Mechanisms involved in the neurotoxic effects of environmental toxicants such as polychlorinated biphenyls and brominated flame retardants

Abstract

Many toxic substances have been distributed to the environment, some of which have properties that promote accumulation and biomagnification in living organisms. Approximately 1.2 million metric tons of polychlorinated biphenyls (PCBs) have been produced and about 30% have been discharged to the environment. Approximately 200 000 metric tons of brominated flame retardants (BFRs) are produced annually, of which considerable amounts have been spread globally, even to the Polar Regions. Behavioral testing of animals has shown that these compounds may affect learning, memory and fine motor functions. Animals are most sensitive during early development. Several epidemiological studies have shown that PCBs and BFRs may be responsible for similar effects in humans. Of especially concern are possible effects of PCBs and BFRs in mixtures containing the highly neurotoxic methyl mercury. The compounds affect several targets in the nervous system that seem to be interconnected, and may be responsible for the observed behavioral deficits. It was shown early that PCBs affect dopamine and serotonin levels in the brain. Later studies showed that transport mechanisms of these neurotransmitters appear to be particularly sensitive to PCBs. Furthermore, PCBs affect intracellular calcium levels and induce formation of reactive oxygen species both in vivo and in vitro, and reduce cell viability in vitro. Neuroendocrine functions, particularly the thyroid hormone system, are also sensitive to disruption by PCBs and BFRs. Their metabolites, such as hydroxy‐metabolites, appear to be particularly potent. We conclude that PCBs are particularly toxic during early development and that the toxic effects are a combination of several factors, including disturbance of calcium homeostasis, oxidative stress, and influence on neurotransmitter transport. Monoaminergic cells appear to be particularly vulnerable.

Anthropogenic flank attack on polar bears: interacting consequences of climate warming and pollutant exposure

“…Field studies of behavioral effects of POPs in polar bears are, of natural causes, difficult to conduct. However, several POPs and methylmercury reported in brain tissue of polar bears, (Greaves et al, 2012(Greaves et al, , 2013Krey et al, 2012;Dietz et al, 2013a) are known or suspected developmental neurotoxicants in humans and experimental animals Landrigan, 2006, 2014;Fonnum and Mariussen, 2009;Mariussen, 2012).…”

“…POPs might affect brain function or development through many mechanisms, such as interacting with brain neurotransmitter systems (Fonnum and Mariussen, 2009). Also, the ability of some POPs to induce epigenetic changes could present a mechanistic pathway of neurodevelopmental perturbations (Mill and Petronis, 2008;Bollati and Baccarelli, 2010;Crews, 2011).…”

An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors

“…Numerous modes of action have been described that may contribute to neurotoxicity. This includes altered neurotransmitter signaling (Fonnum and Mariussen, 2009;Mariussen and Fonnum, 2001;Wigestrand et al, 2013), altered GABA A receptor activity (Fernandes et al, 2010), altered Ca 2þ homeostasis through several mechanisms (Choi et al, 2016;Gafni et al, 2004;Kodavanti and Tilson, 1997;Pessah et al, 2010;Westerink, 2014), induced reactive oxygen species (Stenberg et al, 2011), altered cell viability (Dickerson et al, 2009), and alterations of neuro/endocrine processes (Bell, 2014;Fonnum and Mariussen, 2009;Kodavanti and Curras-Collazo, 2010). Of the modes identified, a particularly sensitive endpoint is the ability of NDL PCBs to enhance the activity of ryanodine sensitive Ca 2þ channels embedded in the sarco/endoplasmic reticulum (SR/ER), namely, the ryanodine receptor (RyR), in both mammals (Pessah et al, 2006) and fish (Fritsch and Pessah, 2013).…”

Highly sensitive determination of dialkyl phosphinate acids in environmental samples by ion chromatography tandem mass spectrometry

“…Aluminum dialkyl phosphinates (ADPs, aluminum salts of phosphinic acid having alkyl and/or aryl substitutes) are a class of the most promising flame retardants used as substitute of brominated flame retardants (BFRs) which have been gradually phased out in the United States (US) and European Union (EU) in recent years [1][2][3][4][5]. ADPs have already been widely used in the electrical and electronic equipments, connectors, switches, and encapsulated electronic components in many countries, including China [6].…”