mouse model. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and weighted gene co-expression network analysis (WGCNA). Core modules were detected using proteinprotein interactions and WGCNA with functional annotation, diagnostic value evaluation, and experimental validation. Pooled functional annotation suggested the involvement of multiple inflammatory pathways, including the TNF signaling pathway, IL-17 signaling pathway, NF-kappa B signaling pathway, rheumatoid arthritis, and p53 signaling pathway. The core modules suggested that responses to cytokines, heat, cAMP, ATP, mechanical stimuli, and immune responses were important in NIHL pathogenesis. These activities primarily occurred on the external side of the plasma membrane, the extracellular region, and the nucleus. Binding activities, including CCR2 receptor binding, protein binding, and transcription factor binding, may be important. Additionally, the hub molecules with diagnostic value included Relb, Hspa1b, Ccl2, Ptgs2, Ldlr, Plat, and Ccl17. An evaluation of Relb and Hspa1b protein levels showed that Relb was upregulated in spiral ganglion neurons, which might have diagnostic value. In conclusion, this study indicates that the inflammatory response is involved in auditory organ changes in NIHL pathogenesis; moreover, several molecules and activities have essential and subtle influences that have translational potential for pharmacological intervention.

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Insulin resistance due to dietary iron overload disrupts inner hair cell ribbon synapse plasticity in male mice

Cited by 10 publications

References 25 publications

RETRACTED: Low Iron Diet Increases Susceptibility to Noise-Induced Hearing Loss in Young Rats

RETRACTED: Low Iron Diet Increases Susceptibility to Noise-Induced Hearing Loss in Young Rats

High-Iron Consumption Impairs Growth and Causes Copper-Deficiency Anemia in Weanling Sprague-Dawley Rats

Systematic Transcriptome Analysis of Noise-Induced Hearing Loss Pathogenesis Suggests Inflammatory Activities and Multiple Susceptible Molecules and Pathways

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