Alteration of serotonin system by polychlorinated biphenyls exposure

doi:10.1016/j.neuint.2012.03.003

Neurochemistry International

Volume 60, Issue 8, June 2012, Pages 809-816

https://doi.org/10.1016/j.neuint.2012.03.003 Get rights and content

Abstract

Although commercial production of polychlorinated biphenyls (PCBs) was banned in 1979, PCBs continue to be an environmental and health concern due to their high bioaccumulation and slow degradation rates. In fact, PCBs are still present in our food supply (fish, meat, and dairy products). In laboratory animals, exposure to single PCB congener or to mixtures of different congeners induces a variety of physiological alterations. PCBs cross the placenta and even exposure at low level is harmful for the foetus by leading to neurodevelopment alterations. Serotonin system which regulates many physiological functions from platelet activation to high cerebral processes and neurodevelopment is one of the targets of PCBs toxicity. The effects of PCBs exposure on serotonin system have been investigated although to a lesser extent compared to its effect in other neurotransmitter systems. This review provides a summary of the results concerning the impact of PCBs exposure (in vitro and in vivo) on serotonin system. Further research is needed to correlate specific deficits with PCB-induced changes in the serotonin system.

Highlights

► PCBs continue to be an environmental and health concern due to their high bioaccumulation and slow degradation rates. ► One of the targets of PCBs toxicity is the serotonin system. ► PCBs exposure alters serotonin metabolism depending on congener tested, gender and schedule of exposure.

Introduction

Polychlorinated biphenyls (PCBs) represent a class of toxins of concern to public health, since they are still present in the environment despite their ban many years ago (Seegal, 1996). One of the targets of PCB’s toxicity is the serotonin (5-HT) system which regulates a variety of physiological functions. In this review, we will analyze experimental data concerning the impact of PCB exposure on the serotonin system in both in vitro and in vivo models. We will also consider the consequences of altering the serotonin system, such as impairment of behavior, immune system and platelet functions. We will first give a general summary of PCBs classification and toxicity. Then, we will review the effect of PCBs on the activity of the enzymes involved in serotonin metabolism, and on serotonin cellular and vesicular uptake. Additionally, we will summarize the data obtained in mammals and in other species (fish and invertebrates) concerning the effect of perinatal or postnatal exposure to PCBs on the concentration of serotonin and its major metabolite 5-hydroxyindole acetic acid (5-HIAA) in different brain areas. Finally, we will summarize the main conclusions and suggest future directions in this research field.

Section snippets

PCBs: ‘dioxin-like’ and ‘non-dioxin-like’ PCBs

All PCB congeners are lipophilic and their lipophilicity increases with their grade of chlorination. The position of the chlorine atoms in benzene rings confers different chemical properties to PCBs, which can be classified in to two subgroups:

–
Coplanar or non-ortho: there are no chlorine atoms in the position 2, 2′, 6 or 6′ (ortho positions). The absence of chlorine atoms in these positions allows the PCB to adopt a coplanar configuration.
–
Non coplanar or ortho-substituted: one or more chlorine

PCB levels and toxicity

Even though the mechanism of action of PCBs, at least regarding dioxin-like-PCBs, is well understood, the threshold amount required to produce toxicity remains unknown. Both the World Health Organization (WHO) and the US Environmental Protection Agency (EPA) work together in order to evaluate the risk of PCBs on human health. The consensus of both agencies regarding the maximum contaminant levels in water and food is summarised here: the maximum contaminant level goal in drinking water is zero

The serotonin system

The human body contains around 10 mg of serotonin, 90% of this amount is localized inside enteric system chromaffin cells. In the blood, serotonin concentration ranges between 40 and 200 ng/mL (Izzati-Zade, 2008, Sasa et al., 1978). Serotonin is synthesized by neurons of the central and peripheral nervous system (CNS and PNS respectively). In the CNS, serotonin acts as a modulatory neurotransmitter with both inhibitory and excitatory actions depending on the receptor subtype that is activated (

Effects of PCB exposure on serotonin release and re-uptake

Once serotonin is released in the extracellular space by the exocytosis of granules containing sequestered monoamine, it can be selectively re-uptaken into the cells by high-affinity membrane proteins called serotonin transporters (SERTs) and low-affinity transporters called plasma membrane monoamine transporters (PMATs).

The isolation of synaptosomal fractions (synaptosomes) from nervous tissue is a useful tool for the in vitro analysis of neurotransmitter release and re-uptake. Synaptosomes

Effects of PCB exposure on serotonin uptake into vesicles

Cytoplasmic serotonin is storedin neurotransmitter vesicles by the vesicular monoamine transporter (VMAT) which also takesup other monoamines such as DA, norepinephrine or histamine (Ahnert-Hilger et al., 2003).

