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Animal models of endocrine disruption

https://doi.org/10.1016/j.beem.2018.03.011Get rights and content

Endocrine disrupting chemicals (EDCs) are compounds that alter the structure and function of the endocrine system and may be contributing to disorders of the reproductive, metabolic, neuroendocrine and other complex systems. Typically, these outcomes cannot be modeled in cell-based or other simple systems necessitating the use of animal testing. Appropriate animal model selection is required to effectively recapitulate the human experience, including relevant dosing and windows of exposure, and ensure translational utility and reproducibility. While classical toxicology heavily relies on inbred rats and mice, and focuses on apical endpoints such as tumor formation or birth defects, EDC researchers have used a greater diversity of species to effectively model more subtle but significant outcomes such as changes in pubertal timing, mammary gland development, and social behaviors. Advances in genomics, neuroimaging and other tools are making a wider range of animal models more widely available to EDC researchers.

Introduction

An endocrine disrupting chemical is an “exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action” [1], [2]. Although classical toxicology heavily relies on rodent models, especially rats, the EDC field owes much of its origins to studies in wild animal species. Its core principles and concepts were derived from studies conducted in a wide range of taxa both terrestrial and aquatic, and species diversity remains a core element of ongoing EDC research [3]. Despite comprehensive experimental and epidemiological data for some of the most notorious chemicals, regulatory action on their manufacture and use has been glacially slow to nonresponsive, leading to frustration among families, communities, activists, and scientists. Difficulty translating effects in animals to humans has been cited as a core obstacle, thus experimental animal model selection is critically important. There is growing consensus that classical, apical endpoint-based toxicity testing is not being conducted at human-relevant doses, during the appropriate life stages, or in appropriately susceptible test models to identify or predict endocrine-related disorders such as endometriosis or premature puberty, or to fully assess complex neurodevelopmental disorders that do not have clear pathology, such as schizophrenia and autism. Thus, although there is growing pressure to move away from animal-based toxicity testing, whole organism-based studies remain a critical tool for EDC research because they allow for the interrogation of chemical influences at the phenotypic, physiological, behavioral, and molecular levels and are particularly useful to assess outcomes that are difficult to model in simpler in vitro or organotypic systems.

EDCs have since garnered considerable attention and rapidly compounding evidence reveals that exposure, particularly during critical windows of organ development, is likely contributing to rising rates of multiple disorders and chronic diseases in humans including premature female puberty, compromised fertility, obesity, cardiovascular disease risk, and disorders of neurodevelopment [1], [2]. The incidence of these diseases/disorders has increased faster than can be explained by genetics alone, and is now thought to be heavily attributable to environmental factors, including EDCs [4]. Although, historically, the field has focused primarily on the estrogen-disrupting effects of EDCs, and effects on reproductive development and function [3], it is now recognized that EDCs can also act via other mechanisms and have impacts on non-reproductive physiology.

Common mechanisms of EDC action include hormone agonism, hormone antagonism, modulation of hormone receptor expression, and disruption of hormone production and/or clearance. While most work still heavily focuses on estrogen, androgen and thyroid disruption via their respective receptors, non-steroidal hormone disruption has repeatedly been shown [5]. For example, studies in multiple species of birds and mammals have revealed that kisspeptin, gonadotropin releasing hormone (GnRH), and oxytocin (OT)/vasopressin (AVP) pathways (vasotocin (AVT) in non-mammalian species) are vulnerable [5], [6], [7], ∗[8], [9]. Some of these effects involve steroid hormone receptor dependent mechanisms, but others do not. There is also growing interest in possible epigenetic, and immune mechanisms of disruption [2], ∗[10], [11].

There are an estimated 90,000 + anthropogenic chemicals in the wild and built environment, although an accurate accounting has proved nearly impossible to obtain, even for regulators such as the US Environmental Protection Agency (EPA) charged with monitoring their distribution and potential toxicity (http://cen.acs.org/articles/95/i9/chemicals-use-today.html). The vast majority have not been tested for any form of toxicity at all, let alone endocrine disruption, so information on their potential health risks is patchy and often contested. A subset of at least a few hundred (estimates vary) are categorized as endocrine disrupting compounds (examples shown in Table 1) with dozens in our bodies at any given time [12]. This complex exposure landscape is largely unavoidable illustrating the critically importance of understanding how EDCs affect human health. Although there is considerable interest and pressure to develop high throughput screening assays and other tools which do not use whole animals to more efficiently and rapidly accomplish the goal of “predictive toxicology [13], ∗[14],” the development and acceptance of effective approaches remains controversial and primarily focused on estrogen, androgen and thyroid activity [15], [16], [17]. Additionally, the inherent biological complexity of the whole organism has not been adequately replicated or modeled in simpler systems and complex behavioral phenotypes and processes such as pubertal onset, affiliative interactions, and learning can only be observed in whole animals. Animal models, with organ and endocrine systems modeling those in humans, allow for the evaluation of chemical influences at many levels and are particularly useful to investigate mechanisms of action, critical windows of susceptibility, sex and age specific effects, and dose responses.

Section snippets

Animal models in toxicology: lessons learned

Justification and utility of animal-based work rests on several key assumptions, the most fundamental of which is that other organisms can serve as accurate predictive models of toxicity in humans. Thus, selection of an appropriately sensitive animal model is key for accurately guiding health decisions. Animal models are simply that, models, all of which have strengths and weaknesses. Understanding the advantages and limitations of any particular model is essential to maximizing the

Human chemical catastrophe and the need to model mechanisms of toxicity

Environmental accidents provide unfortunate and tragic evidence of human susceptibility to chemical exposures and critical windows of exposure. The 1976 pesticide plant explosion in Seveso, Italy [35], revealed a relationship between dioxin exposure and significantly increased cancer rates in women [36], increased metabolic disease in women who were 12 or younger at the time of the explosion [37], permanently reduced sperm quality in men who were breastfed as infants just after the explosion

Novel animal models in EDC research

Although classic toxicology still heavily relies on inbred lines of rats and mice, powerful new options in rodents and other species created to leverage significant advances in gene editing, genomics, and neuroimaging hold the potential to significantly advance EDC research. Although some fields, particularly genetics and the neurosciences, have made significant discoveries with lower order species such as the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster, there is

Summary

In conclusion, numerous considerations must be made when designing studies to address disease conditions that occur in human populations as the result of EDC exposure. Although cell models may be useful in identifying some components of signaling pathways, they lack feedback loops, endocrine systems, and initiation and progression of disease processes that allow for translation of EDC effects. They are also incapable of modeling or recapitulating complex behavior. Rodent and other relevant

Funding

This work was supported by NIEHS grant P30ES025128.

Conflicts of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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