Sustained expression of CYPs and DNA adduct accumulation with continuous exposure to PCB126 and PCB153 through a new delivery method: Polymeric implants

Farrukh Aqil,Hua Shen,Jeyaprakash Jeyabalan,Xing Xin,Hans-Joachim Lehmler,Gabriele Ludewig,Larry W Robertson,Ramesh C Gupta

doi:10.1016/j.toxrep.2014.09.010

Farrukh Aqil, Hua Shen + Show 6 more

Open Access

https://doi.org/10.1016/j.toxrep.2014.09.010

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Abstract

A new delivery method via polymeric implants was used for continuous exposure to PCBs. Female Sprague-Dawley rats received subcutaneous polymeric implants containing PCB126 (0.15% load), PCB153 (5% load), or both, for up to 45 d and release kinetics and tissue distribution were measured. PCB153 tissue levels on day 15 were readily detected in lung, liver, mammary and serum, with highest levels in the mammary tissue. PCB126 was detected only in liver and mammary tissues. However, a completely different pharmacokinetics was observed on co-exposure of PCB153 and PCB126, with a 1.8-fold higher levels of PCB153 in the liver whereas a 1.7-fold lower levels in the mammary tissue. PCB126 and PCB153 caused an increase in expression of key PCB-inducible enzymes, CYP 1A1/2 and 2B1/2, respectively. Serum and liver activities of the antioxidant enzymes, PON1 and PON3, and AhR transcription were also significantly increased by PCB126. 32P-postlabeling for polar and lipophilic DNA-adducts showed significant quantitative differences: PCB126 increased 8-oxodG, an oxidative DNA lesion, in liver and lung tissues. Adduct levels in the liver remained upregulated up to 45 d, while some lung DNA adducts declined. This is the first demonstration that continuous low-dose exposure to PCBs via implants can produce sustained tissue levels leading to the accumulation of DNA-adducts in target tissue and induction of indicator enzymes. Collectively, these data demonstrate that this exposure model is a promising tool for long-term exposure studies.

Highlights

The polymeric implants of PCB126 and PCB153 were prepared by the coating method with a PCB load of 0.15% and 5%, respectively (Fig. 1A)
When 1.5-cm PCB153 implants were shaken in phosphate buffered saline (PBS) containing 10% serum to simulate in vivo extracellular fluid conditions, a gradual release of PCB153 was observed
Dose response is a well-established phenomenon, but studies almost always use bolus doses of test compounds to determine their DNA-damaging and carcinogenic potential. Such bolus doses are far from the normal scenario in which humans are generally exposed to very low doses of toxicants for long durations

Summary

Introduction

Humans continue to be exposed to low doses of PCBs because of their presence in the environment, their accumulation in the food chain, and accidental release from disposal sites [3]. PCBs remain a major contaminant in human tissues [4,5]. Exposure to PCBs in humans results in gastrointestinal effects, respiratory tract symptoms, mild liver toxicity, and effects on the skin and eyes such as chloracne, altered pigmentation, and eye irritation. Other potential adverse health effects of PCBs such as immunological disturbances, neurological defects and implications in cardiovascular and liver diseases have been described [6,7]. Several studies have reported an increase in liver cancer among persons occupationally exposed to some PCB formulations [9]

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