## 1 Introduction
Thus, the NSCLC manifestation is the outcome of either the transcription factor activation followed by translocation to nucleus (activation) or via direct binding with an ERE-promoter-sensitive locus of estrogen-responsive genes (ERG). Besides natural estrogens, females may be additionally exposed to exogenous synthetic estrogens such as ethinyl estradiol (EE) [12; 13; 85] or equine estrogens [86]. The human body, in particular female, is exposed to these estrogens either as contraceptive pill constituents or as the components of hormone response therapy (HRT). Diethylslibestrol (DES) is another synthetic estrogen used in various scientific experiments to monitor the effect of estrogens on the mammalian body [87]. Both EE and DES have carcinogenic potentials. Other synthetic estrogens used by human subjects are estradiol valerate, estropipate, conjugate esterified estrogen and quinestrol. Additionally, the human body may be exposed to a number of phytoestrogens such as genistein as and when consumed through certain plant-derived foods [16]. Some phytoestrogens are considered endocrine disruptors, resulting in significant adverse health effects [20]. Bisphenol-A (BPA, a constituent of various plastic containers including drinking water bottles) is another exposure form of exogenous compounds that acts as an endocrine disruptor and promotes the migration and invasion of lung cancer cells [88]. Numerous studies in the Chinese population showed significantly higher BPA levels in NSCLC patients than in healthy controls, and therefore, BPA exposure is considered an important NSCLC complication risk factor [89]. A large group of environmental agents or pollutants comprise xenoestrogens, exerting estrogen-like effects together acting as endocrine disruptors. Environmental pollutants such as arsenic, pesticides, fungicides, polycyclic aromatic hydrocarbons (PAH), dichlorodiphenyl-trichloroethane (DDT), polychlorinated biphenyl (PCB), heavy metals and other pollutants such as phthalates, alkylphenols and certain drugs (e.g., antiepileptic drugs) may alter the level of estrogens in the blood/tissues or bind to ERs and alter their activities [90; 91; 92; 93; 94; 95]. For example, a comparative study of unexposed versus transplacental exposed arsenic through drinking water in the fetal lungs of female mice showed a significant enhancement in the ER\(\alpha\) expression within the lungs [96; 97]. Additional studies have shown that alcohol drinking increases estrogen synthesis alongside the chances of cancers [98; 99]. Other potential xenoestrogen molecules such as volcano dust, forest fire smoke, air pollution originated from coal-fired power stations and chemical industry pollutants, automobile exhaust, various cosmetic products, cigarette smoke constituents and overcooked foods such as grilled meat affect the endocrine system. However, smoking remains the major cause of lung cancer in humans [100]. Cigarette smoke contains methylnitrosamino-pyridyl-butanone, a compound that acts as a powerful carcinogenic agent and is responsible for ER\(\beta\) activation [101]. Cotinine, a nicotine metabolite, inhibits aromatase [102] and therefore acts in a gender-specific manner [103]. Figure 2 portrays the methylnitrosamino-pyridyl-butanone and cotinine chemical structures, wherein pi-conjugation in the N-substituted phenyl ring and double-bonded oxygen in close proximity of nitrogen are the common features and could have a discrete involvement in the toxicity induction. Knowledge of such structural inputs could aid in moderating the localized toxicity of each of these compounds with the design of accurate scavenging or neutralizing moieties. Figure 2: Chemical structures of (**a**) methylnitrosamino-pyridyl-butanone, a powerful carcinogenic agent involved in ER\(\beta\) activation, and (**b**) cotinine, a potential nicotine metabolite that inhibits aromatase activity and exhibits sex-dependent activities.