PCB153 reduces apoptosis in primary cultures of murine pituitary cells through the activation of NF-κB mediated by PI3K/Akt
Graphical abstract
Introduction
Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants extensively used in the 20th century as dielectric fluids and coolants in electrical apparatuses, and as additives to hydraulic lubricants, carbonless copy paper, and paints (International Agency for Research on Cancer, 2015; Quinete et al., 2014).
Recognition of the detrimental effects of PCBs on health led to the progressive limitation of these substances and ultimately their worldwide ban in 2001. Nevertheless, PCBs remain a threat for living beings due to their chemical stability and the improper disposal of residual sources. This explains the persistence of measurable levels of PCBs in soil, water, and air samples from all over the world (Arinaitwe et al., 2018; Chakraborty et al., 2018; Hens and Hens, 2017; Kolarik et al., 2017; Nøst et al., 2019).
Humans can be exposed to PCBs not only in the workplace or the environment but also, indirectly, by the ingestion of contaminated foods. In fact, PCBs frequently contaminate biological tissues due to their great lipophilicity and tendency to bio-accumulate in the food chain through animal fats (Hens and Hens, 2017; International Agency for Research on Cancer, 2015; Quinete et al., 2014). It is therefore not surprising that traces of PCBs are still even now detected in human tissues and fluids (including milk) (Chen et al., 2017; Lauritzen et al., 2018; Müller et al., 2017; Quinete et al., 2014; van den Berg et al., 2017; Wielsøe et al., 2017).
The biological effects of PCBs are complex and vary according to the structure of the individual congener (i.e., dioxin- and non-dioxin-like PCBs), the dose, and duration of exposure. The response to PCBs also depends on the biological characteristics of the exposed organism (e.g. species, sex, age) or tissue. In humans, PCBs influence the immune, reproductive, nervous, and endocrine systems (International Agency for Research on Cancer, 2015; Quinete et al., 2014). They are also involved in the induction and progression of some cancers and are thus classified as humans carcinogens by the International Agency for Research on Cancer (IARC) (International Agency for Research on Cancer, 2015; Quinete et al., 2014; Zani et al., 2017).
The pituitary is a classic target for PCB toxicity (Brandt, 1975). Most studies have focused on the disruption of the endocrine function, showing that specific PCBs can affect the synthesis and release of pituitary hormones by the interaction with aryl hydrocarbon, estrogen, and thyroid hormone receptor signalling (Bansal and Zoeller, 2008; Bestervelt et al., 1998; Cocchi et al., 2009; Desaulniers et al., 1999; Gauger et al., 2007; Khan and Hansen, 2003; Kitamura et al., 2005; Otake et al., 2007). Together with the modulation of endocrine functions, PCBs have also been associated with effects on the death of pituitary cells, with discrepant results in relation to the specific congener and the type of treated cells (Fortunati et al., 2017; Ghisari and Bonefeld-Jorgensen, 2005; Johansson et al., 2006). In recent years, we have tested the impact of various PCBs on the cell fate of primary cell cultures from the murine pituitary. Our results suggest that the dioxin-like PBCs 77 and 126 do not affect apoptosis. On the other hand, apoptosis was increased or reduced by the non-dioxin-like PCBs 180 and 153 in the pituitary, respectively (Raggi et al., 2016).
PCB153 is currently considered as one of the most persistent PCBs due to its widespread use in the past and its great stability and propensity to bioaccumulate (Center for Disease Control and Prevention, 2018; Kraft et al., 2017; Pavuk et al., 2014). This has led to increasing focus on the biological effects of this congener, highlighting the anti-apoptotic and proliferative effects of PCB153 as indicated by in vivo (Liu et al., 2014; Tharappel et al., 2002) and in vitro studies (Abella et al., 2015; Ferrante et al., 2011; Ptak et al., 2011; Sánchez-Alonso et al., 2003).
The aim of the study was to examine the molecular mechanisms by which PCB153 exerts its anti-apoptotic effects in the murine pituitary. Our results indicated that PCB153 reduce pituitary apoptosis acting by both the death receptors and the mitochondrial pathways. We also found that the PCB153 anti-apoptotic action was induced by the activation of the PI3K/Akt pathway and by an Akt-mediated activation of NF-κB.
Section snippets
Animals
All the procedures were conducted in accordance with EC Directive 86/609/EEC for animal experimentation. The local Committee for Animal Experimentation approved the study protocol prior to its start (protocol n°: 11,033/2017, University of Pisa).
