DEVELOPMENT OF BIOASSAYS FOR ENDOCRINE DISRUPTORS SCREENING AND STUDY THEIR MODE OF ACTION

Abstract

Endocrine system and nervous system are two major modes of communication that coordinate and control different body functions. While the dynamics of nervous system are maintained by conduction of electrical impulses through the complex circuits of nervous system, the messengers of the endocrine system are hormones that are synthesized and excreted at very low quantities from specialized glands and transported to the target organ(s) via the bloodstream. A tuned functioning of endocrine orchestra is necessary for sustained maintenance of different pivotal functions in human or animal body like reproduction and development, growth and maturation, energy production, electrolyte balance, etc. However, increasing scientific evidences depict the existence of a newly defined category of environmental contaminants which may have diverse chemical structures and can alter the normal functioning of the endocrine and reproductive systems (Cargouet et al., 2004). These chemicals mimic/inhibit the actions of endogenous hormones or modulate the synthesis of latter and have been named as "endocrine disrupting chemicals (EDC)" (Sonnennschein & Soto, 1998). In this way EDC may interfere with the usual hormonally regulated biological processes and thus, may adversely affect the development and reproductive function in wildlife, experimental animals, and humans (Satoh et al., 2001). In general EDC have been defined as- "An exogenous agent that interferes with the synthesis, storage/release, transport, metabolism, binding, action or elimination ofnatural blood-borne hormones responsiblefor the regulation ofhomeostasis and ofdevelopmental processes". Depending on the steroid with which the EDC interferes, steroid EDCs can be broadly categorized as (anti)androgenic, (anti)estrogenic and (anti)progestagenic chemicals. They may enter the body of animals/humans through the diet, contaminated water or occupational exposure, and then may lead to the generation of an agonistic or antagonistic effect (Kumar et al., 2008). Once inside the physiological system the EDC may exert their effect by targeting any of the following steps: (i) through arylhydrocarbon receptor (AhR) (Indarto & Izawa, 2001) (ii) direct binding of these chemicals to steroid receptors, steroidogenic enzymes and proteins associated with steroidogenesis (like StAR protein) (Walsh et al., 2000; Sanderson & Vanden Berg, 2003; Rice et al., 2006), and (iii) increasing the stability of transcripts and transcriptional rate of the promoter of steroidogenic enzymes (Lin et al., 2006; Lyssimachou et al., 2006). An increasing body of evidences reveals the association between various therapeutic/environmental compounds that act as EDC and many sex hormone-sensitive disease/disorders (Colborn & Clement, 1992; Satoh et al., 2001; Sone et al, 2005; Guillette, 2006; Massart et al., 2006; Chen et al., 2007). The possibility of various diseases like reduced fecundity, abnormal fetal development, delayed onset of puberty, cryptorchidism, abnormal lactation, testicular dysfunction and even various types of cancers due to the exposure to EDCs have been reported (Sharpe & Irvine, 2004; Roy et al., 2005; Buck et al., 2006; Darbre, 2006; Guillette, 2006; Maffini et al., 2006). In the past decade, the utilization of many chemicals (including pesticides and persistent organic pollutants) has been limited worldwide due to their hazardous potential. However, the chemicals having endocrine disruption (ED) potential are being used directly or indirectly for various purposes in the daily life leading to a chronic exposure to them. These chemicals range from the simple household utilities like detergents, cosmetics and toilet utilities to specialized applications viz. pharmaceuticals, insecticides and pesticides. Therefore there is a continuous discharge of these EDCs from various sources - household utilities, industrial and agricultural applications etc. into the environment without our knowledge of their toxicological potential. Once these chemicals reach the environment, they become the part of the food chain finally reaching the animal/human systems. Although the carcinogenic potential of these compounds are evaluated by routine mutagenicity testing or biophysical tests, the concentrations necessary to disrupt endocrine regulation may be much lower than that required to act as a carcinogen. Chronic exposure even in very low doses of these compounds may disturb the delicate hormone balance and compromise the reproductive health of many species (Ralph et al., 2003). EDCs have already been reported to be in the food chain and different strata of environment in various forms like persistent organic pollutants (POPs) such as the insecticide dichlorodiphenyl-trichloroethane (DDT) and its metabolites, the industrial by-product dioxins, the industrial compounds polychlorinated biphenyls (PCB), several agrochemicals, pesticides and biocides (e.g. chlorinated insecticides, organotins, imidazoles, triazoles, etc.) and other industrial compounds (several phenol compounds such as bisphenol A) (Mantovani et al., 1999). According to one of the environmental scientists (Trivedi, 2007) - "Today and every day, you can expect to be exposed to some 75,000 artificial chemicals. All day long you will be breathing them in, absorbing them through your skin and swallowing them in your food Throughout the night they will seep out of carpets, pillows and curtains, and drift into your lungs. Living in this chemical soup is an inescapable side effect of 21st-century living. The question is: is it doing us any harm?" Once used in various applications and activities, different types of chemicals and their byproducts are discharged finally to sewage water making it a complicated broth of chemicals having diverse structures and different effects on biological organization including endocrine system (Darbre, 2006; Heidler et al., 2006; Sarmah et al., 2006). Thus sewage water receives a number of chemicals which can be potent EDCs, however, the rigorous treatment process that is followed in the sewage treatment plant for the removal of harmful contaminants is found to be ineffective with regard to the EDCs (Kumar et al., 2008). Majority of the adverse physiological observations in the aquatic environment concerning the reproductive system, for instance, the feminization of male fish with sewage treatment plant effluents, are attributed to the presence of EDC in these discharged effluents (Sumpter &Jobling, 1995; Sumpter, 1998; Ternes et al., 1999). It has been hypothesized that the statistical decrease in sperm counts over the last decades, increasing incidents of testicular cancer and other disorders regarding male infertility might have been caused by the intake of these chemicals via food or drinking water