Elsevier

Toxicology Letters

Volume 144, Issue 2, 30 September 2003, Pages 173-182
Toxicology Letters

ortho-Substituted polychlorinated biphenyl (PCB) congeners (95 or 101) decrease pituitary response to thyrotropin releasing hormone

https://doi.org/10.1016/S0378-4274(03)00203-0Get rights and content

Abstract

Polychlorinated biphenyl compounds (PCBs) are global environmental contaminants that cause disruption of the endocrine system in humans and wildlife. Recently, we reported that acute exposures to ortho-PCB congeners 95 (2,3,6-2′,5′) or 101 (2,4,5,-2′,5′) causes changes in the performance of the hypothalamo-pituitary-thyroid (HPT)-axis in developing rats through mechanism(s) not yet clear. The functionality of the HPT-axis was evaluated by using the thyrotropin releasing hormone (TRH) test following acute exposure to PCBs 95 or 101. Weanling female rats received PCBs 95 or 101 intraperitoneally (ip) at 32 mg/kg for 2 consecutive days and synthetic TRH was given 48 h after the last dose. Serum thyroxine (T4) levels decreased following exposure to both the congeners. In PCB 95-treated rats, serum thyroid stimulating hormone (TSH) levels were elevated in response to TRH, but were only 40% of the control response to TRH. No significant changes were seen in serum prolactin (PRL), hypothalamic dopamine (DA), thyroid gland morphology, or epithelial cell proliferation. It is suggested that these congeners, interfere with the HPT-axis by causing a subnormal response of the pituitary and thyroid to TRH stimulation.

Introduction

Polychlorinated biphenyls (PCBs) are of concern because of their worldwide distribution, presence in air, water, fish, and wildlife, as well as in human tissue and milk (ATSDR, 2000, Hansen, 1999). Adverse effects of PCBs have been reported on reproduction, development, and endocrine function including thyroid hormone homeostasis in humans and wildlife (Hansen, 1998). Thyroid hormones are essential for normal body metabolism, growth, and development including reproduction, maturation, and aging (Capen et al., 1991); therefore, fluctuations of thyroid homeostasis are especially important in developing animals during the critical phases of growth (Ingbar, 1985).

Exposure to PCBs and related compounds cause reduction in thyroid hormones in developing and adult animals (Hansen, 1998, Morse et al., 1996, Porterfield, 1994). The toxic effects of PCBs depend on their degree of chlorination and pattern of chlorine substitution. Co-planar or dioxin-like PCBs act through the aryl hydrocarbon receptor (AhR) mechanism. These PCBs alter thyroid homeostasis mainly by binding to the AhR and inducing hepatic UDP-glucuronosyl transferases (UDPGTs), which results in increased biliary excretion of thyroxine (T4) (Kohn et al., 1996).

Non-coplanar or ortho-substituted PCBs such as PCB 95 or 101, do not bind to the AhR and produce AhR-independent toxic effects. Acute exposures to these PCBs cause severe reductions in serum total T4 and hypothalamic dopamine (DA) concentration without causing changes in serum thyroid stimulating hormone (TSH) levels (Desaulniers et al., 1999, Khan et al., 2002, Li et al., 1998, Sajid, 1996). There are several mechanism(s) by which ortho-PCBs may reduce circulating T4 levels including binding to a T4 transport protein, transthyretin (TTR) (Chauhan et al., 2000, Lans et al., 1993), increasing tissue uptake of T4 (Capen et al., 1991, Martin et al., 2001), and possibly mechanisms related to interactions with thyroid hormone receptors (McKinney and Waller, 1994). Limited structure:activity relationships (SARs) for T4 depletion by episodic PCBs (Khan et al., 2002, Rose et al., 2001–2002) correspond with more extensive SARs for perturbing intracellular Ca2+ homeostasis by targeting ryanodine receptors (RyRs) and accessory protein complexes, i.e. FKBP12/RyR (Pessah et al., 1999, Wong and Pessah, 1997). This suggests that some PCBs may disrupt T4 through mechanisms related to intracellular calcium flux. However, the exact mechanism(s) of action of these PCBs is not clear. The hypothalamus could be a relevant target because of known effects of these PCBs on DA content (Khan et al., 2002, Rose et al., 2001–2002). The anterior pituitary gland could be a relevant target because of known effects of more labile PCBs (Jansen et al., 1993) and the partial dependence on RyR-mediated calcium regulation (Sundaresan et al., 1997).

