Search

Endocrine disrupting chemicals (EDCs) are exogenous compounds that can alter normal hormone production, signaling, and function(s), potentially leading to adverse effects on human health and the environment. Exposure during critical windows of development can lead to long-term health effects on an individual and subsequent generations. Therefore, this thesis aims to evaluate the impact of EDCs exposure at various levels of complexity such as effects on cellular health, receptor function, organ development and function, and human health effects. Various in vitro, in silico and quantitative methods have been utilized for the assessment of mixture effects of EDCs. It also highlights the use of quantitative structure-activity relationship (QSAR) models to predict chemicals based on their structural properties that can potentially disrupt the hormonal systems. Overall, this thesis shows that the EDC exposure at cellular level can affect subtle markers of cellular health such as mitochondrial membrane potential, indicating an altered mitochondrial metabolism. At receptor level, the mixture effects of the POPs on estrogen and progesterone receptors are observed. Exposure to POP mixture led to an increased agonistic/ synergistic response in the estrogen responsive MMV-Luc cells and significant antagonist response in progesterone responsive TM-Luc cells. At organ level, EDCs exposure is shown to affect the neuronal connectivity via NGF-induced neurite outgrowth. The early prioritisation of EDCs via the use of alternative in silico methods in combination with in vitro techniques is also assessed. A good correlation between in silico predictions and in vitro bioassays demonstrated the importance of using alternative methods for early prioritisation of EDCs. At human level, the early life exposure to EDCs via breast milk is shown to interact with the GLP-1R gut hormone receptor, leading to the impairment of normal GLP-1R function.

Endocrine disrupting chemicals (EDCs) are referring to several exogenous chemicals or mixtures of chemicals, which are capable of interfering with the normal function of the endocrine system and may cause detrimental health effects. Most importantly, during their lifespans, humans and other living organisms are continuously exposed to a wide range of EDCs. This exposure can increase the risk of male and/or female reproduction system disorders, developmental   abnormalities, metabolic diseases, as well as various cancers. Ultraviolet filters (UV), that are investigated in the current research are chemical or physical molecules found in sunscreen products that are used aiming to provide protection against the negative effects of the UV radiation from the sun. The reason that UV filters have now come under scrutiny is because they are suspected to perturbate the normal function of the endocrine system as such there are indications suggesting that they pose risks to both human health and environment. Humans are encouraged to utilize sunscreens, that contain several UV filters. These are applied on the skin, which enables the penetration of UV filters through the skin and following dermal absorption they can enter the systemic circulation and may contribute to possible adverse health effects, such as endocrine disruption, therefore highlighting the need for further investigations. Investigations carried out in the current research, include both single UV filter in vitro testing as well as testing of final commercial sunscreen products following dermal absorption. The findings of the current thesis may contribute and expand the identification of potential EDCs, such as UV filters, as well as contribute to the development of safer sunscreens, in the near future.

Endocrine disruptors (EDs) are ubiquitous compounds able to interfere with hormone action and impact human health. In this thesis, maternal smoking has been used as a real-life model of in utero exposure to a complex mixture (>5,000 pollutants) of exogenous chemicals. Cigarette smoke contains considerable levels of polycyclic aromatic hydrocarbons (PAHs), which are aryl hydrocarbon receptor (AhR) ligands, cross-talk with the estrogen receptor system and act as EDs. Exposure to cigarette smoke is associated with adverse outcomes, such as intrauterine growth restriction and metabolic syndrome. However, the molecular mechanisms are largely unknown. Using a multidisciplinary approach, I aimed to evaluate endocrine disrupting effects of smoke exposure in human fetuses (8-20 gestation weeks), combining transcriptomics and bioactivity investigations. I found that the fetal liver is a potential target for endocrine and metabolic disruption, as it expresses a wide variety of hormonal and other nuclear receptors. Smoke-exposure was associated with higher expression of AhR in fetal liver and increased AhR-like activity in placenta. Smoke-exposure was associated with increased estrogenic bioactivity levels in fetal plasma and dysregulation of androgen-like activity in plasma, liver and placenta. Furthermore, prenatal smoke exposure was associated with transcript changes of genes involved in hepatic lipid homeostasis. I also characterised expression of the insulin-like growth factor (IGF) system across several fetal organs and showed a critical pattern of changes that would predict a decreased bioavailability of IGF family members. This likely represents a molecular pathway behind smoke-induced intrauterine growth restriction. Preliminary investigation show that there are detectable levels of several classes of other EDs (bisphenols, parabens and phthalate metabolites) in the fetal liver and placenta. This thesis provides unique insights into the effects of cigarette smoke on hormonal signalling during development. These endocrine disrupting effects potentially re-programme fetal development, impacting not only neonatal outcomes but also life-long health.

