Chair in Translational Medical Sciences
Director of Institute of Medical Sciences
BSc (Hons 1st) Zoology, Aberdeen 1982. PhD, Aberdeen 1986, FRSB
I am a signatory of the The 2013 Berlaymont Declaration on Endocrine Disrupters.
HUMAN FETAL PUBLICATION In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver. Drake AJ, O'Shaughnessy PJ, Bhattacharya S, Monteiro A, Kerrigan D, Goetz S, Raab A, Rhind SM, Sinclair KD, Meharg AA, Feldmann J, Fowler PA. BMC Med. 2015 Jan 29;13(1):18. Accessed >12,000 times in first year after publication.
SEWAGE SLUDGE PUBLICATION The fetal ovary exhibits temporal sensitivity to a 'real-life' mixture of environmental chemicals. Lea RG, Amezaga MR, Loup B, Mandon-Pépin B, Stefansdottir A, Filis P, Kyle C, Zhang Z, Allen C, Purdie L, Jouneau L, Cotinot C, Rhind SM, Sinclair KD, Fowler PA. Sci Rep. 2016 Mar 2;6:22279. Accessed 73,517 times in first 13 days after publication.
Links to Scientific Societies:
Professor Fowler received his BSc Hons and PhD in Zoology at the University of Aberdeen. He later moved to Obstetrics & Gynaecology, University of Aberdeen, to work on ovarian hormones and antiprogesterones. In 2000 he moved to the Institute of Medical Sciences, University of Aberdeen as a Professor of Translational Medical Sciences and is currently lead for the Cell, Developmental & Cancer Biology Research programme at Aberdeen.
Professor Fowler has spent much of his career working on elucidating mechanisms in the regulation of reproduction and has over 100 peer-reviewed publications, book chapters and editorials. At each stage he has made contributions in the use of technologies to answer reproductive questions, including: remote telemetry of body-testis temperature differentials, MRI analysis of body composition and mammary gland, phage library and protein purification techniques to investigate reproductive proteins and proteomic and microarray techniques to study fetal development and endometriosis. Since the turn of the century, his research has focused on the effects of environmental exposures and endocrine disruption on fetal development and subsequent health in both human and animal models. His group is one of the few to work on the normal second trimester human fetus and uses maternal smoking as a model to understand how adverse in-utero environment disturbs fetal development in our own species.
Since the breakthrough epidemiological studies of the 1980s it has been clear that adult human health is dependent upon fetal development and fetal programming (‘early life programming’). Fetal growth restriction, for example, can lead to hypertension, type 2 diabetes, obesity and cardiovascular disease in the adult. Dysfunctional changes in the fetus can arise through other mechanisms, such as maternal cigarette smoking or environmental pollutant exposure and the health trajectory of an individual is likely to depend upon the pollutant burden carried at birth. Fetal pollutant exposure has clear adverse effects on development but we currently have very little knowledge about levels of fetal exposure to “real-life” complex pollutant cocktails and developmental consequences. This fundamental lack of knowledge is a major impasse to developing strategies for reducing fetal pollutant burdens and predicting likely health outcomes. Available data is limited, and often indirect (i.e. animal models or surrogates of exposure), but all studies suggest that fetal pollutant exposure affects lifelong health outcomes and, thereby, impacts on the general economy.
Better understanding of events during key stages in reproductive development in the human are key to determining the risks posed by exogenous chemicals, diet and lifestyle on reproductive health in humans, from breast cancer to infertility, testicular cancer to endometriosis, sperm counts to developmental defects. This kind of data is also key to translating the applicability and importance of findings in animal models to the human. Cigarette smoke contains well over 4,000 pollutant chemicals, including potentially toxic elements (PTEs, e.g. cadmium) persistent organic pollutants (POPs, e.g. dioxin) and, of course, nicotine. Many of these chemicals are endocrine-disrupting compounds (EDCs, e.g. nicotine reduces steroidogenesis). Thus, cigarette smoking provides a unique “real-life” model to study endocrine disruption in humans. Since up to 30% of women are smokers and few give up the habit, even when pregnant, it remains a major health challenge. Furthermore, fetal exposure to cigarette smoke chemicals constitutes one of the few models we can use to determine what effects environmental chemicals might have on our own species. This is one of the major models used in my research.
(i) Characterising normal events during human fetal development.
1st gene array study of the human fetal gonad : Gene expression analysis of human fetal ovarian primordial follicle formation. Fowler PA, Flannigan S, Mathers A, Gillanders K, Lea RG, Wood MJ, Maheshwari A, Bhattacharya S, Collie-Duguid ES, Baker PJ, Monteiro A, O'Shaughnessy PJ. J Clin Endocrinol Metab. 2009 Apr;94(4):1427-35.
(ii) Investigating how these events are affected by exposure to cigarette smoke chemicals.
1st fetal testis gene reduced by maternal cigarette smoking: Maternal smoking during pregnancy specifically reduces human fetal desert hedgehog gene expression during testis development. Fowler PA, Cassie S, Rhind SM, Brewer MJ, Collinson JM, Lea RG, Baker PJ, Bhattacharya S, O'Shaughnessy PJ. J Clin Endocrinol Metab. 2008 Feb;93(2):619-26.
