Skip to main content

Advertisement

SpringerLink
Log in

Skeletal toxicity resulting from exposure of growing male rats to coplanar PCB 126 is associated with disruption of calcium homeostasis and the GH-IGF-1 axis and direct effects on bone formation

  • Inorganic Compounds
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Skeletal toxicity has been reported following exposure to polychlorinated biphenyl (PCB) mixtures. However, molecular mechanisms remain poorly understood. We exposed groups of male 4–5-week-old Sprague–Dawley rats to 3,3′, 4, 4′, 5-pentachlorobiphenyl (PCB 126), a dioxin-like coplanar PCB congener by a single i.p. injection of 5 µmol/kg in soy oil vehicle or vehicle alone. After 4 weeks, rats were euthanized. PCB exposure resulted in hypocalcemia (P < 0.05) and significant increases in serum PTH without changes in serum phosphorous. Hyperparathyroidism was accompanied by increased expression of mRNAs of vitamin D3 metabolizing cytochrome P450 enzymes CYP27B1 and CYP24 in the kidney (P < 0.05). PCB exposure also reduced body weight, serum IGF-1, and hepatic expression of mRNAs encoding the male-specific GH-pattern-regulated CYP2C11 and CYP3A2 relative to controls (P < 0.05). PCB exposure reduced long bone length, diameter, and surface area, but increased trabecular thickness and volume (P < 0.05). Serum osteocalcin (P < 0.05), a marker and a regulator of bone formation, was reduced, but PCB exposure had no effect on the bone resorption marker RatLaps. Exposure of human intestinal Caco-2 cells to 10–100 nM PCB 126 in the presence of vitamin D3 resulted in inhibition of mRNAs for the calcium transporters TRPV6 and PMCA1b (P < 0.05). In addition, PCB 126 suppressed osteoblastogenesis in primary bone marrow mesenchymal stem cell cultures which was blunted by the AhR antagonist CH-223191. These data provide novel evidence that skeletal toxicity after exposure to PCB 126 is a result of disruption of calcium homeostasis and the GH-IGF-1 axis, and involves direct AhR-mediated effects on bone formation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Alvarez-Lloret P, Lind PM, Nyberg I, Örberg J, Rodríguez-Navarro AB (2009) Effects of 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) on vertebral bone mineralization and on thyroxin and vitamin D levels in Sprague–Dawley rats. Toxicol Lett 187:63–68

    Article  CAS  PubMed  Google Scholar 

  • Alveblom AK, Rylander L, Johnell O, Hagmar L (2003) Incidence of hospitalized osteoporotic fractures in cohorts with high dietary intake of persistent organochlorine compounds. Int Arch Occup Environ Health 76:246–248

    Article  CAS  PubMed  Google Scholar 

  • Bemis JC, Nazarenko DA, Gasiewicz TA (2005) Coplanar polychlorinated biphenyls activate the aryl hydrocarbon receptor in developing tissues of two TCDD-responsive lacZ mouse lines. Toxicol Sci 87:529–536

    Article  CAS  PubMed  Google Scholar 

  • Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Müller R (2010) Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res 25:1468–1486

    Article  PubMed  Google Scholar 

  • Boverhof DR, Burgoon LD, Tashiro C, Sharratt B, Chittim B, Harkema JR, Mendrick DL, Zacharewski TR (2006) Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague–Dawley rats and C57BL/6 mice. Toxicol Sci 94:398–416

    Article  CAS  PubMed  Google Scholar 

  • Brouwer A (1991) Role of biotransformation in PCB-induced alterations in vitamin A and thyroid hormone metabolism in laboratory and wildlife species. Biochem Soc Trans 19:731–737

    Article  CAS  PubMed  Google Scholar 

  • Chen JR, Singhal R, Lazarenko OP, Liu X, Hogue WR, Badger TM, Ronis MJJ (2008) Short term effects on bone quality associated with consumption of soy protein isolate and other dietary protein sources in rapidly growing female rats. Exp Biol Med 233:1348–1358

    Article  CAS  Google Scholar 

  • Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R (2014) Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 25:2359–2381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Downie DL, Fenge T (2003) Inuit circumpolar conference. northern lights against POPs: combatting toxic threats in the Arctic. McGill-Queens Press, Montreal

