Adult lead exposure increases blood-retinal permeability: A risk factor for retinal vascular disease.
Low-to-moderate level developmental and adult lead exposure produces retinal dysfunction and/or degeneration in humans and experimental animals. Although high level in vivo or in vitro lead disrupts blood-brain-barrier tight junctions and increases its permeability, the blood-retinal-barrier (BRB) has not been examined. There were four overall goals. First, generate environmentally relevant dose-response models of short-term lead exposure in adult rats. Second, assess retinal histology and functional integrity of the BRB. Third, investigate the transmembrane proteins occludin and claudin-5 as targets mediating the increased BRB permeability. Fourth, examine the contribution of the PI3K-Akt signaling pathway as a mechanism underlying increased BRB permeability. Young adult rats were given water, 0.01% or 0.02% lead drinking solutions for six weeks. In control, 0.01% and 0.02% groups the six week mean blood [Pb] were 1, 12.5 and 19μg/dl, respectively. We employed histology, stereology, quantitative image analysis, immunoblots and densitometry, and pharmacology techniques. Major findings were that adult lead exposure produced dose-dependent 1) decreases in outer and inner nuclear layer thickness, 2) increases in BRB permeability, 3) decreases in occludin and claudin-5 expression, 4) increases in pAkt (Ser473), but not pAkt (Thr308), expression, and 5) wortmannin partially or completely blocked the increased BRB permeability and changes in protein expression. These results indicate that lead-induced increases in PI3K-Akt signaling partially underlie the increased BRB permeability and advance our knowledge about lead-induced retinotoxicity. Furthermore, they suggest that environmental and occupational lead exposures are risk factors for increased BRB permeability in diseases such as age-related macular degeneration, diabetes and stroke.
Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, The Fourth Military Medical University, Xi'an, Shanxi Province, PR China.
Xue-Feng
XF
Shen
Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, The Fourth Military Medical University, Xi'an, Shanxi Province, PR China.
Ping
P
Huang
College of Optometry, Department of Biology and Biochemistry, and Department of Pharmacology and Pharmaceutical Sciences, University of Houston, Houston, USA.
Donald A
DA
Fox
Department of Ophthalmology, Xijing Hospital, Eye Institute of PLA, The Fourth Military Medical University, Xi'an, Shanxi Province, PR China.
Yan
Y
Lin
Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, The Fourth Military Medical University, Xi'an, Shanxi Province, PR China.
Zai-Hua
ZH
Zhao
Department of Radiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shanxi Province, PR China.
Wen
W
Wang
Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, The Fourth Military Medical University, Xi'an, Shanxi Province, PR China.
Ji-Ye
JY
Wang
Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, The Fourth Military Medical University, Xi'an, Shanxi Province, PR China.
Xin-Qin
XQ
Liu
Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, The Fourth Military Medical University, Xi'an, Shanxi Province, PR China.
Jing-Yuan
JY
Chen
Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, The Fourth Military Medical University, Xi'an, Shanxi Province, PR China. Electronic address: luowenj@fmmu.edu.cn.
Wen-Jing
WJ
Luo
D000704:Analysis of Variance; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D062507:Claudin-5 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007854:Lead / Q000097:blood / Q000633:toxicity*; D008297:Male; D062793:Occludin / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D000077191:Wortmannin
D000730:Androstadienes; D062507:Claudin-5; D007166:Immunosuppressive Agents; D062793:Occludin; D007854:Lead; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin
Blood-retinal-barrier; Lead; Neurotoxicity; PI3K-Akt; Tight junctions; Vascular permeability