21.1 Air Pollution and Air Pollutants

Over the past decades, rapid industrialization and economic development have been concomitant with large migration from rural areas to cities [1]. This outlook has resulted in urban growth, modernization, and increased concentration of air pollutants, in turn ensuing increased number of exposed people [2]. Atmosphere being a geochemical reservoir of organic compounds partition’s into gaseous and airborne particulate phase that interact with oceans, land, and living organisms [3]. The source and concentration of pollutants in outdoor and indoor atmosphere vary based on point of discharge. The outdoor pollutants are resultant of coal and oil combustion in power plants; disposal of industrial, medical, and municipal solid waste; motor vehicles emissions; industrial and sewage treatment plant discharges; and biomass burning. The causatives of indoor pollutants are unvented combustion, building materials, furnishings, paint, floor and wall coverings, cleaning products, cosmetics, detergents, pesticides, and electronic appliances [4]. The shift-ups in inhaling the above pollutants indeed justify the presence of toxic endocrine-disrupting chemicals (EDCs) body burden in every human being’s blood, urine, and body tissues [5].

21.1.1 Air Pollutants in Terms of EDCs

EDCs are synthetic chemicals used in industrial, agricultural, and household applications, noted for specific property in disrupting endocrine system. On inhaling these chemicals as air particulates, they enter different systems of the body and disrupt normal homeostasis by either mimicking or blocking hormones. EDCs downstream effects start either by interacting with nuclear, hormone, or orphan receptors or by modifying enzymatic pathways involved in steroid biosynthesis or metabolism [6]. The long-range transport of EDCs via atmosphere and ocean routes makes their ubiquitous presence and source of exposure [7]. Distribution of EDCs in the atmosphere is governed by three equilibrium partitioning coefficients: air-water, water-octanol, and octanol-air (Table 21.1).

Table 21.1 Solubility, partition coefficients, and half-life of major EDCs in the atmosphere
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21.1.2 Major EDCs Causing Pathetic Disorders

chemical production in the preceding 20 years correlates to the growing incidence of endocrine-associated pediatric disorders that include male reproductive disorders, early female puberty, leukemia, brain cancer, and neurobehavioral disorders [5]. Early life exposure to EDCs has also been implicated to the alteration of developmental programming, resulting in higher susceptibility to obesity, respiratory disorders, asthma, diabetes, cancer, endometriosis, neurological disorders, thyroid disorders, and cardiovascular disease [8,9,10,11,12,13,14,15]. The major EDCs involved in all of the above anomalies are phthalate esters (PEs), bisphenol A (BPA), polychlorinated biphenyls (PCBs), polyaromatic hydrocarbons (PAHs), polybrominated flame retardants (BFRs), pesticides, dioxins, alkylphenol (APs), perfluorinated compounds (PFCs), and heavy metals.

21.2 Emerging Sources of EDCs

Numerous chemicals were developed to meet wide range of medical, scientific, agricultural and industrial needs. Despite their socioeconomic benefits, the release of chemicals into the environment and exposure had led to serious health consequences irrespective of ages and species (Fig. 21.1).The source and point of discharge of major EDCs into the atmosphere are as follows:

Fig. 21.1
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Schematic representation of air pollution sources, emerging EDCs, and health issues

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21.2.1 Phthalates

PEs are dialkyl or alkyl aryl esters of phthalic acid commonly used as plasticizers and encountered as indoor pollutant [47]. They are used in the manufacture of polyvinylchloride (PVC) products, building materials, toys, clothing, cosmetics, perfumes, food packaging, and medical appliances [48]. Phthalates are not physically bound to the polymers making their diffusion easier out of the plastics into the environment. Release of household and industrial wastewater from production and processing units and disposal of materials are sources of phthalates occurring in the atmosphere [49].

21.2.2 Bisphenol A

BPA is an organic compound composed of two phenol rings connected by a methyl bridge, with two methyl functional groups. It is a high-volume production chemical used worldwide in the manufacture of polycarbonate plastics including numerous consumer products like food and water containers and bottles. BPA is also found in the resin linings of food and beverage cans and dental sealants [50], leaching readily from many of these products lead to exposure in large segments of the population [51].

