Modulation of benzo[a]pyrene induced neurotoxicity in female mice actively immunized with a B[a]P-diphtheria toxoid conjugate

Abstract

Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also neurotoxic for mammalian species. To develop a prophylactic immune strategy against detrimental effects of B[a]P, female Balb/c mice immunized with a B[a]P-diphtheria toxoid (B[a]P-DT) conjugate vaccine were sub-acutely exposed to 2mg/kg B[a]P and behavioral performances were monitored in tests related to learning and memory, anxiety and motor coordination. mRNA expression of the NMDA receptor (NR1, 2A and 2B subunits) involved in the above behavioral functions was measured in 5 brain regions. B[a]P induced NMDA1 expression in three (hippocampus, amygdala and cerebellum) of five brain regions investigated, and modulated NMDA2 in two of the five brain regions (frontal cortex and cerebellum). Each one of these B[a]P-effects was reversed in mice that were immunized against this PAH, with measurable consequences on behavior such as anxiety, short term learning and memory. Thus active immunization against B[a]P with a B[a]P-DT conjugate vaccine had a protective effect and attenuated the pharmacological and neurotoxic effects even of high concentrations of B[a]P.

Keywords: B[a]P; B[a]P-BA; Benzo[a]pyrene; Benzo[a]pyrenyl Butyric Acid; CFA; Cyp1a1; Cyp1b1; Cytochrome P450; Cytochrome P450, family 1 subfamily B, polypeptide 1; Cytochrome P450, family 1, subfamily A, polypeptide 1; DT; IFA; Immunization; MW; N-methyl-d-aspartate; NMDA; NMDA receptor; Neurotoxicity; PAHs; RT; SE; complete Freund's adjuvant; diphtheria toxoid; incomplete Freund's adjuvant; intraperitoneal; ip; molecular weight; n.s.; not significant; polycyclic aromatic hydrocarbons; room temperature; standard error.