    Google Scholar 

  • Fader KA, Nault R, Raehtz S, McCabe LR, Zacharewski TR (2018) 2,3,7,8-Tetrachlorodibenzo-p-dioxin dose-dependently increases bone mass and decreases marrow adiposity in juvenile mice. Toxicol Appl Pharmacol 348:85–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forgacs AL, Dere E, Angrish MM, Zacharewski TR (2013) Comparative analysis of temporal and dose-dependent TCDD-elicited gene expression in human, mouse, and rat primary hepatocytes. Toxicol Sci 133:54–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gadupudi GS, Gourronc FA, Ludewig G, Robertson LW, Klingelhutz AJ (2015) PCB126 inhibits adipogenesis of human preadipocytes. Toxicol In Vitro 29:132–141

    Article  CAS  PubMed  Google Scholar 

  • Gadupudi GS, Klaren WD, Olivier AK, Klingelhutz AJ, Robertson LW (2016) PCB 126-Induced disruption in gluconeogenesis and fatty acid oxidation precedes fatty liver in male rats. Toxicol Sci 149:98–110

    Article  CAS  PubMed  Google Scholar 

  • Gadupudi GS, Elser BA, Sandgruber FA, Li X, Gibson-Corley KN, Robertson LW (2018) PCB 126 inhibits the activation of AMPK-CREB signal transduction required for energy sensing in liver. Toxicol Sci 163:440–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glynn AW, Michaëlsson K, Lind PM, Wolk A, Aune M, Atuma S, Darnerud PO, Mallmin H (2000) Organochlorines and bone mineral density in Swedish men from the general population. Osteoporos Int 11:1036–1042

    Article  CAS  PubMed  Google Scholar 

  • Goltzman D, Hendy GN (2015) The calcium-sensing receptor in bone–mechanistic and therapeutic insights. Nat Rev Endocrinol 11:298–307

    Article  CAS  PubMed  Google Scholar 

  • Gregory CA, Gunn WG, Peister A, Prockop DJ (2004) An alizarin red-based assay of mineralization by adherent cells in culture: comparison with cetylpyridinium chloride extraction. Anal Biochem 329:77–84

    Article  CAS  PubMed  Google Scholar 

  • Harrill JA, Hukkanen RR, Lawson M, Martin G, Gilger B, Soldatow V, Lecluyse EL, Budinsky RA, Rowlands JC, Thomas RS (2013) Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice. Toxicol Appl Pharmacol 272:503–518

    Article  CAS  PubMed  Google Scholar 

  • Iqbal J, Sun L, Cao J, Yuen T, Lu P, Bab I, Leu NA, Srinivasan S, Wagage S, Hunter CA, Nebert DW, Zaidi M, Avadhani NG (2013) Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes. Proc Natl Acad Sci USA 110:11115–11120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jämsä T, Viluksela M, Tuomisto J, Tuomisto J, Juha T (2001) Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on bone in two rat strains with different aryl hydrocarbon receptor structures. J Bone Miner Res 16:1812–1820

    Article  PubMed  Google Scholar 

  • Korkalainen M, Kallio E, Olkku A, Nelo K, Ilvesaro J, Tuukkanen J, Mahonen A, Viluksela M (2009) Dioxins interfere with differentiation of osteoblasts and osteoclasts. Bone 44:1134–1142

    Article  CAS  PubMed  Google Scholar 

  • Kovalova N, Nault R, Crawford R, Zacharewski TR, Kaminski NE (2017) Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells. Toxicol Appl Pharmacol 316:95–106

    Article  CAS  PubMed  Google Scholar 

  • Krishnan V, Safe S (1993) Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs) as antiestrogens in MCF-7 human breast cancer cells: quantitative structure-activity relationships. Toxicol Appl Pharmacol 120:55–61

    Article  CAS  PubMed  Google Scholar 

  • Lai I, Chai Y, Simmons D, Luthe G, Coleman MC, Spitz D, Haschek WM, Ludewig G, Robertson LW (2010) Acute toxicity of 3,3’,4,4’,5-pentachlorobiphenyl (PCB 126) in male Sprague–Dawley rats: effects on hepatic oxidative stress, glutathione and metals status. Environ Int 36:918–923

