Polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene (BaP) and 7,12-dimethylbenz(a)anthracene (DMBA), as well as halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8,-tetrachlorodibenzo-rho-dioxin, (TCDD), are important immunotoxicants that are known to be carcinogenic and immunosuppressive in animals, and also likely in humans. Our work has shown that PAHs, PAH-metabolites (PAH-M, and perhaps HAHs, alter Ca2+-dependent signaling pathways associated with T and B cell antigen and mitogen receptor activation of lymphocytes.
In Aim 1, we will further explore mechanisms by which PAHs and some HAHs (TCDD) alter ca2+ homeostasis in human peripheral blood mononuclear cells (HPBMC), as well as certain human B (Daudi), T (HPB- ALL and Jurkat), and monocyte (Monomac) cell lines. We have shown that PAHs activate Src-related protein tyrosine kinases (PTKs), which may indirect due to inhibition of protein tyrosine phosphatases (PTPases, such as CD45). PAHs also inhibit sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) activity. These studies will focus on the effects of PAHs and PAH-M on PTKs, PTPases, and SERCA examined using highly purified (immunoprecipitated) and/or cloned proteins. We will also examine the effects of AHs on channel-mediated Ca2+ influx. We have shown that alpha-napthoflavone, a PR50 inhibitor, reverses the immunotoxity of BaP and DMBA in T cell mitogen-simulated cultures of HPBMC, suggesting that metabolites may be responsible for the immunotoxicity produced by these PAHs. Therefore, an underlying hypothesis in these studies is that oxidative PAH-M may be responsible for attacking sulphydryl-sensitive proteins associated with Ca2+ signaling.
In AIM 2, we will explore the effects of PAH/PAH- M on downstream signaling pathways in B and T cells to determine the significance of Ca2+ signaling on protein kinase C activation and the expression of certain transcription factors (Fos/Jun, NF-kappaB, NF-AT).
In AIM 3, will continue studies on the molecular mechanisms associated with PAH- induced cell death examining HPBMC for DNA strand breaks- repair by the TUNEL assay, as well as p53 and Bc1-2 expression. Finally, in Aim 4 we will assess the role of monocyte and P450 expression by Western blot and RT-PCR methods in subsets of HPBMC and human cell lines (above).

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG4-ALTX-2 (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of New Mexico
Schools of Pharmacy
United States
Zip Code
Li, Qian; Lauer, Fredine T; Liu, Ke Jian et al. (2010) Low-dose synergistic immunosuppression of T-dependent antibody responses by polycyclic aromatic hydrocarbons and arsenic in C57BL/6J murine spleen cells. Toxicol Appl Pharmacol 245:344-51
Mitchell, L A; Lauer, F T; Burchiel, S W et al. (2009) Mechanisms for how inhaled multiwalled carbon nanotubes suppress systemic immune function in mice. Nat Nanotechnol 4:451-6
Gao, Jun; Mitchell, Leah A; Lauer, Fredine T et al. (2008) p53 and ATM/ATR regulate 7,12-dimethylbenz[a]anthracene-induced immunosuppression. Mol Pharmacol 73:137-46
Burchiel, Scott W; Thompson, Todd A; Lauer, Fredine T et al. (2007) Activation of dioxin response element (DRE)-associated genes by benzo(a)pyrene 3,6-quinone and benzo(a)pyrene 1,6-quinone in MCF-10A human mammary epithelial cells. Toxicol Appl Pharmacol 221:203-14
Burchiel, Scott W; Lauer, Fredine T; Dunaway, Sandy L et al. (2005) Hardwood smoke alters murine splenic T cell responses to mitogens following a 6-month whole body inhalation exposure. Toxicol Appl Pharmacol 202:229-36
Gao, Jun; Lauer, Fredine T; Dunaway, Sandy et al. (2005) Cytochrome P450 1B1 is required for 7,12-dimethylbenz(a)-anthracene (DMBA) induced spleen cell immunotoxicity. Toxicol Sci 86:68-74
Burchiel, Scott W; Lauer, Fredine T; McDonald, Jacob D et al. (2004) Systemic immunotoxicity in AJ mice following 6-month whole body inhalation exposure to diesel exhaust. Toxicol Appl Pharmacol 196:337-45
Kepley, Christopher L; Lauer, Fredine T; Oliver, Janet M et al. (2003) Environmental polycyclic aromatic hydrocarbons, benzo(a) pyrene (BaP) and BaP-quinones, enhance IgE-mediated histamine release and IL-4 production in human basophils. Clin Immunol 107:10-9
Reed, Matthew; Monske, Michael; Lauer, Fredine et al. (2003) Benzo[a]pyrene diones are produced by photochemical and enzymatic oxidation and induce concentration-dependent decreases in the proliferative state of human pulmonary epithelial cells. J Toxicol Environ Health A 66:1189-205
Burchiel, S W; Luster, M I (2001) Signaling by environmental polycyclic aromatic hydrocarbons in human lymphocytes. Clin Immunol 98:2-10

Showing the most recent 10 out of 20 publications