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LOW-DOSE EFFECTS OF AMMONIUM PERCHLORATE ON THE HYPOTHALAMIC-PITUITARY-THYROID (HPT) AXIS OF ADULT MALE RATS PRETREATED WITH PCB126
Citation:
MCLANAHAN, E. D., J. L. CAMPBELL, D. C. FERGUSON, M. MUMTAZ, B. HARMON, J. M. HEDGE, K. M. CROFTON, D. R. MATTIE, L. BRAVERMAN, D. A. KEYS, AND J. W. FISHER. LOW-DOSE EFFECTS OF AMMONIUM PERCHLORATE ON THE HYPOTHALAMIC-PITUITARY-THYROID (HPT) AXIS OF ADULT MALE RATS PRETREATED WITH PCB126. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 97(2):308-317, (2007).
Impact/Purpose:
To characterize the disturbances in the hypothalamic-pituitary-thyroid (HPT) axis resulting from exposure to a binary mixture, 3,3',4',5-pentachlorobiphenyl (PCB126) and perchlorate (ClO_4 ), known to cause hypothyroid-ism by different modes of action
Description:
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',5-pentachlorobiphenyl (PCB126) and perchlorate (ClO_4 ), known to cause hypothyroid-ism 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 mg/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 T4-glucuronide formation, causing a decline in serum thyroxine and fT4, and resulting in increased serum thyroid stimulating hormone (TSH). Serum TSH was also increased in animals that received 7.5 mg 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 mg/kg) on day 0, and followed with ClO4 (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 ClO4 , no interactions between the chemicals occur.