Endocrine disrupting chemicals (EDCs) are exogenous chemicals found in food, consumer products, and the environment. EDCs are ubiquitous in modern life and human exposure is associated with many negative health effects such as reproductive disorders, metabolic disorders, and hormone related cancers. EDCs are a serious public health risk and numerous guidelines and risk messages have been disseminated to inform and protect the public. However, little is known about current levels of public awareness and risk perception of EDCs and how the public respond to EDC risk messages. Understanding how the public characterises and evaluates a risk has important implications in determining societal decision making and behaviour change. Therefore, effective risk communication of EDCs must take into account the public's perspective. This thesis explores the UK public's awareness and risk perception of EDCs to help policy makers design effective risk communication strategies and ultimately protect public health. Effective risk communication strategies will not only help raise awareness and reduce exposure to EDCs, but will also increase the demand for public protection and EDC policy reform.

Fungal contamination of agricultural commodities, particularly by mycotoxigenic fungi, represents a huge concern for global food security in terms of feeding the world's growing population with sufficient and safe food. Not only do they reduce crop yield and quality, but also produce vast number of mycotoxins, which pose serious adverse health effects in human and animals. The overall aim of this thesis was to determine exposure of farm animals to multiple mycotoxins and to assess wide range of products, for their potential to bind mycotoxins. A longitudinal feeding trial (between May 2017 and December 2019) was used to investigate the occurrence and performance-related effect of mycotoxins on broiler chickens. Feed samples given to birds were collected at the beginning of each trial and analysed for multi-mycotoxins using a validated LC-MS/MS method. Furthermore, parameters including feed intake, body weight and feed efficiency were recorded on a weekly basis. Results showed that deoxynivalenol (DON), zearalenone (ZEN), fumonisins (FBs), apicidin, enniatins, emodin, diacetoxyscirpenol (DAS) and beauvericin (BEV), were the most prevalent mycotoxins. Moreover, multiple linear regression analysis also revealed an interaction amongst mixtures of DON, ZEN, FBs, BEV, and DAS, which resulted in a significant impact on broiler chickens feed efficiency. The study clearly showed that prolonged exposure of farm animals to low doses of multiple mycotoxins, below European Union guidance limits can negatively influence performance. Furthermore, three novel natural products with potential to bind or inactivate aflatoxins, DON and ZEN have been identified and characterised. These products have the potential as future technological feed additives, to reduce farm animal exposure to mycotoxins.

Endocrine disrupting chemicals are compounds which can alter the function(s) of the endocrine system by disrupting natural signalling, production and secretion of hormones, contributing to a wide range of adverse health effects. Plastic packaging and films have been identified to leach chemicals/compounds into food and beverages which can negatively affect the consumer and/ or environment. Compounds which leach out of plastic materials often have hormonal activity, therefore highlighting the potential for endocrine disrupting leachates to be present. This thesis assessed novel naturally produced bio-based polymers that are currently being explored as a potentially safer alternative to current synthetic plastics using in vitro bioassays. The in vitro bioassays utilised in this thesis have shown to be valuable for assessing interferences with nuclear receptor signalling and cellular health. This thesis presents novel data and confirms and extends previous research that exposure to plastic leachates may affect the endocrine system via affecting the functioning of steroid hormones; disrupting nuclear receptor signalling. This thesis helps contribute towards the knowledge about potential safety concerns and hormonal activity of plastic leachates in the plastic packaging industry and could provide an innovative proof of concept approach in selectively guiding the development of safer plastic packaging. The knowledge gained from the studies in the thesis can only help to improve the risk assessment of numerous plastic leachates and the development of potentially safer plastic packaging, which humans and animals may be exposed to throughout the food chain and the environment.

