The most common sensory organ defect in the world is hearing loss . Hearing can be impaired directly by high-intensity and long-term noise exposure, eventually leading to NIHL. The number of people with hearing disability is rising year by year, with 42,000 in 1985, 120 million in 1995, 250million in 2001, and up to 360 million in 2011, speculated by the World Health Organization (WHO). NIHL, a multifactoral disease, has been the focus of research in recent years, especially in the study of the association with genetic susceptibility. Population epidemiological studies have shown that after noise exposure, 50% of the variation in hearing loss can be explained by genetic factors[27, 28].
Single-nucleotide polymorphism (SNP) has become the third generation of polymorphism markers due to the characteristics of the high density of genetic markers, high stability, and secure automation of typing tests. There are four theories about the mechanism of NIHL: oxidative stress theory, Ca2 + overload theory, immune inflammation theory, and vascular theory. Previous studies have found that KCNQ4, HSP70, FOXO3, Notch are associated with NIHL. Most of the physiological processes involved in these genes belong to only one of these four theories. However, the STAT3 gene is involved in not only oxidative stress but also immune inflammation. Therefore, to study the potential relationship between STAT3 gene polymorphism and NIHL provides a basis for the future research on the specific molecular mechanism of hearing loss, and may offer a scientific basis for the future prevention of NIHL.
STAT3 is an essential signalling protein. It was improved that STAT3 exerts a vital role in a series of reactions in which extracellular signals are transmitted into the nucleus and promote transcription reactions . An animal experiment shows that STAT3 affects the occurrence and development of NIHL. In this noise-exposed mouse experiment, the mice were processed using JSI-124 before the noise exposure, a JAK2/STAT3 signal path-specific inhibitor, which allowed a significant recovery of hearing sensitivity after two weeks of exposure to noise. This indicates that STAT3 may be as a negative regulatory factor in the development of NIHL in the animal model. But the relationship between the SNP in STAT3 and NIHL need to be illuminated.
The five common SNPs of STAT3 (rs4796793，rs1053004, rs1053005,rs1053023 and rs3744483) were selected in our study. Our results showed that the rs1053023 and rs1053005 loci of STAT3 have statistical significance with NIHL. After adjusting for factors other than genotype such as age, gender, smoking and drinking, individuals carrying the C allele were more susceptible to NIHL than those carrying the T allele in the rs1053023 (OR = 1.367, 95% CI = 1.148- 1.628, P = 0.0001) and rs1053005 (OR = 1.37, 95% CI = 1.147-1.636, P = 0.001) through Logistic regression analysis. In addition, the correlation analysis of different genotypes and a series of risk factors was conducted, and observed the results of that regardless of the locus rs1053023 or rs1053005, the risk of NIHL carrying TC / CC combination genotype is higher than that of the TT genotype (rs1053023, OR = 1.545, 95% CI = 1.215-1.964, P = 0.001 and rs1053005, OR = 1.531, 95% CI = 1.199-1.955, P = 0.002). When stratifying the working years exposed to noise, it is obvious that in the group with a noise exposure period of fewer than ten years or more than 20 years, compared with people with TT genotypes, those with TC / CC genotypes Subjects had a higher risk to NIHL (adjusted: rs1053023, P = 0.001, P =0.031, respectively;rs1053005, P = 0.003, P =0.027). However, there was no statistical significance between the distribution of genotypes and the years of noise exposure within 10~20 years. The reason for this result may be related to complex regulatory functions of STAT3, which may appear as early promotion and late inhibition in immunomodulation.
In the dominant model, in analyzing the impact of smoking and NIHL, we found that people who smoke regularly are more likely to suffer from NIHL than non-smokers or occasional smokers. This coincides with the results of the Mofateh et al.’s study. Using the same manner to analyze the relationship between drinking and NIHL, we found that not drinking but has a higher risk of NIHL, which consistent with of the Upile et al.’s found ( hearing loss can be induced by alcohol even eliminating the effects of noise).
The result of real-time quantitative PCR shows that STAT3 expression is higher in NIHL cases group than the control group. This confirmed that some SNPs of STAT3 might be potentially associated with NIHL. Our study is an association study showing that the C allele of the STAT3 gene increases the risk of NIHL in the Chinese population. Being consistent with the previous experiment, the results of this study show that there is a superimposed effect between the risk factors and SNPs.The interaction between drinking, smoking, and rs1053023/ rs1053005 had an association with NIHL.
At present, the mechanism of NIHL's occurrence is not precise. But many scientists agree that, when the workers are exposed to heavy noise, DNA damage of cochlear hair cells severely affect the development of NIHL . When an individual was exposed to noise, the inner ear tissue can be damaged severely. An important potential cause of that is the production of reactive oxygen[16, 37, 38]. Many scientists have also proposed that apoptosis and necrosis of inner ear cells caused by metabolites or oxidative stress, as well as structural damage directly affecting the structure of the cochlea, maybe the most likely pathogenesis of NIHL[16, 39, 40].
After engaged a multitude of growth factors and cytokines, STAT3 can lead to diverse biological outcomes, such as cell growth, differentiation, and survival，and has a relatively meaningful impact on oxidative stress-mediated tissue injury. More and more experiment research has indicated that the JAK2/STAT3 signalling pathway can effectively regulate damage due to oxidative stress, and the hydrogen peroxide-induced cell death can be effectively reduced through the activity of JAK2/STAT3 signal pathway[41, 42]. In animal models, STAT3 tyrosine 705 phosphorylation can significantly increase due to noise exposure. Inhibition of JAK2 / STAT3 signalling can reduce noise exposure-induced phosphorylation of STAT3 and the expression of STAT3 target genes. The suppression of the JAK2/STAT3 pathway improves the recovery of loud sound exposure. The pathogenic mechanism of NIHL may be explained by further study of STAT3 in depth.
This study is helpful to the development of NIHL's gene chip. Although this study is a relatively complete correlation study based on a large sample population, it also has some shortcomings. First, the subjects of this study come from just a few noise-exposed textile and automobile manufacturing enterprises from China, not all noise-exposed enterprises. Therefore, the research results cannot be generalized to all individuals. Furthermore, the noise exposure characteristics of different enterprises and the operation schedule cannot be the same, so the degree of hearing loss of their employees may also differ.