21.2.3 Polychlorinated Biphenyls

PCBs are aromatic, synthetic chemicals formed by two linked benzene rings with some or all of the hydrogen substituted by chlorine atoms. PCBs have been used commercially since 1929 as insulating fluid in transformers, capacitors, and plasticizers in open systems comprising numerous building materials including adhesives, caulk, ceiling tiles, paints, and sealants [52].

21.2.4 Polyaromatic Hydrocarbons

PAHs are a large group of organic compounds with two or more fused aromatic rings. Based on origin, pyrogenic PAHs are formed by the incomplete combustion of fossil fuels, forest fires, and tobacco smoke; petrogenic PAHs are present in crude oil, its product, and coal [53]. PAHs enter the environment primarily through sewage, road runoffs, smelter industries, and oil spills [54, 55]. The offshore PAHs enter water through oil seeps, spills, and discharges from offshore oil installations [56].

21.2.5 Polybrominated Flame Retardants

In ancient Egypt about 450 BC, alum was used to reduce the flammability of wood, and ever since that time flame retardants have been used in various materials. The halogen-containing compounds are used today as flame retardants in electronic equipment, textiles, plastics, paints, and printed circuit boards preventing fire eruptions by capturing free radicals [57].

21.2.6 Pesticides

Pesticides are substances or chemical mixture intended for preventing, destroying, repelling, or lessening the damage of pest (Fig. 21.2). This includes herbicides, insecticides, fungicides, and rodenticides used in agriculture and public health. Occupational exposure to pesticides in agricultural workplace occurs during preparation (mixing and loading) and application (spraying) [58].

Fig. 21.2
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Structure of major EDCs causing potential threat to health: (1) Di (2-ethylhexyl) phthalate, (2) bisphenol A, (3) polychlorinated biphenyl, (4) polyaromatic hydrocarbon, (5) brominated biphenyl ethers, (6) atrazine, (7) polychlorinated dibenzo-dioxins, (8) nonylphenol, and (9) perfluorooctane sulfonate

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21.2.7 Dioxins

Dioxins are a group of 210 organic chemicals, among which 75 congeners are polychlorinated dibenzo-p-dioxins (PCDDs), and 135 are polychlorinated dibenzo-furans (PCDFs). Prior to industrialization, low concentrations of dioxins existed in nature due to natural combustion and geological processes [59]. Presently, in industries though dioxins are not produced commercially, they are formed as by-products when reaction temperature is not well controlled in chemical manufacturing processes [60]. Dioxins are also produced in small concentrations when organic materials are burned in the presence of chlorine ions or atoms in the fuel formulae [61].

21.2.8 Alkylphenol

APs are widely used as nonionic surfactants in detergents, pesticides, herbicides, emulsifiers, paints, cosmetics, plastic ware, and even in jet fuel [62]. They are commonly found in wastewater discharges and effluents from sewage treatment plants [63].

21.2.9 Perfluorinated Compounds

PFCs are synthetic compounds characterized by long, fully fluorinated carbon chains with different functional head groups resisting them to degradation [64]. PFCs are used in variety of products to resist grease, oil, stains, and water and are also used in fire-fighting foam [65]. PFC contamination in the environment originates from direct or indirect anthropogenic sources. Direct source includes manufacture and use of perfluoroalkylated acids (PFAA), whereas indirect sources include product impurities and production of chemicals that may degrade to PFAA [66].

21.2.10 Heavy Metals

Heavy metals are commonly defined as metals those having a specific density of more than 5 g cm3. The main threats to human health from heavy metals are associated with exposure to lead, cadmium, mercury, and arsenic. Heavy metals are being used in many different areas for thousands of years. Lead has been used for at least 5000 years, early applications including building materials, pigments for glazing ceramics, and pipes for transporting water [67]. Cigarette smoke contains about 30 metals, of which cadmium, arsenic, and lead are in the highest concentrations [68].

