Endocrine disrupting polyhalogenated organic pollutants interfere with thyroid hormone signalling in the developing brain

Abstract

Persistent polyhalogenated organic pollutants are present worldwide and accumulate along the food chain. They interfere with human and animal health and are particularly harmful for pre- and perinatal neurodevelopment. The mechanisms behind the observed effects vary depending on the specific compound investigated. Co-planar polychlorinated biphenyls (PCBs) can act via the arylhydrocarbon receptor while many ortho-substituted PCBs disrupt intracellular Ca(2+) homeostasis. A common mechanism for a wide variety of PCBs is interference with thyroid hormone (TH) signalling in developing brain, by changing intracellular TH availability or by interacting directly at the level of the TH receptors. Studies on gene expression in cortex and cerebellum revealed both hypothyroid- and hyperthyroid-like effects. However, since THdependent gene expression plays a crucial role in the coordination of neuronal proliferation, migration, synaptogenesis, myelination, etc., both reduced/delayed and increased/premature expression may result in permanent structural changes in neuronal communication networks, leading to lifelong deficits in cognitive performance, motor functions, and psychobehavior. In a similar way, PCBs are able to interfere with estrogen- and androgen-dependent brain development and in some studies neurobehavioral outcome was shown to be gender-specific. Other persistent organohalogens like polychlorinated dibenzo-p-dioxins (PCDDs) and polybrominated diphenyl ethers (PBDEs) also act as endocrine disrupters in the developing brain. Several of the mechanisms involved are similar to those of PCBs, but each group also works via own specific pathways. The fact that persistent organohalogens can amplify the neurotoxic effects of other environmental pollutants, such as heavy metals, further increases their risk for human and animal neurodevelopment.

A selective thyroid hormone β receptor agonist enhances human and rodent oligodendrocyte differentiation

“…Acting through nuclear hormone receptors, THs have been shown to promote the expression of a number of oligodendrocyte specific genes including myelin basic protein (MBP), myelin-associated glycoprotein (MAG), proteolipid protein (PLP) and cyclic nucleotide 3’-phosphodiesterase (CNP) (Farsetti et al, 1992; Farsetti et al, 1991; Rodriguez-Pena et al, 1993; Tosic et al, 1992). In vivo , numerous studies of hypo- and hyperthyroid animals as well as genetically modified rodents have provided clear evidence that THs regulate oligodendrocyte differentiation and maturation (Bernal, 2002; Bernal, 2007; Darras, 2008; Dugas et al, 2012; O'Shea and Williams, 2002; Zoeller and Rovet, 2004). Despite unequivocal evidence of the important role played by THs in myelination, we do not yet clearly understand which thyroid hormone receptors (THRs) are required to mediate these effects (Baas et al, 1997; Bernal, 2002; Bernal, 2007; Darras, 2008; O'Shea and Williams, 2002; Zoeller and Rovet, 2004).…”

Differential neurotoxic effects of <i>in utero</i> and lactational exposure to hydroxylated polychlorinated biphenyl (OH-PCB 106) on spontaneous locomotor activity and motor coordination in young adult male mice

“…This system plays important roles in the development of the dopaminergic system, including dopamine neuron differentiation and migration (Blum et al, 1999;Chen et al, 2015;Mittag et al, 2009). It is known that disruption of the TH system during the perinatal period can induce brain dysfunction (Delange, 1994;Koibuchi and Chin, 2000), and previous in vitro and in vivo studies have reported that some parent PCBs affect the TH system in rodents (Branchi et al, 2005;Brouwer et al, 1998;Darras, 2008;Gilbert et al, 2012;Hallgren et al, 2001;Hood et al, 2003). In addition, our previous in vitro studies demonstrated that OH-PCB 106 exposure suppressed TH-mediated transcription (Amano et al, 2010;Iwasaki et al, 2002;Miyazaki et al, 2004Miyazaki et al, , 2008.…”

Impact of Endocrine Disruptors on the Thyroid Hormone System

“…Neuronal cells are more sensitive to PCB metabolites than other cells [72], and Purkinje cells seem to be especially sensitive to endocrine disruptions [75]. Hypothyroidism leads to region-specific alterations of the expression pattern of TR isoforms, of which TRα2 is a non-T 3 -binding isoform [76], and such subtle changes lead to molecular and histological changes [19,73,77,78] that finally may translate into clinical and epidemiological effects of hypothyroidism in humans. …”

“…Low TH is associated with alterations of cell migration in the developing brain [19,77,78], decreased myelination and cell migration and maturation [77] resulting in permanent changes of the cytoarchitecture, especially of the somatosensory cortex and the hippocampus [21], and for these effects, critical windows of sensibility exist during fetal and embryonic development [13]. …”

“…TH is the main driver of proliferation of progenitor populations, lineage decisions, and cell migration in the brain development of the embryo once the neural tube has closed. Alterations of TH due to iodine lack, maternal hypothyroidism, TH transport disturbance, and alterations of peripheral TH metabolism may result in permanent alterations of neuronal development [13,73,78]. …”