Blog: thoughts on the Gordon Conference: Environmental Endocrine Disruptors
(Attendees from IfE: Frances Orton; Kugathas Subramaniam; Margaret Town; Susan Jobling)
In the spirit of the Gordon Research Conferences (GRC) the conference location was remote- a 3hr drive from Boston through beautiful Massachusetts and Vermont to a hotel that is normally a ski resort. Conference rooms and good facilities provided the background for a productive meeting.
For the first time, the GRC was preceded by the “Gordon Research Seminars (GRS)” (2-3 June 2012), which provided a forum for young and early career scientists to showcase their work and take an active part in discussions. As we all know, when you first start giving talks at conferences, it can be a nerve-wracking experience and the GRS gave us the opportunity to hone our skills in an informal atmosphere. It was also really good to be part of discussions instead of just listening and it gave many of us the confidence to take part in discussions in the following GRC – let’s hope they continue with this scheme!
As for the GRC (3-8 June 2012), the introductory session took off straight away on Sunday evening with keynote presentations from Paul Anastas (Yale University) who introduced the concept of designing ‘green’ chemicals and the current obstacles to this –with a need for a fuller understanding of the environment in which such chemicals would operate (physicochemical properties) and for clear strategies- before adequate design rules could be imposed on industry. Pete Myers (CEO, Environmental Health Sciences) drew attention to the 50th anniversary of Rachel Carson’s ‘Silent Spring’ and underlined the motivation for the conference.
The first session was given over to human health and environment and included were discussions centred around women’s health. While this is pertinent to the adult woman, all presentations on this topic focussed on the effect of endocrine disrupting chemicals (EDCs) on developing tissues, mainly breast and ovary, and thus established a theme that was followed throughout the week: that EDCs (such as Dioxin/TCDD/Atrazine) exert their greatest influence at ‘critical windows ‘ during development - when a changing endocrine receptor population and rapid cellular proliferation provide the targets.
Rodent studies showed that for the epithelial cell of the breast such effects could be seen at extremely low doses-below the levels currently detected in humans. The predictive power of such studies has now been underlined by human cohort studies which give a ‘life course perspective’ for large number of pregnant women and their children. These studies have frequently shown associations between parameters such as the concentration of PFAA/phenolics in serum and the incidence of cancer/reproductive abnormalities but now they are also demonstrating a relationship with the incidence of complex disorders (e.g. metabolic syndrome, premature hypertension), indicating a much broader spectrum of effect than previously thought. There is now a call for future studies to have a greater emphasis on mixtures of EDCs paying particular attention to those chemicals which may alter susceptibility to complex disorders.
The importance of the effect of pre-natal exposure was perhaps underlined by the session on men’s health. Here the emphasis shifted to the increasing and unexplained geographically defined incidence of male reproductive abnormalities and function. Again rodent modelling showing the clear association between phthalate EDCs and reduced sperm count, impaired leydig cell function and urogenital abnormalities, providing the hypothesis that EDCs are responsible for the otherwise unexplained decrease in human sperm quality among the last two/three generations, a phenomenon that has occurred specifically in areas that have undergone rapid technological development and urbanization. Each presentation underlined the emerging concept that low semen quality has the potential to be a biomarker not only for reproductive problems such as testicular cancer and infertility but also for life-expectancy.
The conference included a sessions on: Gene-Environment interactions, epigenetics and EEDs. The key word here, which underlies many mechanistic discussions not only at this conference but throughout recent literature, is epigenetics. Of all the topics considered this week this term is probably the most pertinent to the GRC’s ‘unifying goal’ for the conference: linking basic and clinical research to the real world environment.
Epigenetics refers (mainly) to changes in methylation status of certain sites in the DNA or histones (chromatin) which directly regulate gene expression. These changes can be plastic (transient) or permanent but if occur during a critical window of development can re-programme responses to endogenous and exogenous stimuli, resulting in temporally innappropriate signalling activation/silencing. Presenters discussed complex disorders, including tumour development in some reproductive tract cancers, which are known to have a genetic component but still demonstrate incomplete penetrance of the trait in families. In rat models of such disorders exposure to EDCs results in the phenotype becoming fully penetrant. The exposures are directly associated with changes in methylation patterns across hormone responsive genes and/or related histones, demonstrating that mutation and epigenetic regulation act in concert to increase susceptibility to disease.
Each of the speakers emphasized the need to expand these individual exposures to include dose response ranges and to link together more full-epigenome studies with epidemiological life-course phenotyping.
Discussions on neuroendocrine disruptors centred around disruption to energy balance (food intake vs activity) as mediated through the hypothalamus. The complexity of the neuroendocrine response was emphasized by species-specific reactions to different EDCs e.g. the organotins which cause imposex in marine invertebrates but alter adipocyte differentiation in mammals. A further layer of complexity is imposed when exposures occur during critical developmental stages and age/sex specific alterations in behaviour become apparent. This particular class of EDCs, directly attributable to human pharmaceutical and personal care product use, are disturbingly ubiquitous in outflow from WWTP’s and in surface waters with fluoxetine(Prozac) and other selective serotonin receptor inhibitors (SSRI’s) at the top of the list. Their effects are extensive and not restricted to changes in hormone levels. At the levels found in the environment these chemicals are non-toxic and their effect on wild fish populations cannot be extraplolated from toxicity data prepared in support of human consumption.
The final day of the meeting saw a continuation to consideration of the potential for wide ranging impacts of EDCs on wildlife and the species span included plants, alligators and fish.
Plants were presented as potential sources of environmental signals -informing the metabolic and/or reproductive responses of higher grazing animals by changes to the composition of their flavenoid content. Alligators were presented as a model for all amniotes with marked influences of EDCs on steroid synthesis/conversion in the chorioallantoic membrane and yolk. The incidence of intersex/feminisation of fish has been known for some time but starting from there the driving effect on adaptive processes was discussed. It was apparent that over several generations fish become less sensitive and adapt to the presence of e.g. heavy metals, PAHs, PCBs. However, the cost in terms of effect on reproductive fitness, genetic pools, epigenetic mechanisms etc is only now being tested. Lab-based studies show that while the effect of EDCs in reducing male reproductive capability and/or causing sex reversal may have a limited effect on fish populations in combination with their potential to affect other health aspects there is a much wider health impact.
Trans-generational effects of EDCs were discussed with the question of whether ancestral exposure leads to changed susceptibility to disease. Fish models elegantly showed that sexual behavioural responses are changed in a manner which is definitely context-dependent: with differences between fish exposed to EDCs directly and those with only ancestral exposure. Presenters agreed that, in pursuit of such studies, molecular analysis is becoming increasingly important particularly with respect to determining interspecies differences in response to environmental change.
In summary all presenters, questioners and participants agreed that the way towards ‘linking basic and clinical research to the real world environment’ should include future studies which have a greater emphasis the following:
· mixtures of EDCs paying particular attention to those chemicals which may alter susceptibility to complex disorders.
· developing biomarkers for reproductive problems, cancer and life-expectancy
· expansion of exposures to include wide dose response ranges –specifically low (sub-toxic) concentrations
· linkage of full epigenome studies with epidemiological life-course phenotyping
· consideration of effects of EDCs on reproductive health within context of wider health issues
· integration of molecular analysis in determining mechanisms and applications to inter-specific differences
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