Neuroendocrine disruption: Historical roots, current progress, questions for the future

Abstract

Endocrine-disrupting chemicals (EDCs) have captivated the attention of scientists, the public and the media [1; 2]. Since its inception, the endocrine disruption field has been controversial [3], and skeptics of the hypothesis have been just as vocal as the proponents. So why should neuroendocrinologists care about EDCs and why have a special issue on the subject? One fundamental reason is because the two fields are inextricably linked. As neuroendocrinologists, our history is already ingrained with the concept that there are critical periods of development, the disruption of which has permanent effects in adulthood. It has been known for decades that exogenous hormones, or interference with endogenous hormones, during these critical periods of organization and activation can have permanent effects on the physiological and behavioral pathways regulated by hypothalamic neuroendocrine circuits. Thus, neuroendocrinologists in some sense predicted that EDCs would disrupt homeostatic neuroendocrine processes, and that the critical developmental periods would be most sensitive, even before the term “endocrine disruptor” was coined. Another more immediate reason is that EDCs are inescapable. For example, EDCs are now recognized to be pervasive in the laboratory. They are present at high levels in soy-based animal feed and in soy supplements consumed by humans, they leach from plastics, lurk in tap water, and can interfere with hormone sensitive assays, such as MCF-7 breast cancer cells, potentially confounding experimental results. They are also common in house dust, fabrics, cookware, furniture, food containers, an assortment of other household products, and even in the air. We are exposed to a complex cocktail of these compounds every day, from conception to death. Just because EDCs pervade our bodies does not automatically mean that they cause harm, and determining which do and which do not, and by what measure, is where the bulk of the controversy now lies. At issue are both the degree to which low dose exposures to chemicals with low hormonal potency can appreciably affect vertebrate physiology, and the degree to which the potential long term risks of chemicals with sex-, life stage-, and tissue-specific impacts can be swiftly and sufficiently gauged. In humans, both issues are difficult to address experimentally because the timing, duration and level of human exposure are often uncertain, particularly during fetal life. Moreover, the latency between EDC exposure and the emergence of consequential health effects can be markedly long, often decades, and the degree to which some groups might be more sensitive than others, resulting in inter-individual variability, is poorly understood. Finally, predicting human responses from sentinel wildlife cases, or experimental animal and in vitro tests of endocrine action is not straightforward and frequently contested [3]. We believe that rapidly emerging data from numerous labs conducting basic animal research, studies of inadvertent human exposures, and epidemiological analyses overwhelmingly point to the inevitable conclusion that EDC exposures are pervasive, and cause both short- and long-term harm to humans and wildlife. But what is the extent of the problem and what should be done to correct it? Neuroendocrinologists are uniquely poised to tackle this question. In this special edition of Frontiers in Neuroendocrinology, eight articles are devoted to the effects of EDCs on reproductive health, neuroendocrine function, thyroid hormones, energy balance, cognition, and maternal behavior in rodents, non-human primates and humans. These articles underscore the message that neuroendocrine disruption, especially during critical periods of the life cycle, can result in a broad array of effects that may not manifest for years or decades. A few highlight recent evidence for transgenerational effects of EDCs [4; 5] and discuss previously unsuspected mechanisms, including molecular epigenetic changes, for the transmission of EDC effects to future generations even if the exposure to the EDC can be identified and removed [Figure 1]. This alarming possibility makes it all the more imperative for neuroendocrinologists to familiarize themselves with the EDC literature and weigh in on the issue. Figure 1 Schematic representation of exposure of neuroendocrine systems in humans to EDCs. Depicted here is how exposure of multiple generations can occur via maternal exposure. EDCs can directly modify the mother’s brain, hormones and the germ cells in ...