21.3 Mechanism Behind Endocrine Disruption

EDCs exert numerous disrupting mechanisms interfering endogenous hormonal functions depending on certain factors such as exposure level, duration, age, and susceptibility (Table 21.2). Owing to this action, EDCs are able to disrupt two or more endocrinal functions with widespread consequences on the biological processes controlled by vulnerable endocrine glands. In vivo studies predict activation of hormonal receptors at nanomolar (nM) levels and enzymatic disruption at micromolar (mM) levels resulting in genomic instability and alteration of hormonal feedback regulation [69]. EDCs exert their actions through nuclear hormone receptors such as estrogen receptors (ERs), androgen receptors (ARs), progesterone receptors (PRs), thyroid receptors (TRs), and retinoid receptors (RXR) [6]. Indeed, EDCs are also capable of acting through nonsteroid receptors, transcriptional coactivators, enzymatic pathways, and genomic mechanism [70, 71].

Table 21.2 Nuclear receptors, biological half-life, and concentration of EDCs in the atmosphere and humans
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21.3.1 Metabolic Disruption Through Hormone Receptors

Hormone receptors belong to a class of classic hormone receptors that recognize only one or a few molecules with high affinity. Thyroid hormone (TH), mineralocorticoid, glucocorticoid, retinoic acid, estrogen, vitamin D, progesterone, and androgen receptors belong to this class. Interaction of EDCs with these receptors results in developmental and reproductive effects, as well as metabolic alterations.

21.3.1.1 Estrogen Receptor

Estrogen receptors (ERα and β) have well-established roles in reproduction; in addition to that, they are also involved in brain development and function of many other organs such as the skin, bone, and liver (Fig. 21.3). At the molecular level, ERs and estrogens regulate glucose transport, glycolysis, mitochondrial activity, and fatty acid oxidation [94]. Based on experimental evidences, early exposure to BPA enhances adipocyte differentiation or permanently disrupt adipocyte-specific gene expression and leptin synthesis [95, 96]. Estrogenic surfactant octylphenols potentially elevate adipocyte production of resistin through activation of the ER and regulate extracellular signal kinase pathways [97]. Resistin secreted by adipocytes causes insulin resistance and predisposition to type 2 diabetes [98]. BPA also affects ERα activity in the pancreas and increases insulin secretion [99].

Fig. 21.3
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Schematic representation of endocrine glands, hormones, receptors, significant functions, and antagonistic EDCs

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21.3.1.2 Thyroid Hormone Receptor and Glucocorticoid Receptor

TH activity is mediated by the TRs, TRα, and β which form heterodimers with RXR to bind the promoter sequences of target genes. Elevated TH levels accelerate metabolism, increase lipolysis and hepatic cholesterol biosynthesis, and provoke weight loss; the exact vice versa exists with low TH levels. In contrast to TR, GR forms homodimers and resides in the cytosol, forming complexes with molecular chaperones, and influences gene expression. Glucocorticoids act through GRs promoting gluconeogenesis, increasing blood glucose levels, and mobilizing the oxidation of fatty acids. Based on experimental evidences, BPA and PEs stimulate GR-mediated lipid accumulation and synergize with a weak GR agonist to increase expression of adipocyte-specific markers [100]. The effects of BPA on TR during development may be significant in long-term body weight increase, while BFRs decrease glucose oxidation, characteristically associated with obesity, insulin resistance, and type 2 diabetes [101, 102].

21.3.2 Metabolic Disruption Through Xenosensors

The body is protected from the accumulation of toxic chemicals by a complex strategy that takes place in the liver, regulating the expression of drug-metabolizing enzymes and transporters. This adaptive response integrates at least three xenosensors: pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR).

21.3.2.1 Pregnane X Receptor and Constitutive Androstane Receptor

PXR and CAR regulate gene expression by forming heterodimers with RXR that bind to xenobiotic response sequences present in the promoters of their target genes. PXR is located primarily in the nucleus and is strongly activated upon ligand binding. In contrast, in the absence of ligand, CAR is retained in the cytoplasm through association with the cytoplasmic CAR retention protein (CCRP) and heat shock protein 90 (HSP90) [103]. PXR and CAR are highly expressed in the liver and act as master regulators of detoxification pathways [104]. Based on experimental evidence, EDCs such as nonylphenols (NPs), DEHP, MEHP, PCBs, BPA, PFCs PFOA, PFOS, and organochlorine methoxychlor are reported to activate PXR and CAR [105,106,107]. DEHP induces CAR-dependent activation of the nuclear receptor pathway, controlling the cellular clock and functions in energy metabolism [106]. EDC activated PXR and CAR also tends to regulate several CYP (cytochrome P450) family members involved in detoxifying pathways by metabolizing steroids and other endogenous hormones [103].

