Cell death mechanisms in GT1-7 GnRH cells exposed to polychlorinated biphenyls PCB74, PCB118, and PCB153

Abstract

Exposure to endocrine-disrupting chemicals (EDCs) such as polychlorinated biphenyls (PCBs) causes functional deficits in neuroendocrine systems. We used an immortalized hypothalamic GT1-7 cell line, which synthesizes the neuroendocrine peptide gonadotropin-releasing hormone (GnRH), to examine the neurotoxic and endocrine disrupting effects of PCBs and their mechanisms of action. Cells were treated for 1, 4, 8, or 24 h with a range of doses of a representative PCB from each of three classes: coplanar (2,4,4′,5-tetrachlorobiphenyl: PCB74), dioxin-like coplanar (2′,3,4,4′,5′ pentachlorobiphenyl: PCB118), non-coplanar (2,2′,4,4′,5,5′-hexachlorobiphenyl: PCB153), or their combination. GnRH peptide concentrations, cell viability, apoptotic and necrotic cell death, and caspase activation were quantified. In general, GnRH peptide levels were suppressed by high doses and longer durations of PCBs, and elevated at low doses and shorter time points. The suppression of GnRH peptide levels was partially reversed in cultures co-treated with the estrogen receptor antagonist ICI 182,780. All PCBs reduced viability and increased both apoptotic and necrotic cell death. Although the effects for the three classes of PCBs were often similar, subtle differences in responses, together with evidence that the combination of PCBs acted slightly differently from individual PCBs, suggest that the three tested PCB compounds may act via slightly different or more than one mechanism. These results provide evidence that PCB congeners have endocrine disrupting and/or neurotoxic effects on the hypothalamic GnRH cell line, a finding that has implications for environmental endocrine disruption in animals.

Neuroendocrine targets of endocrine disruptors

“…With higher dosages and longer treatment durations, GnRH peptide concentrations were decreased. In general, cellular viability was diminished following PCB treatments in a manner that involved both apoptosis (lower concentrations) and necrosis (higher concentrations) 47. These results show that PCBs can impair viability in the GnRH cell line.…”

“…GT1-7 cells were treated with individual PCBs (PCB 74, 118 or 153) or a mixture of the three. Effects on GnRH peptide levels, cell viability and death, and the mechanism for cell death (apoptosis or necrosis) were quantified 47. At low dosages and short time points, GnRH peptide levels were higher than controls.…”

An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors

“…Numerous modes of action have been described that may contribute to neurotoxicity. This includes altered neurotransmitter signaling (Fonnum and Mariussen, 2009;Mariussen and Fonnum, 2001;Wigestrand et al, 2013), altered GABA A receptor activity (Fernandes et al, 2010), altered Ca 2þ homeostasis through several mechanisms (Choi et al, 2016;Gafni et al, 2004;Kodavanti and Tilson, 1997;Pessah et al, 2010;Westerink, 2014), induced reactive oxygen species (Stenberg et al, 2011), altered cell viability (Dickerson et al, 2009), and alterations of neuro/endocrine processes (Bell, 2014;Fonnum and Mariussen, 2009;Kodavanti and Curras-Collazo, 2010). Of the modes identified, a particularly sensitive endpoint is the ability of NDL PCBs to enhance the activity of ryanodine sensitive Ca 2þ channels embedded in the sarco/endoplasmic reticulum (SR/ER), namely, the ryanodine receptor (RyR), in both mammals (Pessah et al, 2006) and fish (Fritsch and Pessah, 2013).…”

Endocrine-disrupting actions of PCBs on brain development and social and reproductive behaviors

“…A1254 and specific DL and NDL congeners caused an increase and then decrease of GnRH mRNA expression and peptide in hypothalamic GT1-7 cells as dose and duration of treatment increased, suggestive of a non-monotonic dose-response curve in vitro [55,56]. The PCB-suppression of GnRH peptide release was prevented by co-treatment with an ER antagonist, indicating PCB action at the ER on these cells [56]. Finally, the same NDL and DL congeners also increased apoptosis in the GnRH cells in an inverse U curve, with 0.1uM and 1uM having greater effects than higher doses [56].…”

“…The PCB-suppression of GnRH peptide release was prevented by co-treatment with an ER antagonist, indicating PCB action at the ER on these cells [56]. Finally, the same NDL and DL congeners also increased apoptosis in the GnRH cells in an inverse U curve, with 0.1uM and 1uM having greater effects than higher doses [56]. The micromolar doses used in these two studies were relevant to human exposures, as PCBs have been found at levels of 50 ppb in neonatal human brains [57].…”