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

Martin J Ronis; James Watt; Casey F Pulliam; Ashlee E Williams; Alexander W Alund; Ezazul Haque; Gopi S Gadupudi; Larry W Robertson

doi:10.1007/s00204-019-02645-w

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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

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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

Martin J Ronis, James Watt, Casey F Pulliam, Ashlee E Williams, Alexander W Alund, Ezazul Haque, Gopi S Gadupudi and Larry W Robertson

Archives of toxicology, Vol.94(2), pp.389-399

02/2020

DOI: 10.1007/s00204-019-02645-w

PMCID: PMC7047627

PMID: 31820026

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https://www.ncbi.nlm.nih.gov/pmc/articles/7047627View

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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.

Biomarkers - metabolism

Caco-2 Cells

Calcium - metabolism

Growth Hormone - metabolism

Humans

Osteoblasts - drug effects

Osteogenesis - drug effects

Glucuronidase - metabolism

Tibia - diagnostic imaging

Male

Tibia - drug effects

Rats, Sprague-Dawley

beta Catenin - metabolism

TRPV Cation Channels - genetics

Endocrine Disruptors - toxicity

Gene Expression Regulation - drug effects

TRPV Cation Channels - metabolism

Animals

Glucuronidase - genetics

Polychlorinated Biphenyls - toxicity

Tibia - growth & development

Homeostasis - drug effects

Insulin-Like Growth Factor I - metabolism

Details

Title: Subtitle: 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
Creators: Martin J Ronis - Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center-New Orleans, 1901 Perdido Str., New Orleans, LA, 70112, USA. mronis@lsuhsc.edu
James Watt - Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center-New Orleans, 1901 Perdido Str., New Orleans, LA, 70112, USA
Casey F Pulliam - Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center-New Orleans, 1901 Perdido Str., New Orleans, LA, 70112, USA
Ashlee E Williams - Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center-New Orleans, 1901 Perdido Str., New Orleans, LA, 70112, USA
Alexander W Alund - Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Ezazul Haque - IDGP in Human Toxicology and Department of Occupational and Environmental Health, University of Iowa, Iowa City, IA, USA
Gopi S Gadupudi - IDGP in Human Toxicology and Department of Occupational and Environmental Health, University of Iowa, Iowa City, IA, USA
Larry W Robertson - IDGP in Human Toxicology and Department of Occupational and Environmental Health, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Archives of toxicology, Vol.94(2), pp.389-399
DOI: 10.1007/s00204-019-02645-w
PMID: 31820026
PMCID: PMC7047627
NLM abbreviation: Arch Toxicol
ISSN: 0340-5761
eISSN: 1432-0738
Publisher: Germany
Grant note: F32 AA024680 / NIAAA NIH HHS R25 GM12189 / National Institute of General Medicine P42 ES007380 / NIEHS NIH HHS P42 ES013661 / NIEHS NIH HHS R25 GM121189 / NIGMS NIH HHS F30 AA024680 / NIAAA NIH HHS R37 AA018282 / NIAAA NIH HHS
Language: English
Date published: 02/2020
Academic Unit: Occupational and Environmental Health; Radiation Oncology; Iowa Superfund Research Program
Record Identifier: 9984066338802771

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