Thyroid homeostasis is closely regulated by the hypothalamo-pituitary-thyroid (HPT)-axis in animals. The functionality of the HPT-axis is examined in humans by using the thyrotropin releasing hormone (TRH) stimulation test. When hypothyroidism is present without an increase in serum TSH concentration, the TRH test should serve to distinguish between hypothyroidism of thyroid, pituitary, or hypothalamic origin (Ingbar, 1985). Hyper-response of TSH (in 20–30 min) with no response of T4 and T3 (in 2–4 h) indicates primary (thyroid) hypothyroidism. Lack of TSH, T4, and T3 responses indicates secondary (pituitary) hypothyroidism. A retarded response of TSH with no response of T4 and T3 indicates tertiary (hypothalamic) hypothyroidism (Ashkar, 1983, Ingbar, 1985).

Rats are unique in the lack of circulating thyroglobulin so that the half-life of T4 is shorter than in many species. In other aspects, the physiology of the HPT-axis is very similar to humans (Fukuda et al., 1975); therefore, in rats as well as humans, the integrity of the HPT-axis has been examined by administering synthetic TRH. In rats this has been accomplished intraperitoneally (ip) at 20–40 mg/kg (Kulkosky et al., 2000), 600 μg (Gul et al., 1999), or subcutaneously at 25 μg/rat (Winczyk and Pawlikowski, 1999), or intravenously at 100 or 500 μg/animal (Timmerman et al., 1995), or 200 ng/100 g body weight (Chihara et al., 1976), or 7.5 μg/rat (Lu et al., 1972).

The present studies were performed to identify possible mechanism(s) by which ortho-PCB congeners 95 or 101 cause alterations in the HTP-axis in immature female rats. These studies continue our examination of prevalent, but little studied, labile, ortho-PCB congeners. They are known to disrupt calcium regulation (Kodavanti and Tilson, 1997, Wong and Pessah, 1996, Wong and Pessah, 1997) and DA (Shain et al., 1991). Hypothalamic DA exerts negative feedback on the pituitary for prolactin (PRL) secretion and is depressed by PCBs 95 and 101 48 h after dosing (Khan et al., 2002); therefore, it was important to determine the DA status of the hypothalamus in the current 24 h study.

Acute exposure was chosen because it is more relevant to common dietary (episodic) exposure to these labile congeners and consistent with our previous studies (Hansen, 2001, Khan et al., 2002, Li and Hansen, 1996). Weanling female rats were used because (1) our data base is more complete, and (2) weanling rats are still subject to developmental effects, but most major systems including the HPT-axis, are fully functional at this age (Dohler et al., 1979). It was hypothesized that acute exposure to these PCBs cause interruption of the normal feedback mechanism of the HPT-axis (Khan et al., 2002).

Section snippets

Methods

Two studies were carried out (1) a TRH dose selection study, which was conducted to optimize the TRH dose and its concomitant thyroid responses in developing female rats, and (2) a PCB–TRH study, in which rats were administered PCB 95 or 101 and the TRH test was subsequently performed.

Results

No clinical signs of toxicity or moribundity occurred among animal groups following exposure to PCBs 95, 101, or TRH. Similarly, no differences were noted in body weight gains among treated and control animals.

Discussion

Consistent with reported responses to TRH challenge (Ashkar, 1983, Ingbar, 1985), our results indicate that ip administration of 2.5 μg TRH/rat was sufficient to evoke a normal response of the HPT-axis in immature female rats.

In agreement with other studies (Ashkar, 1983, Ingbar, 1985, Lu et al., 1972), no changes were seen in serum T4 levels 30 min following TRH challenge (Fig. 2). However, serum TSH and PRL levels were sharply elevated (6.5- and 2-fold, respectively) within 30 min of TRH

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    1

    Present address: Environmental Carcinogenesis Division, USEPA, RTP, NC 27711, USA.

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