ENDOCRINE MODULATING ACTIVITIES OF SOME ENVIRONMENTAL AND INDUSTRIAL CHEMICALS

Abstract

Diverse categories of synthetic chemicals are being introduced day by day into the environment. Term endocrine modulating chemical is appropriate for those chemicals which have the potential to interact and impair the endocrine system of mammals. The aim of the present thesis entitled “Endocrine Modulating Activities of Some Environmental and Industrial Chemicals” was to study such chemicals and understand the various cellular mechanisms through which these chemicals may pose reproductive and developmental anomalies in mammals. Start from beginning, Chapter 1 introduces briefly the main purpose behind this study. Some important categories of endocrine disrupting chemicals are introduced in this section followed by their modes of endocrine disruption. Further, the anomalies associated with the exposure of such chemicals to both male and female reproductive system are discussed briefly. Besides the reproductive hazards, effects of these chemicals on bone development are also taken into consideration. Finally detailed objectives to be fulfilled in the present study are specified in this section. Down the lane, Chapter 2 represents (1) the detailed review on endocrine system of mammals with special emphasis on steroid biosynthesis and pathways associated with secretion, storage and release of steroidal hormones; (2) various pathways of endocrine disruption like genomic, non-genomic and epigenetic are discussed in detail and cited with appropriate references from existed literature; (3) flamboyant description of screening methods for the detection of harmonically active chemicals with suitable diagrams are discussed; (4) various pathways associated with bone development and importance of some prime transcription factors in osteoblast differentiation are taken into consideration; (5) diseased bone phenotypes in response to hormonal imbalance due to chemicals exposure and their role in osteoblast differentiation are also discussed. The main objective of present thesis was to understand the effects of endocrine disrupting chemicals on reproductive and bone developmental system. Hence, various methods like reporter based transactivation assays, cell proliferation assays, cell toxicity __________________________________________________________________________ Abstract ii assays, mineralization assays and analysis of genes and proteins expression are described in subsequent Chapter 3 in detail. Further, various cell lines, in vivo study models and molecular biology techniques utilized for understanding the molecular mechanisms actuated by test chemicals are also discussed in same section. Exposure to plastic derived compounds and phthalates through air, water and food is matter of grave concern these days. Among various phthalates; diethyl phthalate (DEP) is suspected to be exposed to human via multiple modes due to its use in endless applications specifically in cosmetic industries. Hence, female population is more prone to the harmful effects of DEP. To understand up to which extent DEP may pose female reproductive threat, detailed parameters using both in vitro and in vivo models were used as described in Chapter 4 of the thesis. Results showed that DEP activated estrogen receptor (ERα) in vitro and estrogenic effects were clearly visible in immature rat uterotrophic assay suggesting that long term use of DEP may modulate female reproductive system by causing estrogenic effects. In spite of widespread exposure of low molecular weight phthalates, very few studies have been carried out to understand the potential health risk of these chemicals. In male reproductive system, hormonal imbalance and altered steroid related genes expression in response to phthalates exposure is studied. We emphasized the effects of such chemicals on Sertoli cell structure and functionality. In Chapter 5 we tried to explore the various mechanisms by which low molecular weight phthalates may pose serious threat to Sertoli cell functionality. Concept of blood testes barrier and various molecules associated with its proper functioning are discussed along with devastating effects of test compounds. To mimic the natural way of exposure, rodent model were gavaged with mixture of phthalates at very low doses and we found that in mixture from effects were more severe. Further we were enthusiastic to see the role of estrogens on Sertoli cells proliferation. Literature review suggested that most of the environmental pollutants are either anti-androgenic or weakly estrogenic in nature. Hence, before understanding their effects on Sertoli cells, it is advisable to understand the effects of natural estrogens. Chapter 6 dealt with understanding the genetic and epigenetic pathways responsible for proliferation of immature Sertoli cells in response to estrogens. Our results depicted that estradiol enhanced immature Sertoli cells proliferation and also regulated the Sertoli cells gene expression in unique and interesting ways. __________________________________________________________________________ Abstract iii Compelling evidence regarding the presence of steroid receptors on bone forming cells suggest that these chemicals may exert their harmful effects through these receptors. Bone formation during pre-natal or post natal stages can be directly related to the level of hormones during the course of development. Since endocrine modulating chemicals are reported to alter the hormonal balance inside the female body, so their adverse effects on bone and skeletal development can be imagined clearly. Chapter 7 and Chapter 8 of the thesis are devoted to study the very basic mechanisms by which weakly estrogenic compound e. g. triclosan and anti-androgenic low molecular weight phthalates may modulate the osteoblast differentiation at very low doses. Our data showed that these chemicals do not behave like that of natural estrogens or androgens on bone differentiation. They targeted unique cellular pathways to exert their anti/osteogenic effects. Finally, Chapter 9 summarizes the complete work done in brief along with the need to understand the multicellular target of endocrine disrupting chemicals. Various unknown threats due to release of such chemicals into the environment suggest the need to understand potential health risks. At last, list of bibliographies which were cited in the course of this study is enlisted