Human-made toxic chemicals that linger indefinitely in the environment disrupt the performance of critical helper cells in the mouse brain, leading to impaired function over long-term exposures, say neuroscientists at Georgetown University Medical Center.
Their study, believed to be the first to test polychlorinated biphenyls (PCBs) in astrocytes — cells that support neurons and are critical for homeostasis throughout the central nervous system — suggests that this persistent environmental toxicant could be a contributing factor in the development of neurodegenerative disorders.
They report their findings at the annual meeting of the Society for Neuroscience in Chicago.
The research, conducted in laboratory tests of mouse brain cells, shows how a once widely used mixture of PCBs turns on pathways in astrocytes that attempt to neutralize the toxins.
Many antioxidant genes known to be relevant to neurodegeneration in humans are aberrantly activated in the mice cells, says the study’s lead researcher, Mondona McCann, a PhD candidate in Georgetown’s Interdisciplinary Program in Neuroscience.
“Our findings to date show strong connections between these toxins and the health of astrocytes.
They also contribute to our understanding of how crucial these astrocytes are to maintaining brain functioning,” says McCann, who is conducting her research in the lab of Kathleen Maguire-Zeiss, PhD, chair of Georgetown’s Department of Neuroscience.
These star-shaped cells maintain the blood-brain barrier, support neurons, regulate communication between neurons, and repair nervous tissue following injury, among many other supportive tasks. “If astrocytes fail, neurons die.
They are key to maintaining homeostasis — physiological stability — throughout the brain,” she says.
PCBs are known to cause cancer, suppress the immune system, disrupt hormonal signals and impair reproduction. In postmortem studies, they have also been correlated with death of nigral brain cells — dopamine-producing cells — in patients with Parkinson’s disease.
PCBs were globally manufactured and widely used in the 20th century because the chemicals are stable, heat-resistant and electrically insulating, which made them ideal for use in coolants, flame retardants, lubricants, paints, adhesives and many other industrial products.
Because of their toxicity, some countries began banning their use in the 1970s and 1980s, but worldwide production only ended in 2001.
The effect of these toxins continues, McCann says. “The same stability that made PCBs so useful also made them persist in the environment.”
In addition to several human diseases, PCBs have recently been linked to the decline in the killer whale population; McCann suspects that a combination of environmental stressors such as PCBs and genetic predispositions are linked to neurodegeneration.
PCBs were globally manufactured and widely used in the 20th century because the chemicals are stable, heat-resistant and electrically insulating, which made them ideal for use in coolants, flame retardants, lubricants, paints, adhesives and many other industrial products. Because of their toxicity, some countries began banning their use in the 1970s and 1980s, but worldwide production only ended in 2001.
“People in certain regions are constantly exposed to a low dose of PCBs and other similar compounds for a long time over their lives,” McCann says. “Our lab findings suggest that such an accumulation can lead to oxidative stress in astrocytes, which could not, then, support the neurons they maintain.”
It is unlikely that we will ever be able to remove accumulated PCBs from a person, but if research in humans uncovers the specific pathways affected in the brain, “it maybe possible to compensate, clinically, for the deficits seen in functioning of astrocytes. We might be able to engage compensatory mechanisms to increase the cells’ capacity to buffer these toxicants and promote survival,” she says.
“This concept that environmental stressors impinge on astrocyte health is a fairly understudied area,” says Maguire-Zeiss.
In addition to McCann and Maguire-Zeiss, authors include Harvey Fernandez and Sarah Flowers. The authors report having no personal financial interests related to the studies.
Funding: This work was supported by a Medical Center Student Research Grant, a National Institutes of Health Neural Injury and Plasticity T32 training grant (5T32NS041218) and Georgetown’s Department of Neuroscience.
Many hazardous substances occur in our environment and might pose a dose-dependent risk to human health.
Polychlorinated biphenyls (PCBs) are a group of such substances. In the last century, many industrial sectors used PCBs, for example, as a dielectric in transformers and capacitors [1].
Although PCBs were banned [2,3], they are still of great concern due to their high persistence.