21.3.2.2 Aryl Hydrocarbon Receptor

AhR is a ligand-activated transcription factor which mainly senses and mediates the toxic effects of dioxins TCDD. The inactivated AhR protein resides in the cytosol and, upon ligand-mediated activation, translocates into the nucleus and heterodimerizes with the ubiquitously expressed aryl hydrocarbon receptor nuclear translocator (ARNT). Then AhR/ARNT complex binds to specific regulatory DNA sequences to regulate gene expression [108]. Recently, AhR has also been implicated as a regulator of energy metabolism, organogenesis, embryonic development, the cell cycle, immunosuppression, and carcinogenicity. Experimental studies report that certain EDCs such as PCBs and TCDD trigger inappropriate activation of AhR unrelated to detoxification. This affects the genes in an AhR-dependent manner linked to hepatic circadian rhythm, cholesterol biosynthesis, fatty acid synthesis, glucose metabolism, and adipocyte differentiation [109, 110]. AhR also disrupts ER signaling pathways by increasing ER proteasomal degradation and modulating estrogen levels via CYP expression and altering ER transcriptional activity [111, 112].

21.3.3 Peroxisome Proliferator-Activated Receptors

PPARs are sensor receptors with large ligand-binding domain that accommodates variety of ligands, primarily lipid derivatives. In presence of ligand, PPARs heterodimerize with RXR and bind to the PPAR response elements localized in the promoter regions of target genes [113]. PPAR is composed of three isotypes: PPARα, β/δ, and γ. PPARα is expressed predominantly in tissues characterized by a high rate of fatty acid catabolism such as the liver, kidney, heart, and muscle. PPARβ shares partially overlapping functions with PPARα and has a role in cell differentiation and survival [114, 115]. PPARγ functions in adipogenesis, lipid storage, inflammatory responses, and the control of insulin sensitivity [116]. Plasticizers, surfactants, pesticides, and dioxins modulate PPAR activity, although fairly little is known about the molecular mechanisms and the physiological outputs involved. In utero exposure induces alterations in fat structure and metabolism, with a disorganization of hepatic and gonadal architecture, steatosis in the liver, and an increase in lipid accumulation and mature adipocytes [117].

21.4 Endocrine System and Determination of EDC’s Dose Response

Available literature and reports suggest that endogenous hormones and EDCs act at extremely low serum concentrations, typically in the picomolar to nanomolar range. But question arises whether the risk assessment studies and animal model studies are certainly able to round off such low dose. Complementally, low-dose effect is defined as any biological change that occurs in the range of typical human exposures or the dose lower than those typically used in standard protocols and toxicology assessments [118]. As an account, endocrine system displays specificity in response to endogenous hormones via hormone receptors that may be found specifically in a single cell or few cell types or throughout the body; e.g., thyroid-stimulating hormone (TSH) receptors are found specifically in thyroid gland, while thyroid hormone (TH) receptors are found throughout the body [119]. The receptors found in multiple cell types may also vary in response or effects as different co-regulators influence the behavior of target genes [120, 121].

Concentrations of active endogenous hormones vary based on the age and physiological status of the individual; for instance, plasma testosterone levels are less than 1 ng mL−1 in male children but increase to approximately 5–7 ng mL−1 in adult; during menses, estradiol levels are typically less than 100 pg mL−1 but, prior ovulation, spikes to 800 pg mL−1 [122, 123]. In addition, it is noted that active concentrations of endogenous hormones vary from species to species and even vary between strains of the same species [124]. Apart from endogenous hormone mechanism, EDCs to which exposure is increasing in day-to-day life also mimic and exert several mechanisms in binding to hormone receptors (Fig. 21.4). Single EDC is able to regulate several pathways; in contrast the atmospheric exposure remains to be mixture of EDCs, and occupational exposure may be of higher dose, the effect of which may vary from low-dose response. Considering all of the above, though oblique statement prevails in determining the mechanism, concentration, and effects of EDCs, the postulated mechanisms, determined toxic levels, and health effects may not be unnoticed.

Fig. 21.4
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Mechanisms exerted by EDCs in disrupting normal metabolism of a cell

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