Transient disruption of liver gap junctional intercellular communication and induction of apoptosis after administration of 1,4-bis[2-(3,5 dichloropyridyloxy)]benzene in mice.
Gap junctional intercellular communication (GJIC) and connexin expression (Cx26 and Cx32) in mouse liver were studied after administration of 4-bis[2-(3,5 dichloropyridyloxy)]benzene (TCPOBOP), a phenobarbital-like enzyme inducer. Female C57Bl/6 mice were administered TCPOBOP (5.8 mg/kg BW) and euthanized 0, 24, 48 and 72 hours later. Liver samples were snap frozen, or fixed in formalin, or submitted to GJIC analysis. The proliferating cell nuclear antigen (PCNA) immunohistochemistry and the Western blotting for Cx26 and Cx32 were performed. After 48 and 72 h of drug administration the liver-to-body weight ratio was increased 70% and 117% (p<0.0001), respectively. There were temporal-dependent alterations in liver histopathology and a significant increase in cell proliferation was noted after 48 h and sustained after 72 h, though to a lesser extent (p<0.0001). In addition, TCPOBOP administration induced apoptosis, which appeared to be time-dependent showing statistical significance only after 72 h (p<0.0001). Interestingly, a transient disruption by nearly 50% of GJIC capacity was detected after 48 h of drug ingestion, which recovered after 72 h (p=0.003). These GJIC changes were due to altered levels of Cx26 and Cx32 in the livers of TCPOBOP-treated mice. We concluded that a single administration of TCPOBOP transiently disrupted the levels of GJIC due to decreased expression of connexins and increased apoptotic cell death in mouse liver.
Fukumasu
Heidge
H
Laboratory of Experimental and Comparative Oncology, School of Veterinary Medicine and Animal Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Sanches
Daniel S
DS
da Silva
Tereza C
TC
Ward
Jerrold M
JM
Dagli
Maria L Z
ML
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects*; D000072259:Connexin 26; D017630:Connexins / Q000096:biosynthesis / Q000187:drug effects; D005260:Female; D017629:Gap Junctions / Q000187:drug effects*; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000187:drug effects; D011725:Pyridines / Q000633:toxicity*; D000097002:Gap Junction beta-1 Protein
D002273:Carcinogens; D000072259:Connexin 26; D017630:Connexins; D018809:Proliferating Cell Nuclear Antigen; D011725:Pyridines; D000097002:Gap Junction beta-1 Protein; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene