Endocrine-disrupting chemicals (EDCs) represent not just a threat to public health or indeed to global health, but to planetary health. Pervasive in our environment – in foods, packaging materials, cosmetics, drinking water, and consumer products – EDCs have been linked to a myriad of non-communicable diseases such as obesity, type 2 diabetes, thyroid disorders, neurodevelopmental disease, hormone-dependent cancers, and reproductive disorders.’
These are the opening words of the executive summary of a series on EDCs in The Lancet: Diabetes & Endocrinology.1 How have we got into such a dire position? In retrospect, it is easy to see the answer.
‘There is a striking contrast between the long timescale over which biological signalling systems have evolved and their very recent exposure to man-made chemicals.’
Biological systems have evolved over at least the last 3 billion years. The survival of even the simplest life forms depended on their ability to regulate their internal environments and to respond to changes in the external world. As multicellular organisms evolved, the development of vascular systems allowed endocrine signals to co-ordinate functions within each organism. The Cambrian explosion of life forms (~540 million years ago) was accompanied by the rapid evolution of nuclear receptor signalling, controlling the critical processes of development, metabolism, homeostasis and reproduction. Many of the ligands for nuclear receptors were derived from natural metabolites (fatty acids, terpenoids, porphyrins and amino acids) and some became endocrine signals (e.g. steroid and thyroid hormones).
A CENTURY OF CHEMICAL DEVELOPMENT
There is a striking contrast between the long timescale over which biological signalling systems have evolved and their very recent exposure to man-made chemicals. Scientific advances and technical innovations in the last 100 years or so have allowed the development of thousands (~50,000++) of extraordinarily useful, but entirely novel, organic chemicals for industrial and agricultural uses.
These chemicals and their breakdown products are ultimately released into the environment. Some are very stable and environmentally persistent, while others are much more transient but produced in very large amounts. Some deliberately target biological systems (e.g. pharmaceuticals, pesticides, fungicides, herbicides, anti-microbials), while the structure and hydrophobic/amphiphilic properties of many others (e.g. plasticisers, pigments, flame retardants, surfactants, heat stabilisers, anti-oxidants, UV and light stabilisers, impact modifiers, foaming agents, fillers, lubricants, non-stick compounds etc.) enable them to interact with various degrees of affinity and specificity to a wide range of biological molecules, including a range of components of signalling systems (e.g. nuclear receptors, enzymes, binding proteins etc.).
Many of the compounds are very stable and lipophilic (properties upon which their usefulness is often based) and they bioaccumulate and biomagnify up food chains.
IMPACT ON BIOLOGICAL SYSTEMS
Within the body, the chemicals are like a sticky and occasionally toxic mist, at times obscuring and compromising the finely tuned operation of cellular systems. Endocrine and other signalling systems are particularly vulnerable. Their exquisite sensitivity, dynamic nature and inbuilt amplification cascades mean that even small initial perturbations by environmental chemicals can produce large effects.
Immediate responses may be inhibitory, stimulatory, antagonistic or additive, or any combination of these. The non-specific nature of the perturbations means that, whatever the response, it is likely to be detrimental or – at the very least – non-adaptive. Of particular concern is that exposures in early life can produce small perturbations of developmental pathways that result in large, irreversible effects in later life. Epigenetic changes can be responsible for effects in germ cells that pass through subsequent generations. Depending on the specific chemical(s) and the amounts, duration and timing of exposures, the overall impacts of environmental chemical exposures on individual fitness and survival may range from negligible to lethal, but are usually completely unknown.
INITIAL EVIDENT EFFECTS
The issue of environmental chemicals came to prominence due to a variety of obvious reproductive disturbances in species as diverse as oysters, fish and alligators. The release of ‘oestrogenic’ and other compounds from plastics highlighted potential routes of general exposure. Reproductive effects in humans (especially testicular dysgenesis syndrome: low sperm counts, hypospadias, cryptorchidism, testicular cancer) provided a useful focus for both scientists and the press.
‘Within the body, the chemicals are like a sticky and occasionally toxic mist, at times obscuring and compromising the finely tuned operation of cellular systems.’
As studies expanded, it became clear that the chemical disruption was much wider. In humans, a wide range of adult health issues (ranging, for example, from obesity and metabolic disorders through cancers, neurodevelopmental and reproductive disorders) have been linked with early life exposure to a range of exogenous chemicals (e.g. bisphenol A, phthalates, polybrominated fire retardants, perfluoroalkyl substances, organophosphate pesticides).
THE COMPLEXITY OF MIXED EXPOSURE
Experimental studies of individual chemicals have helped to identify the chemicals of particular concern to humans and to set some regulatory limits. But real-life exposures are to variable mixtures of chemicals simultaneously, in varying amounts and combinations, for variable durations and at different times in the life cycle.
The importance of assessing real-life risks is illustrated by the report by Caporale et al.,2 based on a prospective population-based study linking adverse health outcomes with prenatal EDC exposure. Human-relevant concentrations of a mixture of bisphenol A, phthalates and per- and polyfluoroalkyl substances were then shown to disrupt a variety of biological pathways in human fetal primary neural stem cells and cortical brain organoids in vitro, as well as in two model organisms (Xenopus and zebrafish) in vivo.
LOOKING TO THE FUTURE
The uses of synthetic organic chemicals have undergone exponential increases accompanying the growth of the human population and its economic and technological development. The immense practical benefit of many of the chemicals inevitably means their production and use will continue. But EDCs are an integral part of the increasing pressures on all life forms on this planet.3 Much greater thought needs to be given by industry, end-users and politicians to regulated disposal routes, to limit the entry of such chemicals into the general abiotic and biotic environments.
STUART MILLIGAN
Visiting Professor of Reproductive Biology, King’s College London
REFERENCES
1. Endocrine-disrupting chemicals series 2020 Lancet Diabetes & Endocrinology www.thelancet.com/series/endocrine-disrupting-chemicals.
2. Caporale N et al. 2022 Science 375 eabe8244.
3. Wagner DL et al. 2021 Proceedings of the National Academy of Sciences of the USA 118 e2023989118.
