Keywords

Introduction

In our daily lives, chemicals are considered as an essential component. But there are some chemicals that exert harmful effects on the body’s endocrine (hormone) system and are known as endocrine disruptors. Only a small amount of hormones are required for their action and for the regulation of the body’s development, hormones need a specific time [1]. The US Environmental Protection Agency (EPA) provides a definition of endocrine-disrupting chemicals (EDCs). According to EPA, “EDCs are the exogenous substances that modify the functions of endocrine system and subsequently can cause harmful effects to a healthy organism, or its progeny, populations, or sub-population” [2]. EDCs are known to interfere with binding actions and elimination, metabolism, transport, synthesis, and secretion. They have the ability to imitate the presence of many blood-borne hormones. EDCs contain a variety of chemicals including environmental pollutants, pesticides, and most of the compounds which are used in the consumer products and in the plastic industry [3, 4]. They are common and found everywhere on Earth. Exposure to EDCs poses significant health issues to human populations as well as wildlife [3, 4]. Some EDCs are known to have long half-lives, cannot be easily metabolized, and because of their lipophilicity [for example, organochlorine pesticides, such as heavy metals dichlorodiphenyltrichloroethane (DDT), and dioxins] can be easily reserved in the adipose tissues for years [5]. However, there are many other EDCs that can be metabolized rapidly in the human body or in the environment. They are commonly found in our daily used products like bisphenol A (BPA) which can also exert harmful effects if exposure occurs during critical period of development [3]. The concept of EDCs was proposed for the first about 20 years ago when a large number of observations about their detrimental effects on the development of reproductive system and on the gender discrimination focused on the interference of EDCs with hormones related to sex steroid [6]. Many chemicals possess properties like endocrine-disrupting chemicals, including polybrominated flame retardants, bisphenol A, perfluorinated substances, some organochlorines, polycyclic aromatic hydrocarbons, pesticides, alkylphenols, phthalates, and some household products which contain hair dyes, cleaning products, air fresheners, cosmetics, and sunscreens. Some heavy metals even like arsenic were also shown to possess EDCs like properties. A large number of observations suggest that EDCs show a contribution to obesity, diabetes, cancer, infertility, and the metabolic syndrome [7]. In this chapter our main focus is on the metabolic disorders that are because of exposure to endocrine-disrupting chemicals. This chapter will also provide data on the alteration of gut microbiota as a result of exposure of EDCs and it will ultimately lead to metabolic disorders like obesity, diabetes, and non-alcoholic fatty liver disease.

EDCs-Induced Obesity

Obesity is accompanied by other metabolic disorders and severe health related problems which include type II diabetes, certain types of cancer, and hence, mortality [8]. Change in diet and lack of physical activity may trigger the increase in body weight although certain other factors may also have their role [9]. Furthermore, sedentary behavior in humans which involve prolonged sitting can change the endocrine and other mechanisms of chemical signaling which may promote constant weight gain in a person [10, 11]. Exposure to EDCs also has a significant contribution in the weight gain or obesity [9]. EDCs are the chemicals that produce alteration in the hormonal and other chemical signaling functions in the body [3]. Reproductive and carcinogenic effects of EDCs are mainly focused on too much exposure to endocrine-disrupting chemicals. More recent researches had emerged a hypothesis that these chemicals have their effect on weight homeostasis. However, from the investigations in the past, the adipose tissues were considered as inert storage depots, but in the 1990s, hormone leptin was discovered which suggested that adipose tissues itself are considered as active endocrine organ, releasing various adipokines and hormones and also responsible for the expression of many receptors [12, 13]. Moreover, numerous reports started to evolve that are describing excessive gain of body weight in those animals who are treated developmentally with certain EDCs which involve bisphenol A (BPA) and diethylstilbestrol (DES) [14, 15]. The exact mechanisms of EDCs-induced obesity are still under investigation because there are many potential targets of EDCs on weight homeostasis. Many of the chemicals have the ability to bind with peroxisome proliferator activated receptors (PPARs) which perform the critical roles in lipid metabolism and adipogenesis [16]. PPAR-gamma (PPARɣ), a subtype of PPARs, is a master regulator of the development of fat cells, with activation required for adipocyte maturation and differentiation [17]. The thiazolidinediones are well known as PPARɣ agonist medications that can improve insulin resistance, but they also induced obesity. Some organotin [16] and phthalates [18], which are the environmental contaminants, are PPARɣ agonists and have been associated with increased body weight in animal studies. Alteration in the adipose tissue’s development itself in terms of size, number, and distribution of adipocytes formed occurs upon the in utero exposure of EDCs and it may also affect the largest regulatory systems responsible for body weight homeostasis. In animal studies, upon exposure of oestrogenic chemicals such as bisphenol A (BPA) and diethylstilbestrol (DES) led to an increased body weight [15, 19]. Changes in expression of genes that have their role in the distribution of fat at 19 days of age occur after developmental DES exposure and it is confirmed through various animal studies [13].