As donors of pituitary tissues, we used male C57BL/6J mice aged from 8 to 12 weeks. The animals were housed in standard cages with free access to water and standard pellet chows. The animal room had controlled conditions with a 12-h light/dark cycle,
PCB153 reduced apoptosis in the pituitary through the intrinsic and extrinsic pathways
Our previous results showed that the non-dioxin-like PCB153 reduced apoptosis in primary cultures of murine pituitary cells by both the intrinsic and extrinsic pathways (Raggi et al., 2016). To confirm our observations, we tested the expression and activity of the executioner caspase−3 and the initiator caspases −8 and −9 in pituitary primary cell cultures which had or had not been treated with PCB153 for 24 h. We observed that the treatment with PCB153 significantly decreased the expression of
Discussion
PCB153 is a persistent contaminant that is ubiquitous in the environment as well as in animal and human samples despite being banned globally in 2001.
Several studies have explored the consequences of PCB153 exposure on human health with a particular focus on reproduction, development and endocrine function. Among its adverse influences, in epidemiological studies PCB153 has also been associated with proliferative and anti-apoptotic effects in cellular models and with an increased risk of some
Conclusions
The study explored the molecular pathways by which PCB153 modulates apoptosis in an in vitro model of the murine pituitary. Our results confirm that low doses of PCB153 (10 μM) reduce apoptosis through both the extrinsic and intrinsic pathways. Exposure to PCB153 activates the PI3K/Akt and Erk1/2 pathways and lowers the level of p38-MAPK and p53/21. The selective inhibition of these pathways suggests that PI3K/Akt mediates the anti-apoptotic effects of PCB153. Lastly, we showed that PI3K/Akt
Fundings
This work was supported by University of Pisa, and MIUR (Italian Ministry of Instruction, University and Research) as a part of a Research Project of National Interest (PRIN) grant 2012 (2010TYCL9B_008) to Fausto Bogazzi. This work was also partly supported by MIUR PRIN Grant (2017YF9FBS) to Francesco Cardarelli. The sponsors have no role in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.
Ethical committee approval
The local Committee for the Animal Experimentation approved the protocol of the study before its start (protocol n°: 11033/2017, University of Pisa).
CRediT authorship contribution statement
Claudio Urbani: Conceptualization, Methodology, Validation, Investigation, Data curation, Writing - original draft, Writing - review & editing, Visualization. Alessandro Mattiello: Conceptualization, Methodology, Software, Formal analysis, Investigation, Data curation, Writing - original draft, Writing - review & editing, Visualization. Gianmarco Ferri: Methodology, Formal analysis, Investigation, Writing - review & editing. Francesco Raggi: Methodology, Validation, Investigation, Resources,
Declaration of competing interest
None.
Acknowledgements
We would thank Prof. Enio Martino for the careful reading of the manuscript. We are also grateful to Dr Silvia Burchielli (Fondazione Toscana Gabriele Monasterio (FTGM), Pisa, Italy) for the precious support for animal handling.
References (71)
- et al.
Non-dioxin-like polychlorinated biphenyls (PCB 101, PCB 153 and PCB 180) induce chondrocyte cell death through multiple pathways
Toxicol. Lett.
(2015) - et al.
PCB153, TCDD and estradiol compromise the benzo[a]pyrene-induced p53-response via FoxO3a
Chem. Biol. Interact.
(2014) - et al.
Prevalence and sources of polychlorinated biphenyls in the atmospheric environment of Lake Victoria, East Africa
Chemosphere
(2018) - et al.
Evidence for ah receptor mediation of increased ACTH concentrations in primary cultures of rat anterior pituitary cells exposed to TCDD
Toxicol. Sci.
(1998) - et al.
PCBs and PCDD/Fs in soil from informal e-waste recycling sites and open dumpsites in India: levels, congener profiles and health risk assessment
Sci. Total Environ.
(2018) - et al.
Persistent organic pollutants in infants and toddlers: relationship between concentrations in matched plasma and faecal samples
Environ. Int.
(2017) - et al.
Relationship between NF-κB, MMP-9, and MICA expression in pituitary adenomas reveals a new mechanism of pituitary adenomas immune escape
Neurosci. Lett.
(2015) - et al.
Chronic treatment with polychlorinated biphenyls (PCB) during pregnancy and lactation in the rat. Part 1: effects on somatic growth, growth hormone-axis activity and bone mass in the offspring
Toxicol. Appl. Pharmacol.
