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dc.contributor.authorUllah, Asad-
dc.date.accessioned2020-05-08T07:43:04Z-
dc.date.available2020-05-08T07:43:04Z-
dc.date.issued2019-
dc.identifier.govdoc18569-
dc.identifier.urihttp://prr.hec.gov.pk/jspui/handle/123456789/12595-
dc.description.abstractBackground: Environmental health has emerged recently from observing the low outcomes of reproductive success of wildlife, birds and fish population in relation of their exposure to industrial chemicals. The intensive use of pesticides in agriculture and exposure of toxic chemicals which directly or indirectly lead to alterations in the reproductive functions of both human and wildlife to the concept of endocrine disrupting chemicals (EDCs). In the modern day EDCs list bisphenol A (BPA) has taken a prominent place. BPA is mainly used these days in the manufacturing of plastic bottles, plastic utensils, food containers, baby toys, feeding bottles and medical equipment. Studies have also shown that apart of wide range of useful applications BPA has hazardous mode of action on many systems of the body. Due to its wide range of toxic actions BPA has been banned in many countries including the European Union (EU) in several daily use items. This ban has led to the introduction of many BPA analogues which are considered to be safer than BPA and are these days used in the production of many daily use items. Bisphenol B (BPB), bisphenol F (BPF) and bisphenol S (BPS) are among the top of the safe BPA list. These all analogues consist of two phenol groups attached with a carbon of any other chemical bridge. Since these structurally similar compounds to BPA are expected to have similar or even stronger toxicological effects on humans and wildlife. Due to the ban of BPA in some other countries the production of these BPA analogues is at rise and is expected that this production is going to increase by double in the future. On the other hand, BPA analogues have already registered their presence in many environmental compartments as well as food, beverages and drinking water which has not only increased the risk of exposure to occupational and also general population. In the recent years studies have also shown that some of these analogues have shown estrogenic activity, potentials of inducing oxidative stress and as well as anti-androgenic effects in many experimental animal studies. Although the toxicity of BPA has been studied in great detail regarding reproductive functions in both mammalian and nonmammalian species though data regarding BPA analogues is scare. This brings the need for making a comprehensive data bank on the so called safe analogues of BPA. The main purpose of the present set of studies is to assess both in-vitro and in-vivo effects of these analogues on the sperm and testicular tissues of male rats. In this regard another set of sub-chronic study was done to compare the reproductive toxicity in male rats after exposure to the BPA analogues. In the last but not the least another set of experiments was carried out to understand the potential effects of BPA and its analogues BPB, BPF and BPS on the development of male reproductive system in both prenatal and neonatal male rats. Materials and methods: BPA and its analogues BPB, BPF and BPS stock solutions were prepared in ethanol and were later diluted in distilled water and the final concentration in every stock solution was less than 0.5% ethanol. In our first experiment we incubated male adult rats’ testicular tissues and sperms in different concentrations (0, 1, 10 and 100 µg/L) of BPA, BPB, BPF and BPS for two hours. The temperature was maintained as 37 0C, CO2 was 5 % and air was 95 %. Oxidative stress in the reproductive tissues was determined through antioxidant enzymes and hormonal concentration was determined through Enzyme Linked Immuno Sorbant assay (ELISA). In the second sub-chronic experiment adult male rats were treated with different concentrations of BPA and its analogues BPB, BPF and BPS for 28 days. The third experiment was chronic experiment where adult male rats were again exposed to different concentrations of BPA and its analogues BPB, BPF and BPS through drinking water for a period of 48 weeks. After the completion of sub-chronic and chronic experiment animals were euthanized and different biochemical, hormonal and histological tests were carried out. In the next set of experiments, effects of BPA and its analogues BPB, BPF and BPS on the development of male gonads was assessed by exposing the animals to different concentrations of BPA and its analogues BPB, BPF and BPS during pre-natal and neonatal period of development. In the fourth experiment female pregnant rats were exposed to different concentrations of BPA and its analogues BPB, BPF and BPS from pregnancy day 1 (PD1) to PD 10. The born pups were checked for any alterations