Dose-dependent incidence of hepatic tumors in adult mice following perinatal exposure to bisphenol A.

BACKGROUND: Bisphenol A (BPA) is a high production volume chemical with hormone-like properties that has been implicated as a potential carcinogen. Early-life exposure has been linked to increased risk for precancerous lesions in mammary and prostate glands and the uterus, but no prior study has shown a significant association between BPA exposure and cancer development. OBJECTIVE: We explored the effects of BPA exposure during gestation and lactation on adult incidence of hepatic tumors in mice. METHODS: Isogenic mice were perinatally exposed to BPA through maternal diets containing one of four environmentally relevant doses of BPA (0, 50 ng, 50 µg, or 50 mg per kilogram of diet), and we followed approximately one male and one female per litter until they were 10 months of age. Animals were tested for known risk factors for hepatocellular carcinoma, including bacterial and viral infections. RESULTS: We found dose-dependent incidence of hepatic tumors in 10-month-old BPA-exposed mice. Of the offspring examined, 23% presented with hepatic tumors or preneoplastic lesions. We observed a statistically significant dose-response relationship, with an odds ratio for neoplastic and preneoplastic lesions of 7.23 (95% CI: 3.23, 16.17) for mice exposed to 50 mg BPA/kg diet compared with unexposed controls. Observed early disease onset, absence of bacterial or viral infection, and lack of characteristic sexual dimorphism in tumor incidence support a nonclassical etiology. CONCLUSIONS: To our knowledge, this is the first report of a statistically significant association between BPA exposure and frank tumors in any organ. Our results link early-life exposure to BPA with the development of hepatic tumors in rodents, and have potential implications for human health and disease.

Age-specific locomotor response to nicotine in yellow and mottled yellow A(vy)/a mice.

BACKGROUND: Most Agouti viable yellow (Avy) mice display constitutive expression of agouti protein, which acts as an inverse agonist at the melanocortin receptor 4 (Mc4r), resulting in adult-onset obesity as well as an altered sensitivity to some drugs of abuse. We investigated the influence of excessive agouti expression on open-field locomotor response to daily 0.5 mg/kg (-)-freebase nicotine injections in 27 early adolescent and 27 young adult male Avy/a and a/a mice, and assessed the effects of nicotine administration (0.5 mg/kg) followed by open-field testing on serum corticosterone levels in a separate group of 25 young adult male Avy/a and a/a mice. FINDINGS: Young adult Avy/a mice displayed pronounced nicotine-induced hypolocomotion (a 24% reduction in distance traveled) compared to their a/a littermates. Early adolescent Avy/a mice did not differ from their a/a littermates or saline-matched controls in locomotion following nicotine administration. Young adult Avy/a mice also displayed increased thigmotaxis (a 5% increase in time spent outside the center of the apparatus) on the first day of nicotine administration as compared to saline-matched controls, while a/a mice did not. An increase in serum corticosterone levels 20 minutes after nicotine injection in a separate group of young adult male mice (n = 25) was proportionally similar between Avy/a and a/a mice. CONCLUSIONS: Overall, the results suggest an age- and epigenotype- or genotype-specific response to nicotine administration in young adult male Avy/a mice. It appears the Avy/a locomotor and thigmotaxic responses to acute nicotine administration are not mediated solely by hypothalamic-pituitary-adrenal (HPA) axis stimulation.

Gustatory, trigeminal, and olfactory aspects of nicotine intake in three mouse strains.

Studies of nicotine consumption in rodents often intend to investigate nicotine's post-absorptive effects, yet little is known about the pre-absorptive sensory experience of nicotine drinking, including gustatory, trigeminal, and olfactory influences. We conditioned taste aversion (CTA) to nicotine in males of 3 inbred mouse strains: C57BL/6J, DBA/2J, and 129X1/SvJ by repeatedly pairing 150 µg/ml nicotine drinking with lithium chloride injections. Generalization to a variety of bitter, sour, sweet, salty, and irritant solutions and to nicotine odor was then examined. Nicotine CTA generalized to the bitter stimulus quinine hydrochloride and the chemosensory irritant spilanthol in all strains. It also showed strain specificity, generalizing to hydrogen peroxide (an activator of TRPA1) in C57BL/6J mice and to the olfactory cue of nicotine in DBA/2J mice. These behavioral assays demonstrate that the sensory properties of nicotine are complex and include multiple gustatory, irritant, and olfactory components. How these qualities combine at the level of perception remains to be assessed, but sensory factors clearly exert an important influence on nicotine ingestion and their contribution to net intake of nicotine should not be neglected in animal or human studies.