Low-Dose Effects of Ammonium Perchlorate on the Hypothalamic-Pituitary-Thyroid Axis of Adult Male Rats Pretreated with PCB126

Abstract

The objective of this research was to characterize the disturbances in the hypothalamic-pituitary-thyroid (HPT) axis resulting from exposure to a binary mixture, 3,3',4,4',5-pentachlorobiphenyl (PCB126) and perchlorate (ClO(4)(-)), known to cause hypothyroidism by different modes of action. Two studies were conducted to determine the HPT axis effects of ClO(4)(-) on adult male Sprague-Dawley rats pretreated with PCB126. In dosing study I, rats were administered a single oral dose of PCB126 (0, 7.5, or 75 microg/kg) on day 0 and 9 days later ClO(4)(-) (0, 0.01, 0.1, or 1 mg/kg day) was added to the drinking water until euthanasia on day 22. Significant dose-dependent trends were found for all thyroid function indices measured following ClO(4)(-) in drinking water for 14 days. Seventy-five micrograms PCB126/kg resulted in a significant increase in hepatic T(4)-glucuronide formation, causing a decline in serum thyroxine and fT(4), and resulting in increased serum thyroid-stimulating hormone (TSH). Serum TSH was also increased in animals that received 7.5 microg PCB126/kg; no other HPT axis alterations were found in these animals. When pretreated with PCB126, the ClO(4)(-) dose trends disappeared, suggesting a less than additive effect on the HPT axis. In dosing study II, animals were given lower doses of PCB126 (0, 0.075, 0.75, or 7.5 microg/kg) on day 0, and followed with ClO(4)(-) (0 or 0.01 mg/kg day) in drinking water beginning on day 1 and continuing for several days to explore transient HPT axis effects. No statistical effects were seen for PCB126 or ClO(4)(-) alone, and no perturbations were found when administered sequentially in dosing study II. In conclusion, these studies demonstrate that HPT axis disturbances following exposure to ClO(4)(-) are less than additive when pretreated with relatively high doses of PCB126. At relatively low doses, at or near the no-observed-effect-level for PCB126 and ClO(4)(-), no interactions between the chemicals occur.

Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming

“…In reality, endocrine disruptors are rarely present in isolated forms. Interactions among different disruptors are complex and may be additive, sub-additive, and super-additive, depending on the individual combination of substances and their respective concentrations (389–391). This makes the effects difficult to predict in the individual situation.…”

In Vivo Evaluation of Transdermal Iodide Microemulsion for Treating Iodine Deficiency Using Sprague Dawley Rats

“…Iodide ions excreted in urine is the result of metabolic processing of thyroid hormones or due to an excess in plasma concentration after an increase in oral iodine uptake (43). It was reported that about 95% of the daily iodide intake in rats was excreted in urine (11).…”

Competitive Inhibition of Thyroidal Uptake of Dietary Iodide by Perchlorate Does Not Describe Perturbations in Rat Serum Total T 4 and TSH

“…We previously simultaneously optimized V max T i (nanomoles per hour) and K NIS TSH (nanomoles per liter) (McLanahan et al 2008) to euthyroid, dietary-iodine–sufficient (~ 20 μg/day) rat data for serum and thyroid iodide reported by Eng et al (1999) and McLanahan et al (2007), respectively. The other parameter, NIS affinity constant for iodide ( K m i , nanomoles per liter) in Equation 1 was obtained from Gluzman and Niepomniszcze (1983) as reported by McLanahan et al (2008).…”

“…We obtained physiologic parameters (Table 1) for tissue volumes and blood flows from previous studies (Brown et al 1997; Everett et al 1956; Malendowicz and Bednarek 1986; McLanahan et al 2007, 2008). The BBDR–HPT axis model parameters had been calibrated for the euthyroid adult rat previously and used to describe iodide-deficient conditions (McLanahan et al 2008).…”