EDCs-Induced Diabetes Mellitus

According to evolving evidence, it is proposed that EDCs play a vital role in the etiology of diabetes and metabolic disorders [3, 20]. From the industry side, the EDCs’ effects are divided into small-exposure groups; however, the chemicals which reflect a risk for a much larger group via the food chain are coming from agro and food products. Diabetogen is defined as any chemical or chemical compound that can change the endocrine system of pancreas and metabolism of glucose. According to several epidemiological and experimental studies, it is demonstrated that a positive association exists between EDCs and hyperglycemia, insulin resistance, and glucose intolerance [3, 21,22,23]. The suggested mechanisms of action consist of interactions of EDCs with the aryl hydrocarbon receptor (AhR) and nuclear hormone receptors which include dysregulated hepatic metabolism, estrogen receptors, induction of oxidative and nitrosative stress, alteration in the ERK/Akt signaling pathways, and pancreatitis [24]. While accumulating data show that these molecular modes of action reinforce the effects of endocrine-disrupting chemicals on the development of diabetes. However, their exact mechanism of action is still not clarified. In the metabolism of drugs and dietary products the role of the gut microbiota is now well established, and this aspect has been covered by many different reviews [25,26,27,28]. Antidiabetic drugs are also well known for the induction of remarkable changes in the gut microbiota, and this may also suggest their antihyperglycemic effects [29]. Microbial degradation of various chemicals which also include EDCs with the help of gut microbiota can be associated with microbial dysbiosis that is a shift in the structure of microbial community, altered microbial transformation of molecules, and the induction of certain specific bacterial genes [30, 31]. Moreover, EDCs can also be transported to the liver cells, whereby EDCs can be conjugated and released into the gut via bile secretion for further microbial degradation. β-lyases, nitroreductases, azoreductases, lipases, esterases, methylases, β-glucuronidases, and thiolases are all the enzymes which are responsible for the microbial metabolism of environmental chemicals [25,26,27,28, 30, 31].

Heavy Metals

Arsenic (As) is also known as one of the recognized causative factors for metabolic disorders. According to WHO, As is considered as leading massive poisoning worldwide [32]. Several families of Firmicute (a bacterial phylum) were significantly reduced upon the exposure of As, while no change was reported in Bacteroides levels [33]. In animal studies, As exposure induced a remarkable change in the gut microbiome and also induced alteration in the microbial metabolites. In addition to this, the composition of microbiome and metabolomic profiles in mice significantly changes when they are exposed to 10 mg/L of arsenic for 4 weeks [33]. Generally, the level of Bacteroidetes increases significantly but the level of Firmicutes decreases due to exposure of As. Lu et al. [33] had also found that these alterations were closely associated with the metabolites of bile acid, isoflavone, lipid, and indole-containing metabolites. Likewise, when chronic exposure to arsenic occurs in male mice hosts, it induced compositional and structural changes in the microbiome which is present in the colon and also promoted amino acid and nitrogen metabolism. A variety of metabolites including bile acid intermediates, isoflavones, indoles, fatty acids, glucuronides, and carnitines were significantly changed in As-exposed animal model (Table 9.1). These perturbations in metabolites reflected that capability of biotransformation in the gut microbiota also changes due to arsenic exposure [33]. The changed metabolic profile associates with altered structure of microbial community and associated metabolomics alterations are also known to affect lipogenesis, gluconeogenesis, inflammation, and adipogenesis in the male mice host [33].

Table 9.1 Effect of EDCs on gut microbial ecophysiology and their impact on host glucose metabolism
Full size table

Another heavy metal that was found to increase triacylglycerol level in liver, triglyceride level, and serum free fatty acids is cadmium (Cd). These changes occur upon the exposure to Cd is accompanied by a perturbation of gut microbiota (decreased Proteobacteria and Firmicutes) in animal studies. These microbial alterations led to increase the hepatic inflammation and also increase the level of LPS in serum that may further responsible for changes in energy homeostasis (Table 9.1) [34].

In male offspring, not in female offspring, lead (Pb) exposed during gestation and lactation through maternal drinking water gives rise to an increased adult bodyweight. An inverse shift in Bacteroidetes and Firmicutes ratio upon the exposure of Pb will occur and it is demonstrated through analysis that has been done on the gut microbiota of offspring without any sex bias. According to several studies it was found that the environmental chemicals have a role in shaping the adult gut microbiota when exposure to these chemicals occurs during pregnancy and also have their effect on the physiology of body (Table 9.1) [36].