Thus, PCB exposure of the general population is present in developed, as well as in developing, countries [4].
According to the degree of chlorination, the resulting path of exposure (e.g., via nutrition or inhalation), and their chemical structure (non-coplanar vs. coplanar), PCBs can be classified into three separate groups: lower-chlorinated PCBs (LPCBs), higher-chlorinated PCBs (HPCBs), and dioxin-like PCBs (dlPCBs). LPCBs have five or less chlorine atoms and are typically associated with occupational exposure and exposure via the inhalation of contaminated air in buildings [5].
LPCBs can be metabolized in humans and diminished in the environment and are therefore not detectable with ambient monitoring. HPCBs have more than five chlorine atoms and typically represent environmental exposure via the food chain [6].
The focus of this study according to LPCBs, as well as HPCBs, is the degree of chlorination.
In the third group, the chemical structure is focused; the coplanar dlPCBs with a similar chemical structure to dioxins. Related to PCB exposure, many negative health consequences such as skin diseases [7], changes in thyroid function [8], or cancer [9] are reported.
Furthermore, previous studies also show negative consequences for mental health (e.g., [10]).
The most consistent findings are related to depression and depressive symptoms after occupational (e.g., [10,11]), as well as environmental PCB exposure (e.g., [12]).
Prior findings on possible mechanisms to explain depressive symptoms after PCB exposure are rare. In this study, we focus on the toxic effects of PCBs on the nervous system (i.e., the dopamine system), as well as the effects on the thyroid function, to consider a possible mechanism.
The first considered approach for an underlying pathomechanism between PCB exposure and depressive symptoms is related to the central dopamine (DA) system.
DA, as well as serotonin and norepinephrine, are neurotransmitters of the monoaminergic system. The monoamines in the central nervous system play an important role in the development of depression.
In depressive patients, lower levels of these neurotransmitters were found compared to healthy control groups (e.g., [13]), indicating that there is a negative association between DA levels and depressive symptoms.
A great number of animal studies (e.g., [14]), as well as human studies (e.g., [15]) show that the neurotransmitter system of DA is affected by PCBs. PCB intervenes in various ways in the DA system; it may interfere with the synthesis of DA via disturbing tyrosine hydroxylase activity [16], the transport of DA from the synaptic cleft back into the synapsis via blocking the DA transporter [15], and the inhibition of the DA transporter by influencing DA metabolism [17,18].
A prior study of the HELPcB population found a negative association between each type of PCB and the main metabolite of DA, homovanillic acid (HVA), directly after the end of PCB exposure [17].
A further study found that the association between PCB body burden and the number of reported depressive symptoms one year after exposure was mediated by HVA [19]. These results indicate that the influence of PCBs on HVA as a proxy for DA influences the amount of depressive symptoms one year after exposure.
In addition to the approach of a DA-related mechanism, we focus on an extended mechanism via thyroid hormones, because PCBs disturb the thyroid system and the thyroid system can interact with the DA system.
With regard to PCBs, various studies reported that PCB exposure alters thyroid function in both directions. Bloom et al. report a negative association of thyroid-like PCBs (28, 52, 60, 74, 77, 95, 99, 101, 105, 114, 118, and 126) with total triiodothyronine (T3), as well as fT4 [20]. Additionally, lower levels of fT3 and fT4 were reported for PCB exposed humans compared to a non-exposed control group [21].
In contrast, positive associations were reported between different PCB congeners and fT4 in fish eaters [22]. In a prior study, we found an association of PCB with lower levels of free T3 over a period of three years after PCB-exposure [8]. In this previous study, we found changes in thyroid function after PCB exposure that might be involved in the development of depressive symptoms.
In non-PCB exposed humans, previous studies reported that serum fT4 can be an indicator for fT4 concentration in the brain [23].
When trying to link thyroid hormone levels and depressive symptoms in patients with hypo- or hyperthyroidism, more depressive symptoms occurred compared to healthy controls [24].
Similarly, Berent et al. [25] reported a positive association of fT4 with the improvement of depression. However, thyroid hormones have been elevated in studies with depressive humans [25,26].
