Mechanisms of polyhalogenated biphenyl enhancement of endotoxicity

Thesis/Dissertation · Fri Jan 01 04:00:00 EST 1993

OSTI ID:6519551

Hoglen, N C

Polyhalogenated aromatic hydrocarbons (PHAHs) are a class of environmental contaminants that can produce a number of toxic responses. Many of their toxicities are thought to be mediated by a cytosolic receptor called the aryl hydrocarbon (Ah) receptor. Among the most toxic compounds in this class, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3,3[prime],4,4[prime]-tetrabromobiphenyl (TBB), have been shown to markedly increase the sensitivity of rodents to lipopolysaccharide (LPS)-mediated hepatotoxicity and lethality. The purpose of this study was to define what mechanisms are involved in PHAH-enhancement of endotoxicity and hepatotoxicity using TBB and a related PHAH, 3,3[prime],4,4[prime],5-pentachlorobiphenyl (PeCB). A number of findings were demonstrated. First, it was confirmed that TBB markedly enhanced LPS-mediated hepatotoxicity and lethality, and this enhancement was greatest when LPS was administered one day after the PHAH. In addition, the TBB markedly elevated peak serum activity of tumor necrosis factor (TNF), a cytotoxic cytokine produced by macrophages after LPS exposure. However, increased TNF after LPS was seen at all time points after TBB treatment. Dexamethasone blocked both increased TNF production and hepatotoxicity. PeCB also markedly enhanced LPS-mediated hepatotoxicity/lethality with similar increases in TNF. In addition to increasing TNF, it was demonstrated that PeCB could sensitize the liver to TNF hepatotoxicity. Studies using 3-methylcholanthrene (3MC), a compound that binds as avidly to the Ah receptor as the PeCB, found no enhancement of endotoxicity, suggesting that Ah receptor activation alone does not mediate PHAH enhancement. 3MC did, however, increase LPS-stimulated serum TNF levels. 2,2[prime],4,4[prime],5,5[prime]-Hexachlorobiphenyl, a PHAH that does not bind to the Ah receptor, did not enhance endotoxicity or TNF production.

• Research Organization: Kentucky Univ., Lexington, KY (United States)
• OSTI ID: 6519551
• Country of Publication: United States
• Language: English

Related Subjects

3-METHYLCHOLANTHRENE
550200 -- Biochemistry
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADRENAL HORMONES
ANIMAL CELLS
ANTIGENS
AROMATICS
BIOLOGICAL PATHWAYS
BIPHENYL
BODY
CARBOHYDRATES
CONDENSED AROMATICS
CONNECTIVE TISSUE CELLS
CORTICOSTEROIDS
DEXAMETHASONE
DIGESTIVE SYSTEM
DIOXIN
DRUGS
ENDOTOXINS
GLANDS
GLUCOCORTICOIDS
GLUTATHIONE
HAZARDOUS MATERIALS
HETEROCYCLIC COMPOUNDS
HORMONES
HYDROCARBONS
HYDROXY COMPOUNDS
KETONES
LIPIDS
LIPOPOLYSACCHARIDES
LIVER
MACROPHAGES
MATERIALS
NECROSIS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
PEPTIDES
PHAGOCYTES
POLYCYCLIC AROMATIC HYDROCARBONS
POLYPEPTIDES
POLYSACCHARIDES
PREGNANES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
SACCHARIDES
SOMATIC CELLS
STEROID HORMONES
STEROIDS
TOXIC MATERIALS
TOXICITY
TOXINS