Domestic animals, like humans and all other animals, are exposed to environmental pollutants through exposure to contaminated food, water, air and soil. Environmental pollutants include a range of (mainly) anthropogenic chemicals which have the capacity to interfere, subtly, with hormonal systems and therefore with their capacity to reproduce, rear offspring and fight disease); these chemicals, which included heavy metals and organic compounds of many different classes are described as endocrine disrupting compounds (EDCs). The physiological insult associated with exposure to EDCs involves many different chemical types, each acting on different physiological systems. Furthermore, while environmental concentrations of most individual chemicals are very low and below the No Observable Effect Level (NOEL), in many cases they can act additively to induce a physiological change, even when concentrations of individual chemicals appear harmless.
Empirical evidence in support of this has been provided by our previous work involving exposure of sheep to low (environmental) levels of EDCs through grazing pastures fertilised with sewage sludge (contains high concentrations of multiple EDCs). This work has shown that maternal exposure to sewage sludge treated pasture was associated with perturbation of the fetal hypothalamus-pituitary and ovary, despite the fact that fetal and adult tissue concentrations of individual EDCs at the time of slaughter were minimally increased by such exposure and were at concentrations below the NOEL. Work funded by the Wellcome Trust and the European Union is addressing the effects of exposure during specific windows of time, before and during gestation, on patterns of tissue accumulation and associated physiological changes.
MRC funded project (layperson summary):
It is well known that if a woman smokes while pregnant there are bad consequences for the resulting offspring, especially slowed growth in the womb. However, other serious problems are also likely to occur in children exposed to their mothers’ cigarette smoke chemicals during pregnancy. These include an impaired immune system (e.g. increased asthma), poorer educational performance and a raised chance of developing obesity, diabetes and heart disease (called metabolic syndrome). Many of these effects also happen if the mother regularly drinks alcohol while pregnant, even if not to the extent of addiction. We do not know exactly how much the chance of somebody developing metabolic syndrome is altered if their mother smoked and/or drank while pregnant. However, a recent study of 74,000 women found that if their mothers smoked while pregnant, the women had a 53% higher chance of becoming obese. This would be a major added drain on the NHS and would mean that many more people would be likely to suffer these debilitating conditions since smoking and/or alcohol use during pregnancy continues in 20-40% of women. In 2006-07 costs to the English NHS of lifestyle and related conditions were: smoking £3.3 billion, alcohol £3.3 billion, overweight/obesity £5.1 billion and diabetes £3.5 billion annually.
Adult health is partly programmed by events during fetal life when the individual is still in the womb and an individual may be badly adjusted for life if the mother uses recreational drugs. Growth restriction is important in this process and the liver is one of the organs most affected by disturbed growth before birth. The fetal liver is a key organ, protecting the fetus from harmful chemicals and controlling fetal growth. Progress in understanding the effects of maternal drug use on fetal development suffers from two problems: firstly, our ignorance of the levels of drugs to which the fetus is exposed and, secondly, the mechanisms by which these drugs affect development. Two factors contribute to our ignorance. Firstly, very little research uses normal human fetuses. Secondly, there is a lack of low-cost means with which to measure how much/which chemicals (nicotine, alcohol, cannabis etc.) are getting into the human fetus during pregnancy. This project aims to resolve these issues using our uniquely large collection of normal, second trimester human fetal livers and by collecting both the liver and the placenta from further terminations of normal pregnancies.
We will use highly sophisticated methods at the National Institute on Drug Abuse (USA) to measure chemicals from tobacco, cannabis, cocaine and alcohol in the fetal liver and in matched pairs of fetal livers and placentas. This will tell us how much the fetus has been exposed to drugs taken by the mother and whether the placenta can be used to measure the fetal burden of drugs and chemicals from the mother. This would allow us to carry out much larger studies of newborn babies to measure exposure levels in the placenta and their contribution to adult ill-health.
At the same time as measuring drug levels in the fetal liver we will work out how those drugs have affected liver function. Then, by using cell culture, it will be possible to re-create the effects of drug exposure in the culture dish with a view to understanding the long-term consequences. We will also be able to find out more about how liver function develops and how it differs between male and female babies Overall, our aim is to relate changes in the control of fetal liver development to the effects of chemicals in cigarette smoke. This will allow us to understand liver mal-development turns to metabolic syndrome. The information from this study will allow us to measure, and to understand, the effects of exposing the developing fetus to its mother’s recreational drug use. This will enable treatments to be designed to reverse these effects and to lower the incidence of the modern scourge of metabolic syndrome.
Recent plenary and invited presentations:
Real-world chemical mixtures disturb fetal endocrine systems and gonad development humans and animal models. Symposium: “Mixtures, medicines and diet, where now for endocrine disrupting compounds?” ECE2016: European Congress of Endocrinology, 28-31 May 2016, Munich, Germany.
Some press releases:
I am a co-author of the EFSA (European Food Safety Authority) Scientific Opinion on the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs as a member of the Toxicology Working Group. 3 documents available for download:
European Commission: Science in Society - How gender analysis contributes to research - REEF Project as a case study in Gendered Innovation.
I work to foster research at Aberdeen via my responsibility for the management, monitoring and generic training of laboratory postgraduate researchers in the School of Medicine under the aegis of the Graduate School, College of Medicine & Life Sciences.