Biochemical effects induced by the hexachlorocyclohexanes

The hexachlorocyclohexanes (HCHs) are synthetic compounds that have been widely used for the control of pests. The most common HCH isomers are the α-, β, δ-, and γ-HCH. Although they have the same chlorine substitution pattern, the spatial orientation of chlorine atoms is different on each one of them, resulting in unique structures that have distinct molecular properties. Humans are exposed to individual HCH isomers through various routes, including ingestion of contaminated water or food, absorbed through the skin or by inhalation, and because of their liposolubility, these chemicals are mostly stored in fat-containing tissues. The isomer-specific spectrum of biochemical actions for these compounds has been well characterized for different endpoints such as enzyme activation, calcium homeostasis, gap junctional intercellular communication, endocrine disruption, and cancer, among others. The interaction with the GABA receptor has been one of the most extensively studied properties of the HCHs. For instance, γ-HCH acts as a GABA_A channel blocker, whereas α-and β-HCH potentiate GABA-activated currents, all working as allosteric modulators of the receptor. The changes in calcium homeostasis elicited by HCHs are both isomer and cell-type specific. For example, in neurons, both the δ-and γ-isomers of HCH stimulate Ca²⁺ influx through different voltage-gated Ca²⁺ channels. In human neutrophils, α-, δ-, and γ-HCH, but not b-HCH, increase intracellular Ca²⁺ concentrations. This isomer-dependent behavior is also similar to that observed for phospholipase A₂ activation and also correlates with oxidative stress generation. On the other hand, there are several lines of evidence suggesting that HCHs alter genomic integrity, and, therefore, these compounds have been classified as possibly carcinogenic to humans. Finally, HCHs have been reported to be endocrine disrupters. In fact, γ-and β-HCH have been shown to have weak estrogenic activity, and together with the α-and the δ-isomer, also interfere with steroidogenesis. In short, the HCH isomers are good examples of structurally related chemicals, for which the geometrical patterns present in each one of the different conformers create structures that possess specific mechanisms of action and toxicological properties.