Transgenerational consequences of exposure to chemical mixtures on reproductive and metabolic health

Human healthcare faces a number of immediate, significant and interlinked challenges pertaining to dramatic declines in metabolic and reproductive health. Specifically, an increase in metabolic disease, including type 2 diabetes (T2D), Non-alcoholic fatty liver disease (NAFLD) and obesity, collectively referred to as metabolic syndrome (MetS), has occurred in parallel with a global decline in fertility and increased incidences of male and female reproductive dysfunction. Although the etiologies of these conditions are complex, there is increasing evidence that they are associated with exposure to environmental factors, most notably the complex mixture of chemicals that surround us as a result of anthropogenic activity. Many of these environmental chemicals (ECs) are non-biodegradable and exhibit both bioaccumulation and biomagnification, and it is widely accepted that such ECs pose a “significant global public health concern”. ECs can disrupt physiological processes through modification of endocrine signalling or direct actions on underlying biological processes. Developmental exposure to ECs has already been shown to be associated with reproductive disorders and more recently MetS and/or obesity. While exposure could therefore pose a direct threat, there is also growing evidence that the health issues that we face today could be due to epigenetic effects of mixed chemical exposure experienced by previous generations.

The effects of chronic exposure to a complex mixture of chemicals such as that which exists within our environment is poorly understood. Much of the existing research has focused on acute pharmacological exposure, to single chemicals, in altricial animal models, often only in a single sex. We have developed a unique, more appropriate model, with which to investigate the effects of in utero exposure to a real-life mixture of chemicals in longer lived outbred mammals, the biosolids exposed sheep model. Biosolids are derived from the solid waste generated in wastewater treatment plants therefore contains a chemical load that reflects the normal human exposome. Biosolids are routinely used as an agricultural fertilizer and when animals are grazed on biosolids treated pasture, they are exposed to our exposome. We have already shown that when pregnant sheep are grazed on biosolids treated pasture their offspring show alterations in thyroid, liver and gonadal function, bone development and behaviour. Using this model, this project will contribute to investigation of the longitudinal effects of exposure to a chemical mixture during in utero development, on the reproductive and metabolic health of F1, F2 and F3 offspring. The project will use a combination of in vivo animal based interventional and observational studies e.g. timing of puberty, glucose tolerance tests and ex vivo investigation of physiological function using immunohistochemical and molecular biological approaches. 

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