Thus, there are contradictory outcomes, depending on the target group in question (depressive patients vs. patients with thyroid disorder).
In general, however, there seems to be a link between the thyroid system and the DA system, which is also present in depressive disorders; the thyroid system can be affected by DA and the DA system by thyroid hormones. In mice, DA inhibits the release of the thyroid hormone thyroxine [27].
Further animal studies report an elevation in DA level after T4 injection [28,29] and vice versa, and a lower DA level in experimentally-induced hypothyroidism [30]. Hassan et al. [29,30] have demonstrated an important role of T4 in the synthesis of DA. If there is too little T4 in the brain, insufficient DA can be synthesized or released, leading to more depressive symptoms. However, T4 is only active in its free from (fT4).
In humans, the majority of T4 is bound to transport proteins (95%–99%), such as TBG (thyroxin-binding globulin, 75%), TTR (transthyretin, 20%), or albumin (5%) [31]. It is assumed that TBG is responsible for T4 transport in the body, while TTR is supposed to pass the blood-brain barrier and transports T4 into the brain [32].
Prior findings confirm this mechanism and show that the TTR concentration in cerebrospinal fluid (CSF) is relatively high compared to other proteins [33]. Patients with major depression have a lower TTR level in the CSF than healthy controls [34]. PCBs have a similar chemical structure to T4 [35] and therefore, some PCBs have a higher affinity to bind with TTR than T4 itself [36]. Additionally, hydroxy-PCBs (OH-PCBs), as the main metabolites of PCBs, have an even higher affinity to bind on TTR than the parent congeners [37].
In the case that PCBs or OH-PCBs bind to TTR rather than T4, one can assume that there is more fT4 in the blood, while less T4 can be transported into the brain and the synthesis of DA is disturbed. The concentration of DA decreases and typical symptoms of depression may occur.
The aim of this study is to investigate the interaction between fT4 levels and PCB exposure as one possible physiological underlying mechanism to explain the occurrence of depressive symptoms. Two main interaction hypotheses will be tested for several types of PCBs.
With regard to non PCB-exposed humans, and in consideration of past literature, we assume that there is a positive association between ft4 and the main DA metabolite HVA.
In the case of a high PCB blood concentration, a negative association is postulated. Therefore, an interaction hypothesis with opposite directions of the simple slopes was postulated.
The negative association between fT4 and HVA exposure is expected in the case of high PCB blood concentration, which means that a higher PCB and OH-PCB blood concentration should be accompanied with a negative association; so that higher concentrations of fT4 are associated with a lower HVA concentration. In contrast, a positive association between fT4 and HVA is expected in the case of no PCB exposure.
Humans with low or no PCB body burden should show a positive association where a low fT4 level is accompanied with a lower HVA concentration.
To summarize, there is an interaction between PCBs and fT4 related to HVA.
We expect that the correlation between fT4 and HVA is negative in a high PCB blood concentration and positive in a low and no PCB blood concentration (interaction hypothesis 1).
We expect the same interaction for OH-PCBs. Since depressive symptoms are associated with a low HVA concentration, this interaction should be inverse to the first postulated interaction. In the case of high PCB body burden, a high fT4 level should be associated with more depressive symptoms and in the case of no or low PCB body burden, a high fT4 level should be associated with fewer depressive symptoms. We suppose in interaction hypothesis 2 that there is a positive correlation between fT4 and depressive symptoms in high PCB exposure and a negative correlation in low or no PCB exposure. We again suspect the same interaction for OH-PCBs, because OH-PCBs are highly correlated with the parent PCB congeners [38]. A graphical illustration of the postulated interaction hypotheses is presented in Figure 1.
Schematic illustration of the postulated interaction hypotheses. Note: PCB = polychlorinated biphenyls, HVA = homovanillic acid, fT4 = free thyroxin.
Source:
Georgetown University Medical Center
Media Contacts:
Karen Teber – Georgetown University Medical Center
Image Source:
The image is in the public domain.
Original Research: The findings will be presented at Neuroscience 2019.