Mariussen and co-workers (1999) examined the effect of selected non-planar orthochlorinated biphenyls on vesicular uptake of serotonin (as well as DA, glutamate or GABA). PCBs inhibit the vesicular uptake of serotonin and DA more powerfully than that of glutamate or GABA (Mariussen et

Effects of PCB exposure on serotonin metabolism

The effect of PCB exposure on the uptake of the aromatic aminoacid l-tryptophan, the serotonin precursor, has not been explored. In contrast, in PC12 cells, the uptake of the aromatic aminoacid l-tyrosine (DA precursor) is reduced following exposure to high doses of PCB (Angus et al., 1997). Serotonin is synthesized from l-tryptophan by two reactions: the first one is catalyzed by the enzyme tryptophan hydroxylase (TPH) (the rate-limiting step in serotonin synthesis) and leads to

Effect of prenatal exposure to PCBs on serotonin content in the brain

Morse et al. (1996a) administered Aroclor 1254 (0, 5 or 25 mg/kg p.o.) to pregnant rats from GD10 to GD16 and measured tissue content of serotonin and its main metabolite, 5-HIAA in several brain areas (lateral olfactory tract, prefrontal cortex, striatum, hippocampus and hypothalamus) in male and female offspring at PND21 (weaning) and at PND90. The main finding of this study was that prenatal exposure to Aroclor 1254 increased 5-HIAA in the lateral olfactory tract and in the prefrontal cortex

Effect of postnatal exposure to PCBs on serotonin content in the brain

Acute oral administration of Aroclor 1254 (0.33 mg/g body weight) to young rats decreased serotonin concentration in some brain areas (frontal cortex) but not in other brain regions (brainstem and hypothalamus) one week later (Khan and Thomas, 2004). Administration of the non-dioxin like PCB 153 (5 or 50 μg/g) to bluegill sunfish (Lepomismacrochirus) decreased serotonin content in the brain three days later (Duffy-Whritenour et al., 2010). Studies performed in Atlantic croakers orally exposed to

Alteration of the brain serotonin system and behaviour by PCB exposure

Although PCB exposure has been associated with a variety of behavioural alterations in humans and in experimental animals, the direct consequence of altered brain serotonin system function caused by PCB exposure, and its role in behavioural modulation has not been investigated. Only one report (Lilienthal et al., 1997) has demonstrated a direct relationship between behavioural processes modulated by the serotonin system by using a drug discrimination paradigm and prenatal exposure to PCB 77. In

Effect of PCB exposure and serotonin regulation of the immune system

Serotonin receptors (5-HT 1-7) and serotonin reuptake transporters are expressed in several immune cells from fish to mammals (Khan and Deschaux, 1997, Lawrence and Kim, 2000, Mossner and Lesch, 1998). For instance 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT6, and 5-HT7 receptor mRNAs are found in spleen, thymus, and peripheral blood lymphocytes. In addition, mitogen activation of T- and B-lymphocytes is accompanied by an increase of 5-HT 3 receptor mRNA expression (Stefulj et al., 2000). Exposure to

Effect of PCB exposure on serotonin in platelets

Raulf and Konig (1991) investigated the effects of four different non-dioxin like PCBs congeners (PCB11, PCB101 or PCB40) and one dioxin-like congener (PCB77) on different platelet responses, including the ability of PCBs (0–6 μM) to stimulate the release of serotonin. Incubation of platelets with PCBs increases the release of serotonin. The dioxin-like PCB 77 congener was able to increase platelet serotonin release the most potently (Raulf and Konig, 1991). The effect of PCBs on serotonin

Concluding remarks

PCB exposure alters serotonin and 5-HIAA concentration in the brain in several animal species. The effect depends on several parameters such as PCB congener, exposure dose, duration of treatment, brain region, gender and schedule of exposure (perinatal or postnatal) (summarized in Table 2, Table 3, respectively) suggesting that the molecular mechanisms by which PCB exposure alters the serotonin system are complexes and not fully understood. By analyzing all data in the literature we can draw

Declaration of Interest

The authors declare that there are no conflicts of interest. The author’s affiliation is as shown on the cover page. The authors have sole responsibility for the writing and content of the paper.

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ReviewAlteration of serotonin system by polychlorinated biphenyls exposure

Abstract

Highlights

Introduction

Section snippets

PCBs: ‘dioxin-like’ and ‘non-dioxin-like’ PCBs

PCB levels and toxicity

The serotonin system

Effects of PCB exposure on serotonin release and re-uptake

Effects of PCB exposure on serotonin uptake into vesicles

Effects of PCB exposure on serotonin metabolism

Effect of prenatal exposure to PCBs on serotonin content in the brain

Effect of postnatal exposure to PCBs on serotonin content in the brain

Alteration of the brain serotonin system and behaviour by PCB exposure

Effect of PCB exposure and serotonin regulation of the immune system

Effect of PCB exposure on serotonin in platelets

Concluding remarks

Declaration of Interest

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Regulation of vesicular neurotransmitter transporters

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Inhibition of l-aromatic amino acid decarboxylase by polychlorinated biphenyls

Neurotoxicology

The expanded biology of serotonin

Annu. Rev. Med.

Differential long-term effects of developmental exposure to polychlorinated biphenyls 52, 138 or 180 on motor activity and neurotransmission. Gender dependence and mechanisms involved

Neurochem Int.

Prenatal exposure to polychlorinated biphenyls: a neuropsychologic analysis

Environ. Health Perspect.

Are reductions in industrial organic contaminants emissions in rich countries achieved partly by export of toxic wastes?

Environ. Sci. Technol.

Goodman & Gilman’s The pharmacological basis of therapeutics

(Polychlorinated biphenyl-induced reduction of dopamine transporter expression as a precursor to Parkinson’s disease-associated dopamine toxicity

Toxicol. Sci.

Polychlorinated biphenyls, lead, and mercury are associated with liver disease in American adults: NHANES 2003–2004

Environ. Health Perspect.

Subchronic toxicity of PCB 105 (2,3,3′,4,4′-pentachlorobiphenyl) in rats

J. Appl. Toxicol.

(Toxicity of 2,2′,4,4′,5,5′-hexachlorobiphenyl in rats: effects following 90-day oral exposure

J. Appl. Toxicol.

Review
Alteration of serotonin system by polychlorinated biphenyls exposure