Synthetic musks are incorporated extensively in personal care products to improve their scent, increase their fragrance stability, and prolong their shelf-life. As a consequence, these persistent musks are being released at a considerable rate by wastewater treatment plants and are frequently detected in surface water, bottom sediment, air, and aquatic biota near urban areas. In addition to their hydrophobicity, two synthetic musks, Galaxolide (HHCB) and Tonalide (AHTN), were reported to cause endocrine disruption in fish species. Although most of the toxic effects in past studies were observed at high doses, HHCB and AHTN were shown to bioaccumulate very differently depending on the aquatic species tested. As bioaccumulation and fate of contaminants are important considerations when regulating persistent chemicals, an improved understanding of the bioaccumulation potential of these chemicals is needed. In this thesis, an assessment of the presence, bioconcentration and fate of HHCB and AHTH was provided in an area exposed to the effluent of the Gold Bar wastewater treatment plant in the North Saskatchewan River (Edmonton). HHCB and AHTN were quantified in fathead minnows (Pimephales promelas) exposed downstream of the effluent, with an adapted method for analysis of musks in fish, using PAHs as recovery standards. Method development and recoveries are summarized. Highest bioconcentration factors were 24,500 and 22,300 for HHCB and AHTN respectively, and were observed 1 km downstream of the outfall. Musks were found in most fathead minnows exposed at reference sites upstream as well as at the furthest site, 9.9 km from the outfall. Musk concentrations in water at these sites were used in the assessment of the fate of HHCB and AHTN by fugacity modeling with QWASI software. In order to assess fate, a contaminated portion of the North Saskatchewan River was divided in a series of compartments that were each treated as connected individual water bodies. HHCB and AHTN losses were mostly due to water advection and sedimentation fluxes. Model fit was assessed by comparing predicted to measured data.

Blood-brain barrier (BBB) is a unique membranous barrier, which segregates brain from the circulating blood. It works as a physical and metabolic barrier between the central nervous system (CNS) and periphery. In mammals, endothelial cells were shown to be of BBB and are characterized by the tight junctions along with efflux system which are responsible for the restriction of movement of molecules within the cells. Efflux system consists of multidrug resistance proteins such as P-glycoprotein (P-gp). P-gp removes substances out back from the brain to the blood before they reach to the brain. So the barrier is impermeable to many compounds such as amino acids, ions, small peptides and proteins, making it the most challenging factor for the development of new drugs for targeting CNS. Curcumin is a bioactive compound that has a number of health promoting benefits such as anti-inflammatory, anticancer, anti-oxidant agent; as well as a role in neurodegenerative diseases, but low oral bioavailability is the major limiting factor. Low water solubility and rapid metabolism are the two important factors responsible for poor bioavailability of curcumin. Galaxolide is a musk compound and previously known for the bioaccumulation of toxic components in the aquatic animals by interference with the activity of multidrug/multixenobiotic resistance efflux transporters (MDR/MXR). The bioavailability of curcumin can be enhanced when administered with galaxolide. This study was carried out to investigate the effect of galaxolide on the permeation of curcumin through the epithelial cell monolayers. MDCKII-MDR1 cell monolayer is used an in vitro blood-brain barrier model while Caco-2 monolayer is used as an in vitro intestinal model, which also expresses the P-glycoprotein. The curcumin and galaxolide were separately solubilised in the DMSO and used in combination to perform permeation study, to determine the effect of galaxolide on curcumin permeation through epithelial cell monolayers. The galaxolide shows an efflux protein inhibition activity and this activity was used to enhance permeation of curcumin through the Caco-2 monolayer. In summary, galaxolide is a novel permeation enhancer molecule, which can be used for the improvement of drug delivery of other bioactive compounds in future.

Blood-brain barrier (BBB) is a unique membranous barrier, which segregates brain from the circulating blood. It works as a physical and metabolic barrier between the central nervous system (CNS) and periphery. In mammals, endothelial cells were shown to be of BBB and are characterized by the tight junctions along with efflux system which are responsible for the restriction of movement of molecules within the cells. Efflux system consists of multidrug resistance proteins such as P-glycoprotein (P-gp). P-gp removes substances out back from the brain to the blood before they reach to the brain. So the barrier is impermeable to many compounds such as amino acids, ions, small peptides and proteins, making it the most challenging factor for the development of new drugs for targeting CNS. Curcumin is a bioactive compound that has a number of health promoting benefits such as anti-inflammatory, anticancer, anti-oxidant agent; as well as a role in neurodegenerative diseases, but low oral bioavailability is the major limiting factor. Low water solubility and rapid metabolism are the two important factors responsible for poor bioavailability of curcumin. Galaxolide is a musk compound and previously known for the bioaccumulation of toxic components in the aquatic animals by interference with the activity of multidrug/multixenobiotic resistance efflux transporters (MDR/MXR). The bioavailability of curcumin can be enhanced when administered with galaxolide. This study was carried out to investigate the effect of galaxolide on the permeation of curcumin through the epithelial cell monolayers. MDCKII-MDR1 cell monolayer is used an in vitro blood-brain barrier model while Caco-2 monolayer is used as an in vitro intestinal model, which also expresses the P-glycoprotein. The curcumin and galaxolide were separately solubilised in the DMSO and used in combination to perform permeation study, to determine the effect of galaxolide on curcumin permeation through epithelial cell monolayers. The galaxolide shows an efflux protein inhibition activity and this activity was used to enhance permeation of curcumin through the Caco-2 monolayer. In summary, galaxolide is a novel permeation enhancer molecule, which can be used for the improvement of drug delivery of other bioactive compounds in future. / Department of Social Welfare, Govt. of Maharashtra (India)