PCB toxicity depends on multiple variables including the type of PCB (ie. mixture or congener), its structure, animal model studied, dose, and route of exposure. Research suggests that mechanisms of PCB toxicity are multifactorial, but appear to involve both Ah receptor dependent and Ah receptor independent mechanisms.
The Ah receptor is a ligand-activated transcription factor involved in gene regulation. When PCBs bind to the Ah receptor, they can disrupt the modulation of normal gene expression. It is postulated that coplanar PCBs bind to the Ah receptor in a target cells cytosol and then is transported to the nucleus where it induces changes in gene expression. PCBs have been found to induce hepatic Phase I (Cytochrome P450 enzymes) and Phase II enzymes (ex. UDP glucuronyltransferases and glutathione transferase). Although PCBs have shown toxicity in multiple organs and organ systems of the body, here we will focus on mechanisms of toxicity related to the endocrine and reproductive system.
Hormones produced by the thyroid gland, thyroxine (T4) and triiodotyronine (T3) play important roles in human development, growth, and metabolism. Underproduction of these hormones can results in hypothyroidism, a disease characterized by lethargy, fatigue, cold-intolerance, weakness, hair loss, and reproductive failure. Hypothyroidism in children can result in cretinism and mental retardation. Overproduction of thyroid hormones leads to a condition called hyperthyroidism, which can result in nervousness, insomnia, high heart rate, eye disease and anxiety. Thyroid hormones exert their effects by binding to DNA-binding proteins that function as hormone-responsive transcription factors.
PCBs can disrupt both the production and distribution of thyroid hormones by a variety of different mechanisms:
- Stimulation of the thyroid gland and interfering with follicular colloid processing, which plays a role in the secretion of thyroid hormones.
- Reducing serum T4 and T3 levels.
- Increasing the rate at which T4 and T3 are eliminated from the body.
- Increasing elimination of T4 and T3 by increasing the activity of the metabolizing enzyme T4-UDP-GT in the liver.
- Decreasing the activity of iodothyronine sulfotransferases in the liver, which effects the metabolic elimination of iodothyronines.
- Disrupting the production of T3 through decreased activity of iodothyronine deiodinases.
- Decreasing the binding of T4 to the transport protein transthyretin, which can inhibit the delivery of thyroid hormones to their target tissues.
The Ah receptor
The molecular mechanisms underlying PCBs disruption of thyroid hormone levels are thought to involve both Ah receptor dependent and independent mechanisms. The Ah receptor is a ligand-activated transcription factor involved in gene regulation. When PCBs bind to the Ah receptor, they can disrupt the modulation of normal gene expression. One potential example of this is the overproduction of UDP-GT in the liver, which catalyzes the metabolic elimination of T4. Increased elimination of T4 leads to decreased levels of this hormone in the serum. However, not all types of PCBs are able to bind to the Ah receptor and evidence exists that Ah receptor independent mechanisms are also responsible for the toxicity of PCBs.
General structure of PCBs
The numbers 2-6 and 2'-6' represent possible chlorine positions on each benzene ring. There are 209 specific PCB family members (congeners). Each PCB congener is unique with respect to chlorine position. For example, a PCB with four chlorine atoms is a tetrachlorobiphenyl ("biphenyl" refers to the two benzene, or "phenyl" rings); a more specific name, e.g., 3,3',4,4'tetrachlorobiphenyl, would indicate the exact positions of the four chlorines on the benzene ring.
Reproductive impairment in minks
Studies in minks suggest the importance of the Ah receptor in reproductive toxicity of PCBs. Minks given low doses of PCBs with high Ah receptor affinity had reduced litter sizes, reduced fetal survival, and increased incidence of interrupted pregnancies than when given a similar dose of PCBs with lower affinity for the Ah receptor (1). However, other mechanisms of toxicity that appear to be Ah independent have also been demonstrated. When pregnant minks were given a low dose of a PCB with known low affinity to the Ah receptor, toxic effects such as decreased embryo survival and the weight, crown-to-rump length, and head length of surviving embryos were seen (1). The precise mechanisms of PCB-induced fetal death in minks are unknown, but are believed to occur due to changes in the placental vasculature. Because PCBs alter steroid hormone synthesis and functions, have estrogenic and anti-estrogenic effects, and may effect the regulation of estrogen and progesterone receptor levels, mechanisms of reproductive toxicity are most likely due to a combination of effects.
