**8. Stress responsive parathyroid hormone (PH) in occupational settings**

Corticosterone (CORT) is stress regulating hormone in human and its reduction in cortisol levels causes low blood pressure, fatigue, weakness in stress condition. Addison's disease, damage adrenal gland, neurological, immunological and metabolic effects were reported in stress condition. Importantly, CORT is responsible to reduce calcium absorption levels and reabsorption from intestine, kidney by increasing the secretion of PH hormones [50, 70, 71]. Parathyroid hormone involved in the calcium regulation which is secreted by parathyroid gland and control via hypothalamus axis. The main mechanism of action of PTH that exerts its effects on kidney, bone and intestine via tubular reabsorbtion and absorption of calcium. Scientists reported that interconnection between parathyroid gland and CORT during first trimers were maintained via differentiation of bone cells and chondrocytes [72]. Recently, PTH suppression in occupationally Bauxite dust exposed workers were reported at the time smelting, mining operations, and beneficiation of Bauxite but its impact in response to stress were less approached by scientists [73, 74]. Therefore, experimental studies reported that aluminium overload supressed PTH levels but still not yet confirmed and indistinguishable that whether Al involved in decline in synthesis/release of PTH because aluminium toxicity effect on bone metabolism and changes in calcium and phosphorus can be modulated by PTH [75, 76]. Earlier reported that Aluminium suppresses PTH by increasing calcium levels and directly affected PTH synthesis this suggested that direct approach is frequent and important as compared to indirect PTH inhibition. Therefore, agreed with serious effects of aluminium in bones that is multi factorial which alters mineralisation, cellular activity of bone cells and leads to cell death because of alteration in cell metabolism [77–80]. The interconnection of aluminium, Calcium, and PTH were well reported but in context to occupational Bauxite dust exposed workers studies not yet reported. In-vitro and in-vivo studies showed that both indirect and direct methods helped evaluation of effect of Al on parathyroid function. Decreased level of PTH with increased Al levels were observed in the occupationally dust exposed bauxite workers. Further, significant negative correlation were observed between PTH and blood aluminium levels and inverse correlation were noted between PTH and calcium. Other studies reported that Al overload decreased PTH and calcium in circulating system [80, 81]. From this studies were suggested that direct and indirect PTH regulation mechanism and Al interferes in PTH secretion/release rather than its synthesis.

### **9. Stress responsive protein in occupational settings**

Heme oxygenase-1 (HO-1) has been identified in many different cell types from lower to higher organisms to tolerate the different forms of stress. Environmental influence alters the pattern of cellular protein expression, performs physiological

activities by acting as a molecular chaperon [82]. Anti-inflammatory actions of HO-1 (rate limiting enzyme) in biochemical pathways are may be due to breakdown of the pro-oxidant heme by own, signal effects of carbon monoxide (CO), the antioxidant biliverdin/bilirubin, and the sequestration of free iron by ferritin in human. Stress responsive HO-1 protein has ability to inhibit inflammation and provide cytoprotection that can be attributed through by-product of HO-1. Heme oxygenase another form of protein, HO-2 were present in neurones and astrocytes, but HO-1 generally worked as inducible form in cell types of central nervous system and by product of HO-1 performs similar work [83, 84]. Numerous stimuli can induce HO-1 gene expression, including oxidative stress and Aβ peptides [85–88]. Induction of HO-1 occurs due to inflammatory processes insults of the cells by environmental factors and the activation of an oxidative stress generated by nuclear factor erythroid 2-related factor-2 (Nrf2), Interleukin-1 (IL-1), and other inflammatory markers. Induction of HO-1 were regulated through Nrf2 contain transcription factor BTB and CNC homology 1 (Bach1) competes with Nrf2 and represses transcription factors [89, 91]. The Nrf2 present in the cytoplasm which interacted with Kelch-like ECH associating protein 1 (Keap1). Keap1 which regulated Nrf2 activity and behave as a sensor for oxidative and electrophilic stresses, degraded by the ubiquitin proteasome pathway. Finally, Nrf2 slightly accumulated in the nucleus and inhibited transcription of the HO-1 gene. Thus, Nrf2-Keap1 complex system played as role in defence mechanism in human [92–95].

In occupational settings, high levels of HO-1 were reported due to bauxite dust exposure and responsible for catabolism of heme in aluminium exposed workers [96]. High levels of Al reported in bauxite exposed workers were assorted and its cellular mechanism fails to appear in published article. Other studies reported that decrease in the level of haemoglobin and high levels of HO-1 in Bauxite dust exposure group which may be due to increased catabolism of heme and generation of ROS and OS in them [97]. Previous study reported that HO-1 deficient and heavy metal exposure at cellular level were more prone to cytotoxicity injury. The functional role of HO-1 induction in OS is not well established in the occupational settings. HO-1 exerts protective role as neurodegenerative, cardiovascular, cancer, metabolic, iron metabolism disorders and various inflammatory diseases in human after oxidative injury [98]. Scientist gave more attention towards role of Ho-1 in silicotic patients, respiratory diseases, and asthma in sub mucosal macrophages and airway epithelium which helps to defend against the insults in lungs in the occupational settings [99–104]. However, induction and molecular regulation HO-1 acts as a anti-inflammatory, antioxidative and antiapoptotic and in response to oxidative stress.
