Maternal Exposure to Benzo[A]Pyrene Alters Development of T Lymphocytes in Offspring

Abstract

Childhood cancer has been increasing significantly over the past two decades in the United States, suggesting that environmental exposures may be playing a causative role. One such cause may be maternal smoking during pregnancy. Suspected carcinogens in cigarette smoke and environmental pollution include N-nitrosamines and polycyclic aromatic hydrocarbons, which may be several micrograms per exposure. Previously, we have shown that mouse progeny of mothers exposed to benzo[a]pyrene (B[a]P) during midpregnancy had abnormalities in their humoral and cell-mediated immune response. Immunodeficiency was detectable during gestation, at one week after birth and persisted for 18 months. Tumor incidences in progeny were eight to 10-fold higher than in controls. The present study compared frequencies of CD4+, CD8+, V gamma 2+, and V beta 8+ T cells in progeny following in utero exposure to B[a]P. The significant reduction in newborn CD4+CD8+, CD4+CD8+V beta 8+ thymocytes and CD4+ splenocytes from 1-week-old progeny, suggests that B[a]P induces abnormal changes in developing T cells. These early alterations may lead to postnatal T cell suppression, thus providing a more suitable environment for the growth of tumors later in life. These results suggest that developmental immunosuppression mediated by B[a]P may play a critical role in the relationship between maternal exposures and childhood carcinogenesis.

Molecular interactions between the Wilms' tumor transcription factor and the aryl hydrocarbon receptor during nephrogenesis and its impact on fetal programming of renal disease.

“…Similarly, studies examining the embryotoxicity and teratogenicity of PAH compounds focused on overt developmental differences (Lummus and Henningsen, 1995;MacKenzie and Angevine, 1981 a;Peters et al, 1999a;Rodriquez et al, 1999;Winn and Wells, '1997) Our findings of modest changes in glomerular number, urinary albumin, and podocyte number in response to PAH exposure highlight the need to reevaluate endpoints for developmental deficits and measure subtle effects which are a better estimate of human environmental exposure and risk of renal disease. Novel renal biomarkers such as RPA 1, GSTYb1, and GSTMu are designed to detect nephropathy with more sensitivity than conventional methods (Falkenberg et al, 1996;Hildebrand et al, 1999;Kilty et aI., 1998).…”

“…Classical studies establishing PAHs as known embryotoxic and teratogenic agents used dosages of BaP ranging from 1 0 mg/kg to 250 mg/kg, thus far exceedin~1 even that of the highest possible human exposure (Lummus and Henningsen, 1995;MacKenzie and Angevine, 1981 a;Rodriquez et al, 1999; Wells et a/., 1997; Winn and Wells, 1997).…”

“…Extensive in utero exposure studies have identified PAHs as potent modulators of fetal development that exert teratogenic and embryotoxic effects, (Lummus and Henningsen, 1995;MacKenzie and Angevine, 1981 a;Rodriquez et al, 1999;Wells et aI., 1997;Winn and Wells, 1997). However, the subtle effects stemming from environmentally relevant Goncentrations of PAHs have yet not being characterized.…”

“…To ascertain whether our in vitro model of AHR dependent BaP-induced deficits in nephrogenesis correlated to effects obtained from environmentally relevant PAH exposure we chose concentrations considerably lower than those established for in utero toxicity and teratogenicity (Lummus and Henningsen, 1995;MacKenzie and Angevine, 1981 a;Rodriquez et al, 1999;Wells et aI., 1997;Winn and Wells, 1997). When normalized for species-dependent temporal difference~s in development, this exposure is representative of human exposures of at risk populations (Menzie et aI., 1992a: Menzie et aI., 1992bRebagliato et aI., 1995).…”

“…PAH exposure during critical windows of fetal development exhibit teratogenic and embryotoxic effects (Lummus and Henningsen, 1995;MacKenzie and Angevine, 1981a;Rodriquez et al, 1999; Winn and Wells, 1997). Murine in utero exposure of 150 mg/kg BaP causes T cell deficiencies in offspring (Lummus and Henningsen, 1995).…”