Endocrine disrupting chemicals (EDCs) are exogenous compounds that interfere with natural signalling, production, secretion, and emission of hormones. EDCs cover a wide range of sources, exposure pathways, chemicals classes, and ultimately effects with unknown mechanisms. Persistent organic pollutants (POPs) are highly stable compounds resistant to environmental degradation. POPs can biomagnify with the food supply chain and bioaccumulate in the body. The detrimental health effects of EDC exposure has been observed in wildlife and lab animals. In epidemiological studies, exposure to EDCs has been linked to reproductive impairment, adverse birth outcomes, and cancer. In recent decades, the increasing rate of obesity and diabetes across the world have been linked to ubiquitous exposure to EDCs. EDCs with obesity inducing and energy metabolic disrupting properties have been defined as obesogens. Obesogens can alter energy homeostasis by disrupting the endocrine system. Moreover, obesogens can induce direct alterations in metabolic targets such as adipose tissue and the gastrointestinal (GI) system. Although regulation and legislation has helped to use synthetic compounds wisely, ubiquitous exposure to EDCs is difficult to be eliminated. The understanding of mechanisms of EDCs in obesity and diabetes pathogenesis is needed to be thoroughly studied. Methods to compensate for the detrimental effects after EDCs exposure also require further explorations.

Man-made chemicals are a part of everyday life and may mimic hormonal signalling in wildlife and humans. These exogenous mixtures or substances are called endocrine disrupting chemicals and may lead to adverse health effects in those exposed. Persistent organic pollutants (POPs) are a class of organic compounds that are structurally resistant to processes of degradation and thus are ubiquitous in the environment upon release. Due to their long elimination half-lives and affinity for lipid-rich tissue, POPs have a tendency to bioaccumulate, and subsequently have been detected in human tissues such as adipose, breast, placenta and blood. The overall aim of this thesis is to investigate novel human blood-based concentrations of POP mixtures and individual perfluoroalkyl acids (PFAAs) for disrupting androgen receptor (AR) signalling. The Total POP mixture using in this project consisted of a combination of 29 chemicals modelled on the exposure profile of a Scandinavian population and 6 sub-mixtures: brominated (Br) chlorinated (Cl), Cl + Br, PFAA, PFAA + Br, PFAA + Cl, ranging from 1/10x to 500x relative to what is found in human blood.

The presence of phytoestrogens (PEs) in soya based baby foods has attracted a lot of attention due to their ability to act as endocrine disruptive compounds (EDCs). Infants and young children have critical windows of sensitivity to EDCs during their development. Positive health effect of PEs are many such as being anti-cancer, antiobesity, promotes bone formation and wound healing. The negative health effects reported include increased incidences of hypospadias, cryptochidism, prepubertal gynecomastia and reduced fertility. Use of soya-based weaning gruels is widespread in Kenya. Estrogenic and androgenic reporter gene assays (using MMV-Luc and TARM-Luc cell lines respectively) were used to characterise the transcription activity of ten PEs (apigenin, daidzein, daidzin, genistein, genistin, enterodiol, equol, formononetin, glycitein and matairesinol) and in the Kenyan based gruel/flour extracts. A modified Hygiene Based Margin of Safety (HBMOS) method was used to estimate the estrogenicity due to daidzein and genistein in the flours. Standard curves of 17(3-estradiol and testosterone hormones and some PEs in the MMV-Luc and in TARM-Luc cell lines respectively were established. PEs and flour/gruel extracts enhanced testosterone hormone androgenic activity and gave more additive and synergistic bioactive effects in a dose and flour blend dependent manner respectively. The effect of heating and storage on the transcriptional capability of the PEs apigenin, genistein and formononetin and flour extracts was dose and flour type dependent and compound specific in MMV-Luc cell line. Quantification of the estrogenicity of the flour extracts (both uncooked and those cooked and/or stored) on MMV-Luc cell line revealed potent estrogenicity. The exposure level of genistein and daidzein in baby gruel flours was above the acceptable daily intake ADI for phytoestrogens which is I mg/Kgbw/day for each phytoestrogen. The total estrogenicity due to genistein and daidzein in the flour was below the tolerable daily intake (TDI) of 50 ng/kgbw and was of partial agonist proportions as determined by HBMOS. In conclusion our results indicate that the two cell lines can characterise the estrogenic and androgenic activity of PEs. The results on effect of heat and storage on the bioactivity of PEs underline the need to couple up the RGA method with physico-chemical methods which can elucidate on actual chemical changes in future studies. This is to enable ease of interpretation as the three chemicals varied in their bioactivity and no generalisation was possible. They also show that the PEs and the flour extracts can act as potential endocrine disrupters at the level of nuclear receptor which may have health implications, which could be positive or negative. Caution can be directed to especially mothers of boy infants due to ability of PEs and flour extracts to synergistically interact with testosterone and give significant androgenic activity.