Research projects

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

Supervisors: Michelle Bellingham, Neil Evans

Project description: 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.

References

1. C.S. Elcombe, A. Monteiro, M. Ghasemzadeh-Hasankolaei, N.P. Evans, M. Bellingham (2021) Morphological and transcriptomic alterations in neonatal lamb testes following developmental exposure to low-level environmental chemical mixture. EnvironToxicol Pharmacol 86:103670. doi: 10.1016/j.etap.2021.103670.
2. M. Bellingham, P.A. Fowler, ES. Macdonald S.M. Rhind, C. Cotinot, B. Mandon-Pepin, R.M. Sharpe and N.P. Evans (2016). Timing of maternal exposure and fetal sex determine the effects of low-level chemical mixture exposure on the fetal neuroendocrine system in sheep. J. Neuroendocrinology. 28(12). doi: 10.1111/jne.12444.
3. Evans NP, Bellingham M, Sharpe RM, Cotinot C, Rhind SM, Kyle C, Erhard H, Hombach-Klonisch S, Lind PM, Fowler PA. 2014 Does grazing on biosolids treated pasture pose a pathophysiological risk associated with increased exposure to endocrine disrupting compounds? J Animal Sci. 92: 3185-3198.

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Overview

Individual research projects are tailored around the expertise of principal investigators within our Schools. A variety of approaches are used, including experiments in field and laboratory conditions, epidemiology, mathematical, computational and statistical modelling, bioinformatics, physiology, molecular biology, parasitology, immunology and polyomics (genomics, transcriptomics, proteomics, metabolomics). Basic and applied science projects are available for study, as are field-based projects with research programs underway in both the UK and overseas.

Specific areas of interest include:

• interplay between physiology, behaviour and life history
• wild immunology
• avian reproduction
• mammalian reproductive physiology and neuroendocrinology
• poultry science
• environmental factors, chemical exposure and reproductive function
• maternal smoking and development
• the effect of environmental stressors on ageing and longevity
• evaluating stress in companion animals
• organic production systems and animal welfare
• physiology, ecology and migration of birds
• annual and daily rhythms of wild organisms
• biological clocks and response to environmental change
• neuroendocrinology and steroid biochemistry
• livestock and wildlife management
• behavioural ecology, evolutionary ecology, life history strategies and environmental change
• thermal biology of temperature regulation and cold adaptation in marine mammals and birds.
• veterinary ethics and animal welfare assessment
• welfare and wildlife conservation
• ethics and welfare of wildlife interventions
• behavioural, physiological and ecological impacts on ageing
• maternal and transgenerational effects
• causes and consequences of variation in metabolic rate, mitochondrial functioning and oxidative stressGenetic and environmental interventions that extend healthspan and lifespan: dietary restriction, insulin/IGF1, mTOR
• resource allocation trade-offs
• mechanisms of ageing in animals: mitochondria, oxidative stress,proteostasis, telomere biology, stem cell function

Ageing affects almost all species, but the rate at which it occurs varies considerably among and within species. People are now living much longer than previous generations, with ageing being the major risk factor for many diseases. This has given rise to the concept of not only our ‘life span’ but also our ‘health span’ which is the length of a disease free life. We know that the environment we live in can influence how we age. It is now increasingly recognised that the ageing process and its' associated disease risk can be ‘set up’ or programmed by events experienced before we are born, ‘prenatal programming’, or during postnatal development i.e. pre and peripubertal as well as in adult life. Consequently, understanding why we age, how we age, the factors responsible for variation in ageing and longevity, and the impact ageing has on health and wellbeing is a major challenge in science today.

We are uniquely placed to employ a highly integrative, comparative and collaborative approach for the study of ageing, health and animal welfare. We study ageing at the molecular, cellular and organism level, in the field and in the laboratory, and combine mechanistic, functional and applied perspectives. We currently use a range of interventions and techniques to examine key issues in both laboratory and field settings. Using these approaches we are interested in a range of factors (e.g. stress, pollution, chronobiology, diet, growth pattern, metabolism, reproduction, epidemiology, immunity), how they are affected by ageing and their impact on human and animal health.

Given the rapidly expanding human population, a second major societal challenge is the requirement to produce sufficient safe, nutritious, affordable and sustainable foodstuffs. We are particularly interested in ways to sustain efficient animal production in a manner which protects animal health and welfare, while mitigating against pests and disease and reducing environmental impact. We have expertise in the development and application of behavioural, physiological and neurophysiological approaches to welfare assessment in managed and wild animals.

Health of managed and wild animals, as well as of humans, is also at risk from processes and products that arise during food production, for example endocrine disruptors and animal and human digestive end products. We investigate effects of such substances and of various other pollutants and stressors in projects at the intersection of animal biology and veterinary medicine.

To achieve these overall aims, this research theme actively collaborates with others in this university (e.g. biomedics, clinicians, veterinarians, Glasgow Polyomics facility) and elsewhere, including Government agencies (e.g. DEFRA), external institutes (e.g. The James Hutton Institute, Moredun Research Institute) and commercial partners.

Study options

PhD

• Duration: 3/4 years full-time; 5 years part-time

Individual research projects are tailored around the expertise of principal investigators.

MSc (Research)

• Duration: 1 year full-time; 2 years part-time