(2009) - et al.
Prenatal PCBs disrupt early neuroendocrine development of the rat hypothalamus
Toxicol. Appl. Pharmacol.
(2011) - et al.
Effects of non-dioxin-like polychlorinated biphenyl congeners (PCB 101, PCB 153 and PCB 180) alone or mixed on J774A.1 macrophage cell line: modification of apoptotic pathway
Toxicol. Lett.
(2011)
Effects of environmental pollutants on signaling pathways in rat pituitary GH3 adenoma cells
Environ. Res.
Impact of environmental chemicals on the thyroid hormone function in pituitary rat GH3 cells
Polychlorinated biphenyls (PCB-153) and (PCB-77) absorption in human liver (HepG2) and kidney (HK2) cells in vitro: PCB levels and cell death
Environ. Int.
Inhibition of the promotion of hepatocarcinogenesis by 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB-153) by the deletion of the p50 subunit of NF-κB in mice
Toxicol. Appl. Pharmacol.
Exposure in utero to 2,2′,3,3′,4,6′-hexachlorobiphenyl (PCB 132) impairs sperm function and alters testicular apoptosis-related gene expression in rat offspring
Toxicol. Appl. Pharmacol.
Cell death mechanisms in AtT20 pituitary cells exposed to polychlorinated biphenyls (PCB 126 and PCB 153) and methylmercury
Toxicol. Lett.
Metastatic function of BMP-2 in gastric cancer cells: the role of PI3K/AKT, MAPK, the NF-ΚB pathway, and MMP-9 expression
Exp. Cell Res.
Ortho-substituted polychlorinated biphenyl (PCB) congeners (95 or 101) decrease pituitary response to thyrotropin releasing hormone
Toxicol. Lett.
Thyroid hormone-like and estrogenic activity of hydroxylated PCBs in cell culture
Toxicology
Laboratory investigation of PCB bake-out from tertiary contaminated concrete for remediation of buildings
Chemosphere
Quantification of all 209 PCB congeners in blood—can indicators be used to calculate the total PCB blood load?
Int. J. Hyg Environ. Health
JNK pathway decreases thyroid hormones via TRH receptor: a novel mechanism for disturbance of thyroid hormone homeostasis by PCB153
Toxicology
The PI3K/Akt and ERK pathways elevate thyroid hormone receptor b 1 and TRH receptor to decrease thyroid hormones after exposure to PCB153 and p , p 0 -DDE
Chemosphere
Coactivation of the PI3K/Akt and ERK signaling pathways in PCB153-induced NF-kB activation and caspase inhibition
Toxicol. Appl. Pharmacol.
Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in human breast milk and associated health risks to nursing infants in Northern Tanzania
Environ. Res.
Time trends of persistent organic pollutants in 30 year olds sampled in 1986, 1994, 2001 and 2007 in Northern Norway: measurements, mechanistic modeling and a comparison of study designs
Environ. Res.
Quantitative imaging assay for NF-kappaB nuclear translocation in primary human macrophages
J. Immunol. Methods
Thyroid hormone status of newborns in relation to in utero exposure to PCBs and hydroxylated PCB metabolites
Environ. Res.
Serum concentrations of polychlorinated biphenyls (PCBs) in participants of the Anniston Community Health
Survey. Sci. Total Environ.
Intestinal exposure to PCB 153 induces inflammation via the ATM/NEMO pathway
Toxicol. Appl. Pharmacol.
Polychlorinated biphenyls (PCBs) exposure and cardiovascular, endocrine and metabolic diseases: a population-based cohort study in a North Italian highly polluted area
Environ. Int.
Temporal trends of polychlorinated biphenyls serum levels in subjects living in a highly polluted area from 2003 to 2015: a follow-up study
Int. J. Hyg Environ. Health
Apoptosis-mediated neurotoxic potential of a planar (PCB 77) and a nonplanar (PCB 153) polychlorinated biphenyl congeners in neuronal cell cultures
Toxicol. Lett.
Regulation of cell proliferation , apoptosis , and transcription factor Activities during the promotion of liver carcinogenesis by polychlorinated biphenyls
Toxicol. Appl. Pharmacol.
Polychlorinated biphenyls-153 induces metabolic dysfunction through activation of ROS/NF-κB signaling via downregulation of HNF1b
Redox Biol
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Present address: Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Savi, 10–56,126 Pisa, Italy.