    Article  CAS  PubMed  Google Scholar 

  • Lai IK, Klaren WD, Li M, Wels B, Simmons DL, Olivier AK, Haschek WM, Wang K, Ludewig G, Robertson LW (2013) Does dietary copper supplementation enhance or diminish PCB 126 toxicity in the rodent liver? Chem Res Toxicol 26:634–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lind PM, Larsson S, Johansson S, Melhus H, Wikström M, Lindhe Ö, Orberg J (2000a) Bone tissue composition, dimensions and strength in female rats given an increased dietary level of vitamin A or exposed to 3,3’,4,4’,5-pentachlorobiphenyl (PCB 126) alone or in combination with vitamin C. Toxicology 151:11–23

    Article  CAS  PubMed  Google Scholar 

  • Lind PM, Larsson S, Oxlund H, Hakansson H, Nyberg K, Eklund T, Orberg J (2000b) Change of bone tissue composition and impaired bone strength in rats exposed to 3,3’,4,4’,5-pentachlorobiphenyl (PCB 126). Toxicology 150:41–51

    Article  CAS  PubMed  Google Scholar 

  • Lind PM, Örberg J, Edlund UB, Sjöblom L, Lind L (2004) The dioxin-like pollutant PCB 126 (3,3′,4,4′,5- pentachlorobiphenyl) affects risk factors for cardiovascular disease in female rats. Toxicol Lett 150:293–299

    Article  CAS  PubMed  Google Scholar 

  • Moore RW, Parsons JA, Bookstaff RC, Peterson RE (1989) Plasma concentrations of pituitary hormones in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated male rats. J Biochem Toxicol 4:165–172

    Article  CAS  PubMed  Google Scholar 

  • Moyer BJ, Rojas IY, Kerley-Hamilton JS, Hazlett HF, Nemani KV, Trask HW, West RJ, Lupien LE, Collins AJ, Ringelberg CS, Gimi B, Kinlaw WB 3rd, Tomlinson CR (2016) Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1. Toxicol Appl Pharmacol 300:13–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamichi Y, Udagawa N, Horib K, Mizoguchi T, Yamamoto Y, Nakamura T, Hosoya A, Kato S, Suda T, Takahashi N (2017) VDR in osteoblast-lineage cells primarily mediates vitamin D treatment-induced increase in bone mass by suppressing bone resorption. J Bone Miner Res 32:1297–1308

    Article  CAS  PubMed  Google Scholar 

  • Nishimura N, Nishimura H, Ito T, Miyata C, Izumi K, Fujimaki H, Matsumura F (2009) Dioxin-induced up-regulation of the active form of vitamin D is the main cause for its inhibitory action on osteoblast activities, leading to developmental bone toxicity. Toxicol Appl Pharmacol 236:301–309

    Article  CAS  PubMed  Google Scholar 

  • Pavuk M, Olson JR, Sjödin A, Wolff P, Turner WE, Shelton C, Dutton ND, Bartell S (2014) Serum concentrations of polychlorinated biphenyls (PCBs) in participants of the Anniston Community Health Survey. Sci Total Environ 473–474:286–297

    Article  PubMed  CAS  Google Scholar 

  • Peacock M (2010) Calcium metabolism in health and disease. Clin J Am Soc Nephrol 5:23–30

    Article  CAS  Google Scholar 

  • Poole KES, Compston JE (2006) Osteoporosis and its management. BMJ 333:1251–1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rasinger JD, Carroll TS, Lundebye AK, Hogstrand C (2014) Cross-omics gene and protein expression profiles in juvenile female mice highlights disruption of calcium and zinc signaling in the brain following dietary exposure to CB-153, BDE-47, HBCD or TCDD. Toxicology 321:1–12

    Article  CAS  PubMed  Google Scholar 

  • Ryan EP, Holz JD, Mulcahey M, Sheu T-J, Gasiewicz TA, Puzas JE (2007) Environmental toxicants may modulate osteoblast differentiation by a mechanism involving the aryl hydrocarbon receptor. J Bone Miner Res 22:1571–1580

    Article  CAS  PubMed  Google Scholar 

  • Sebastian EM, Suva LJ, Friedman PA (2008) Differential effects of intermittent PTH (1–34) and PTH (7–34) on bone microarchitecture and aortic calcification in experimental renal failure. Bone 43:1022–1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seeman E (2002) Pathogenesis of bone fragility in women and men. Lancet 359:1841–1850