Persistent Organic Pollutant (POPs)

POPs consist of dioxins, polychlorinated dibenzofurans, organochlorines, and polychlorinated biphenyls. There is a positive link between diabetes and POPs exposure which is supported by the meta-analysis of 72 various epidemiological studies [20, 39]. In animal studies, exposure of polychlorinated biphenyls (PCBs) induced significant alterations in gut microbiota with reduction in the abundance of Proteobacteria. It is very interesting to find that PCB-induced alterations in gut microbiota appeared to reverse by doing exercise training [40]. Exposure of 2,3,7,8-tetrachlorodibenzofuran (TCDF) can also induce the alterations in the gut microbiota and caused reduction in the ratio of Firmicutes and Bacteroidetes, but in Ahr−/−mice, no dysbiosis was found [41]. TCD increased the levels of Butyrivibrio species and Flavobacteria and also decreased the levels of Clostridia and Oscillobacter species. These changes in the gut microbiota were accompanied by an enhanced bile acid metabolites (Table 9.1). Flavobacteria species were reported to produce an enzyme known as halogenases that can cause degradation of TCDF and other important halogenated compounds [42].

Phthalates

Phthalates are actually the esters of phthalic acid which are commonly used as emulsifying agents, dispersants, plasticizers, lubricants, and stabilizers. In personal care products which include nail polishes, cosmetics, and perfumes these chemicals are considered as the important components. Dysregulation in the metabolism of glucose, adipogenesis, and insulin resistance has been reported upon the exposure of phthalates [20, 43]. Urinary levels of phthalates in the individuals who participate in the National Health and Nutrition Examination Survey (2001–2010) showed that phthalates exposure was accompanied by a higher prevalence of diabetes, predominantly among woman—the predominant consumers of personal care products [44]. In animal model, upon exposure of diethyl phthalate led to decrease in Firmicutes (Bacilli) and increase in the levels of Bacteroidetes (Prevotella). These induced perturbations in the bacterial community were associated with consistent loss of weight in animal model that is also suggesting the role of phthalates in glucose and lipid homeostasis [45].

Bisphenol A

Bisphenol A (BPA), a commonly used plasticizer, is mainly present in our daily used plastic products which include water bottles. Bisphenol A can also contribute to the etiology of diabetes mellitus as it causes alteration in pancreatic β-cell function and lipid metabolism [20, 46]. It is very interesting to find that in animal studies, a high-fat diet or high-sucrose diet and dietary intake of BPA both are responsible for similar changes in gut microbiota. BPA can also favor the growth of Helicobacteraceae and Proteobacteria, with a decrease in the levels of Clostridia and Firmicutes (Table 9.1) [38]. These microbiota perturbations parallel the microbial structure in patients who are suffering from diabetes [47, 48]. In the development of metabolic disorders as obesity or type 2 diabetes, the prenatal exposure to BPA is considered a potential contributor. Among different studies, diabetogenic effect of BPA is considered as consistent after prenatal or perinatal exposure. The first evidence came about the diabetogenic effect of BPA from a study published in 2010 [49]. In male offspring of 6 months of age, significant alterations in pancreatic β-cell function, marked glucose intolerance, and insulin resistance have been observed upon the treatment with BPA (10 or 100 mg/kg/day) from day 9 to 16 of gestation.

Organophosphates (OPs)

OPs are also well known as a group of non-persistent chemicals which are widely used as lubricants, insecticides, oil additives, plasticizers, herbicides, and chemical weapons. These organophosphates have replaced persistent organochlorine pesticides due to their biodegradable nature. A positive association exists between OPs exposure and diabetes prevalence confirmed through several human studies [50,51,52,53]. Intestinal inhabiting bacteria such as Enterococcus faecalis, Lactobacillus plantarum, Escherichia coli, Lactobacillus lactis, and Lactobacillus fermentum were also found to degrade chlorpyrifos, a widely used OP related insecticide [54].

Conclusion

According to the significant evidence, it is stated that endocrine disruptors have their role in various disorders related to metabolism. So, it is recommended that regulatory authorities also WHO should pay attention to the production of endocrine-disrupting chemicals and their release as a policy to control metabolic disorders. The assessment of new chemicals or chemical compounds for their effects on the gut microbiota should be observed and added to the traditional toxicity assessment tests as these chemicals cause modulation of gut microbiota and provide preventive measures that how to keep itself away from the reach of these harmful chemicals. There is a small number of data supporting the field based studies. Therefore, the association of gut microbiota with EDCs and metabolic disorders remains mostly unexplored. So, to elucidate the interplay between EDCs, gut microbiota, and metabolic disorders, further research will be necessary.