in the early sexual development and any reproductive complacency during the adulthood. In the last and fifth experiment male newborn pups were exposed to different concentrations of BPA and its analogues BPB, BPF and BPS from Post natal day 1(PND 1) to PND 10 and early sexual development or any alteration in the reproductive functions were checked throughout the experimental period. Biochemical, hormonal and histological tests were carried out of different reproductive organs. Results: The results of the in-vitro study showed that BPA and its analogues BPB, BPF and BPS led to oxidative stress in the testicular tissues and sperms and antioxidant enzyme activity was also increased after the treatment with BPA and its analogues BPB, BPF and BPS. The higher treatment groups caused lipid peroxidation, increased DNA fragmentation and affected superoxide dismutase levels in the spermatozoa of male rats. BPA and its analogues BPB, BPF and BPS higher dose groups also reduced the testosterone concentration in the rat testis. Subchronic and chronic in vivo studies on the other hand showed reduced plasma and intra-testicular testosterone, plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations in the groups with higher treatment of BPA and its analogues BPB, BPF and BPS. Antioxidant enzymes activity significantly reduced after exposure to BPA and its analogues BPB, BPF and BPS when compared to the control. Histopathological results revealed alterations in the normal morphology of testicular tissues as compared to control. Histological observations showed significant reduction in the epithelial height of the testis along with disrupted spermatogenesis. Other prominent observations were empty lumen of the seminiferous tubules and caput region of the epididymis. Daily sperm production (DSP), sperm motility and oxidative stress markers in the testis in the chronic and sub-chronic groups after treatment with different concentrations of BPA and its analogues BPB, BPF and BPS showed disturbed hormonal concentrations and antioxidant enzymes. The results of the pre-natal and post-natal exposure of different concentrations of BPA and its analogues BPB, BPF and BPS showed no prominent sign of early puberty and development of sexual organs. On the other hand, significant decrease was observed in the gonadosomatic index (GSI) and organs weight when higher doses treatment groups of BPA and its analogues BPB, BPF and BPS were compared to the control. Significant reduction was observed in the hormonal concentrations of testosterone, LH and FSH when compared to the control. Significant reduction was observed in the DSP and sperm number in the caput and cauda region in the highest treatment groups of BPA and its analogues BPB, BPF and BPS as compared to control. Histopathological analysis showed that BPA and its analogues BPB, BPF and BPS treatment reduced epithelial height and sperm arrest as compared to the control group; there were also alterations observed in the morphology of different cells in the reproductive organs of male rats after exposure to BPA and its analogues. Conclusions: BPA and its analogues BPB, BPF and BPS induced oxidative stress in the reproductive organs and also showed endocrine disrupting potentials and toxicological results in the in-vivo and in-vitro studies. The results of the present study also showed that exposure to BPA and its analogues BPB, BPF and BPS in the pre-natal and post-natal life not only lead to toxicity in the development of reproductive organs but also lead to changes in the reproductive organs which cannot be reversed in the adult life. BPA and its analogues BPB, BPF and BPS also resulted in adverse structural and functional changes in the reproductive system by inhibiting the cell defense system. These effects also lead to suppression of gonadotropins, antiandrogenic and estrogenic mode of actions which can cause deleterious alterations in the reproductive tissues which can harm the normal fertility of individuals. After the present study results the question arise that whether this shift towards the analogues of BPA is safe or more life threatening than BPA exposure? The present data results are raising concerns that there shall be comprehensive data bank on the comparative analysis of BPA and its analogues made on both mammals and non-mammalian species.en_US
dc.description.sponsorshipHigher Education Commission Pakistanen_US
dc.language.isoen_USen_US
dc.publisherQuaid-i-Azam University, Islamabad.en_US
dc.subjectReproductive Physiologyen_US
dc.subjectPhysiology Reproductiveen_US
dc.subjectPhysiologyen_US
dc.titleAre Structural Analogues to Bisphenol A Safe Alternatives? Comparative In-Vitro and In-Vivo Approaches to Study Reproductive Toxicity in Male Ratsen_US
dc.typeThesisen_US
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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