    Article  PubMed  Google Scholar 

  • Suva LJ, Hartman E, Dilley JD, Russell S, Akel NS, Skinner RA, Hogue WR, Budde U, Varughese KI, Kanaji T, Ware J (2008) Platelet dysfunction and a high bone mass phenotype in a murine model of platelet-type von Willebrand disease. Am J Pathol 172:430–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanabe S (1988) PCB problems in the future: Foresight from current knowledge. Environ Pollut 50:5–28

    Article  CAS  PubMed  Google Scholar 

  • Waxman DJ, O'Connor C (2006) Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol 20:2613–2629

    Article  CAS  PubMed  Google Scholar 

  • Weaver CM, Gordon CM, Janz KF, Kalkwarf HJ, Lappe JM, Lewis R, O'Karma M, Wallace TC, Zemel BS (2016) The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. Osteoporos Int 27:1281–1386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winneke G, Walkowiak J, Lilienthal H (2002) PCB-induced neurodevelopmental toxicity in human infants and its potential mediation by endocrine dysfunction. Toxicology 181–182:161–165

    Article  PubMed  Google Scholar 

  • Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, Dawson-Hughes B (2014) The recent prevalence of osteoporosis and low bone mass in the united states based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res 29:2520–2526

    Article  PubMed  Google Scholar 

  • Xue Y, Xiao Y, Liu J, Karaplis AC, Pollak MR, Brown EM, Miao D, Goltzman D (2012) The calcium-sensing receptor complements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice. Am J Physiol Endocrinol Metab 302:E841–E851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yakar S, Isaksson O (2015) Regulation of skeletal growth and mineral aquisition by the GH/IGF-1 axis : lessons from mouse models. Growth Horm IGF Res 28:26–42

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yu H, Du Y, Zhang X, Sun Y, Li S, Dou Y, Li Z, Yuan H, Zhao W (2014a) The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway. Toxicol Appl Pharmacol. 280:502–510

    Article  CAS  PubMed  Google Scholar 

  • Yu TY, Kondo T, Matsumoto T, Fujii-Kuriyama Y, Imai Y (2014b) Aryl hydrocarbon receptor catabolic activity in bone metabolism is osteoclast dependent in vivo. Biochem Biophys Res Commun 450:416–422

    Article  CAS  PubMed  Google Scholar 

  • Zierold C, Mings JA, DeLuca HF (2003) Regulation of 25-hydroxyvitamin D3–24-hydroxylase mRNA by 1,25-dihydroxyvitamin D3 and parathyroid hormone. J Cell Biochem 88:234–237

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Dr. Kim Pedersen for his insightful comments on the manuscript.

Funding

This work was supported in part by National Institute of Environmental Health Sciences (P42 ES013661) awarded to L.W.R., National Institute on Alcohol Abuse and Alcoholism (R37 AA018282 and F32 AA024680) awarded to M.J.R. and J.W., respectively, The National Institute of General Medicine (R25 GM12189) funded LSUHSC-New Orleans Post-baccalaureate Research Education Program (PREP) in Biomedical Sciences and the Iowa Superfund Training Core. The opinions expressed are solely those of the authors.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center-New Orleans, 1901 Perdido Str., New Orleans, LA, 70112, USA

    Martin J. Ronis, James Watt, Casey F. Pulliam & Ashlee E. Williams

  2. Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Alexander W. Alund

  3. IDGP in Human Toxicology and Department of Occupational and Environmental Health, University of Iowa, Iowa City, IA, USA

    Ezazul Haque, Gopi S. Gadupudi & Larry W. Robertson

Authors
  1. Martin J. Ronis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James Watt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Casey F. Pulliam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ashlee E. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alexander W. Alund
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ezazul Haque
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gopi S. Gadupudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Larry W. Robertson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin J. Ronis.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ronis, M.J., Watt, J., Pulliam, C.F. et al. Skeletal toxicity resulting from exposure of growing male rats to coplanar PCB 126 is associated with disruption of calcium homeostasis and the GH-IGF-1 axis and direct effects on bone formation. Arch Toxicol 94, 389–399 (2020). https://doi.org/10.1007/s00204-019-02645-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-019-02645-w

Keywords

Search

Navigation