Current concepts in neuroendocrine disruption

Abstract

In the last few years, it has become clear that a wide variety of environmental contaminants have specific effects on neuroendocrine systems in fish, amphibians, birds and mammals. While it is beyond the scope of this review to provide a comprehensive examination of all of these neuroendocrine disruptors, we will focus on select representative examples. Organochlorine pesticides bioaccumulate in neuroendocrine areas of the brain that directly regulate GnRH neurons, thereby altering the expression of genes downstream of GnRH signaling. Organochlorine pesticides can also agonize or antagonize hormone receptors, adversely affecting crosstalk between neurotransmitter systems. The impacts of polychlorinated biphenyls are varied and in many cases subtle. This is particularly true for neuroedocrine and behavioral effects of exposure. These effects impact sexual differentiation of the hypothalamic-pituitary-gonadal axis, and other neuroendocrine systems regulating the thyroid, metabolic, and stress axes and their physiological responses. Weakly estrogenic and anti-androgenic pollutants such as bisphenol A, phthalates, phytochemicals, and the fungicide vinclozolin can lead to severe and widespread neuroendocrine disruptions in discrete brain regions, including the hippocampus, amygdala, and hypothalamus, resulting in behavioral changes in a wide range of species. Behavioral features that have been shown to be affected by one or more these chemicals include cognitive deficits, heightened anxiety or anxiety-like, sociosexual, locomotor, and appetitive behaviors. Neuroactive pharmaceuticals are now widely detected in aquatic environments and water supplies through the release of wastewater treatment plant effluents. The antidepressant fluoxetine is one such pharmaceutical neuroendocrine disruptor. Fluoxetine is a selective serotonin reuptake inhibitor that can affect multiple neuroendocrine pathways and behavioral circuits, including disruptive effects on reproduction and feeding in fish. There is growing evidence for the association between environmental contaminant exposures and diseases with strong neuroendocrine components, for example decreased fecundity, neurodegeneration, and cardiac disease. It is critical to consider the timing of exposures of neuroendocrine disruptors because embryonic stages of central nervous system development are exquisitely sensitive to adverse effects. There is also evidence for epigenetic and transgenerational neuroendocrine disrupting effects of some pollutants. We must now consider the impacts of neuroendocrine disruptors on reproduction, development, growth and behaviors, and the population consequences for evolutionary change in an increasingly contaminated world. This review examines the evidence to date that various so-called neuroendocrine disruptors can induce such effects often at environmentally-relevant concentrations.

Keywords: Bisphenol A; Growth; Organochlorine pesticides; Pharmaceuticals; Polychlorinated biphenyls; Reproduction.

Figure 1

Neuroendocrine disruption has gained more attention from the scientific community in the past decade (Web of Science, November 2013). Published manuscripts and reports that use the specific phrase “neuroendocrine disruption.” In addition, citations of these articles have steadily increased over the past 20 years.

Figure 2

Building a case for neuroendocrine disruption. Environmental pollutants (e.g. , pesticides, PCBs, phthalates, pharmaceuticals, etc.) can act directly on cells within neuroendocrine tissues of the central nervous system (CNS) as well as on neurotransmitter systems that regulate neurohormone release, for example dopamine (DA), gamma-aminobutyric acid (GABA), norepinephrine (NE) and serotonin (5HT), among others. Altered neuropeptide synthesis and release will have downstream consequences on pituitary hormone release (arrow A), affecting homeostasis, growth and reproduction. Neuroendocrine disruptors are also proposed to regulate behaviors by modulating neuropeptide synthesis and release, the mechanisms of which are not fully characterized but likely involve membrane bound receptor (e.g., estrogen, progesterone) signaling and/or nuclear receptor (e.g., androgen, glucocorticoid, estrogen) pathways and post-translational protein modifications (i.e., phosphorylations) within neuroendocrine cells. Changes in behaviors (e.g., feeding, sociosexual) will adversely impact homeostasis, growth and reproductive output (arrow B). The CNS will be responsive to these physiological changes, and may be altered by longer acting effects of neuroendocrine disruptors, such epigenetic modifications (e.g., DNA methylation state) resulting in transgenerational effects (arrow C). Focused studies that address some of the questions proposed will assist to better define the scope of neuroendocrine disruption. Abbreviations: 5-HT, 5-hydroxytryptamine; GnRH, gonadotropin-releasing hormone; KP, kisspeptin; OXT, oxytocin (known as isotocin in fish), PCBs, polychlorinated biphenyls; PIT, pituitary; POA, preoptic area; TRH, thyrotropin-releasing hormone; VP, vasopressin.