Lindane (Gamma‐Hexachlorocyclohexane) Exposure Impairs [Ca2+]i‐Mediated Vascular Reactivity

Abstract

Gama hexacholorocyclohexane (γHCH; lindane), Gammallin is an organochlorine chemical that has been used as an agricultural insecticide as well as a pharmaceutical treatment for lice and scabies. It is reported to be neurotoxic, interfering with GABA neurotransmitter functions and other biological functions from brain to endocrine and cardiovascular systems. Despite being a banned persistent organic pollutant, it's still in use and can leach and contaminate our foods and water. We have investigated the effects and the mechanism(s) of lindane‐induced vascular dysfunctions in rat aorta. Rats treated with low dose of single pesticide Lindane (100 or 300 μmol/kg;1/5LD50; SP) or multiple pesticides (MP) (aldrin, endosulfan, lindane, 4,4‐DDT, and endrin: 1/100, 1/50, and 1/25 of the LD50, MP) orally or dermal application for 2 or 4 weeks showed significantly attenuated vascular relaxation (57 ± 5% to 36 ± 0.8%; ACh 10−3 M), MP attenuated relaxation (57 ± 5% to 19.8 ±5.8% and 19.0 ±4.0% respectively for 1/100 and 1/25 LD50). Paradoxically, 4 weeks SP enhanced relaxation to ACh (60.5 ± 4.6% to 83.5 ± 8.8%). In aorta from dermal group (SP), relaxation to ACh was significantly attenuated (59.4 ± 5.0 to 23.7 ± 6.0%). Vasoconstriction to PE (10−8 ‐10−3 M) were significantly attenuated by 4 weeks' treatment with oral SP or dermal MP reducing the contraction (0.64±0.06 to 0.15 ± 0.02gm or 0.49±0.01 gm; 10−3 M), but not for 2 weeks oral MP for PE‐induced contraction. Further investigation into the mechanism behind the observed vascular dysfunction reveals that in CHO cell line stably expressing M1‐ACh receptors, Lindane diminishes carbachol (10−8 to 10−3 M)‐induced increases in [Ca2+]i mediated by M1‐ACh receptor. Lindane diminishes Carbachol effects only at Carbachol's maximum activation and these results indicate that the vascular dysfunction by the pesticides could be due to disruption of intracellular Ca2+ regulation. Thus, 24‐hour Lindane exposure facilitates IP3‐mediated [Ca2+]i signaling. Month‐long Lindane exposure induces vascular dysfunction possibly via disruption of IP3‐mediated in [Ca2+]i signaling leading to dysregulated vasoresponsiveness to hormones/neurotransmitters contributing to cardiovascular dysfunctions.Support or Funding InformationThis research was supported by the National Heart, Lung, and Blood Institute (Grants HL03674 and HL070669) and by the use of TSU Research infrastructure support provided by grants G12RR003045 and CO6RR012537 awarded by the National Center for Research Resources, National Institutes of Health (NIH). The G12 program is now a part of the National Institute on Minority Health and Health Disparities (NIMHD) and the C06 program is in the Office of Research Infrastructure Programs in the Office of the Director, NIH.