Estrogenic and anti-estrogenic properties of PCBs
PCBs have been shown to have estrogenic properties, but are weak compared to the natural hormone, 17b-estradiol. It is believed that metabolites of PCBs may exert estrogenic effects by inhibiting the metabolism of estradiol (2). Evidence of PCBs anti-estrogenic activities is stronger and appears to be mediated by PCBs that act as Ah receptor agonists. The anti-estrogenic activity of PCBs seems to depend somewhat on the pattern of chlorine substitutions on the parent PCB molecule as well as the extent of the formation of hydroxylated metabolites. Predicting estrogenic activity based on PCB structure is more difficult. Evidence of PCBs estrogenic activities is less clear, but evidence exists that suggests some hydroxylated PCBs competitively bind to estrogen receptors in mice.
Some studies suggest the potential for PCBs to lead to increased uterine weight and interfere with normal uterine contractions in pregnant rats (3). Effects on uterine weight appear to depend on the type of PCB or metabolite the rats are exposed to. Premature uterine contractions in rats exposed to specific PCBs and mixtures of PCBs may be influenced by the activation of phospholipase A2, which then releases arachidonic acid, which activates voltage-operated calcium channels of uterine muscle cells stimulating uterine contraction.
Reproductive effects in males
Adult male offspring of rats and guinea pigs exposed to various PCB mixtures during pregnancy showed reduced testes weight and reduced fertility (4). Another study showed that when male rats were given subcutaneous doses of PCBs on postnatal days 0-25, they presented with elevated testes weight and increased sperm production (5). Because sperm production, morphology and motility as well as plasma FSH and testosterone concentrations were not reduced in these rats, the reduced fertility is believed to result from an impaired ability of the sperm to fertilize the egg.
These findings demonstrate PCBs potential toxic effects on the male reproductive system. Mechanisms of toxicity to this system have yet to be elucidated, but it has been hypothesized that toxicity depends on the specific time period of exposure. For example, in utero exposure to PCBs may lead to persistent elevation of testosterone-metabolizing enzymes, which may then lead to reduced testes weight (6). Numerous studies have demonstrated PCBs effects on thyroid hormone levels. Persistent depression of thyroid hormone levels during the sensitive period prior to Sertoli cell proliferation in males can lead to increased testes weight (5).
Studies of PCBs in vivo and in vitro have not produced any solid evidence that PCBs display genotoxic activities.
The majority of information came from the ATSDRs toxicological profile for PCBs. The studies referenced in the content of this web page are some of the specific studies referenced in the ATSDR article. Other information came from the sites listed under useful links below.
1. Patnode KA, Curtis LR. 1994. 2,2',4,4',5,5'- and 3,3',4,4',5,5'-Hexachlorobiphenyl alteration of uterine progesterone and estrogen receptors coincides with embryotoxicity in mink (mustela vison). Fundam Appl Toxicol 127:9-18.
2. Kester MHA, Bulduk S, Tibboel D, et al. 2000. Potent inhibition of estrogen sulfotransferase by hydroxylated PCB metabolites: A novel pathway explaining the estrogenic activity of PCBs. Endocrinology 141(5):1897-1900. (Kester et al 2000).
3. Bae J, Peters-Golden M, Loch-Caruso R. 1999. Stimulation of pregnant rat uterine contraction by the polychlorinated biphenyl (PCB) mixture Aroclor 1242 may be mediated by arachidonic acid release through activation of phospholipase A2 enzymes. Journal of Pharmacology and Experimental Therapeutics 289:1112-1120.
4. Lundkvist U. 1990. Clinical and reproductive effects of Clophen A50 (PCB) administered during gestation on pregnant guinea pigs and their offspring. Toxicology 6:249-257.
5. Cooke PS, Zhao Y-D, Hansen LG. 1996. Neonatal polychlorinated biphenyl treatment increases adult testis size and sperm production in the rat. Toxicol Appl Pharmacol 136:112-117.
6. Hany J, Lilienthal H, Sarasin A, et al. 1999b. Developmental exposure of rats to a reconstituted PCB mixture or Aroclor 1254: Effects on organ weights, aromatase activity, sex hormone levels, and sweet preference behavior. Toxicol Appl Pharmacol 158:231-243.
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