Cylindrospermopsin toxicity in mice following a 90-d oral exposure.

Cylindrospermopsin (CYN) is a toxin associated with numerous species of freshwater cyanobacteria throughout the world. It is postulated to have caused an episode of serious illnesses in Australia through treated drinking water, as well as lethal effects in livestock exposed to water from farm ponds. Toxicity included effects indicative of both hepatic and renal dysfunction. In humans, symptoms progressed from initial hepatomegaly, vomiting, and malaise to acidosis and hypokalemia, bloody diarrhea, and hyperemia in mucous membranes. Laboratory animal studies predominantly involved the intraperitoneal (i.p.) route of administration and confirmed this pattern of toxicity with changes in liver enzyme activities and histopathology consistent with hepatic injury and adverse renal effects. The aim of this study was designed to assess subchronic oral exposure (90 d) of purified CYN from 75 to 300 µg/kg/d in mouse. At the end of the dosing period, examinations of animals noted (1) elevated organ to body weight ratios of liver and kidney at all dose levels, (2) treatment-related increases in serum alanine aminotransferase (ALT) activity, (3) decreased blood urea nitrogen (BUN) and cholesterol concentrations in males, and (4) elevated monocyte counts in both genders. Histopathological alterations included hepatocellular hypertrophy and cord disruption in the liver, as well as renal cellular hypertrophy, tubule dilation, and cortical tubule lesions that were more prominent in males. A series of genes were differentially expressed including Bax (apoptosis), Rpl6 (tissue regeneration), Fabp4 (fatty acid metabolism), and Proc (blood coagulation). Males were more sensitive to many renal end points suggestive of toxicity. At the end of exposure, toxicity was noted at all dose levels, and the 75 µg/kg group exhibited significant effects in liver and kidney/body weight ratios, reduced BUN, increased serum monocytes, and multiple signs of histopathology indicating that a no-observed-adverse-effect level could not be determined for any dose level.

A critical review of the postulated role of the non-essential amino acid, ß-N-methylamino-L-alanine, in neurodegenerative disease in humans.

The compound BMAA (ß-N-methylamino-L-alanine) has been postulated to play a significant role in four serious neurological human diseases: Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) found on Guam, and ALS, Parkinsonism, and dementia that occur globally. ALS/PDC with symptoms of all three diseases first came to the attention of the scientific community during and after World War II. It was initially associated with cycad flour used for food because BMAA is a product of symbiotic cycad root-dwelling cyanobacteria. Human consumption of flying foxes that fed on cycad seeds was later suggested as a source of BMAA on Guam and a cause of ALS/PDC. Subsequently, the hypothesis was expanded to include a causative role for BMAA in other neurodegenerative diseases including Alzheimer's disease (AD) through exposures attributed to proximity to freshwaters and/or consumption of seafood due to its purported production by most species of cyanobacteria. The hypothesis that BMAA is the critical factor in the genesis of these neurodegenerative diseases received considerable attention in the medical, scientific, and public arenas. This review examines the history of ALS/PDC and the BMAA-human disease hypotheses; similarities and differences between ALS/PDC and the other diseases with similar symptomologies; the relationship of ALS/PDC to other similar diseases, studies of BMAA-mediated effects in lab animals, inconsistencies and data gaps in the hypothesis; and other compounds and agents that were suggested as the cause of ALS/PDC on Guam. The review concludes that the hypothesis of a causal BMAA neurodegenerative disease relationship is not supported by existing data.

Metabolism of the environmental toxicant benzo(a)pyrene by subcellular fractions of human ovary.

Knowledge of the ability of the female reproductive system to metabolize environmental chemicals is critical not only from the standpoint of toxicity but also from infertility risk assessment. Benzo(a)pyrene (BaP) is a toxicant that is released into the environment from automobile exhausts, cigarette smoke, burning of refuse, industrial emissions, and hazardous waste sites. In exposed animals, BaP becomes activated to reactive metabolites that interfere with target organ function and as a consequence cause toxicity. Studies on animal models conducted in our laboratories and those of others have shown that BaP possess endocrine disrupting properties. Thus, this chemical has the potential to cause infertility and cancers in the female genital tract. An understanding of BaP metabolism in the female reproductive system will be of importance in the diagnosis and management of female fertility as well as cancers in the reproductive tissues. Therefore, the objective of our study was to examine the metabolism of BaP by human ovarian subcellular fractions. Human ovary samples (eight individuals) were obtained from postoperative tissue removed from subjects with uterine tumors. Subcellular fractions (nuclear, cytosolic, mitochondrial, and microsomal) were prepared by differential centrifugation. BaP (1 µM and 3 µM) was individually incubated with individual subcellular fractions for 15 min and the products were analyzed by high-performance liquid chromatography. Among the different fractions tested, microsomal BaP metabolism was higher than the rest of the fractions. The BaP metabolites identified were as follows: BaP-9,10-diol, BaP-4,5-diol, BaP-7,8-diol, 9(OH) BaP, 3(OH) BaP, BaP-1,6-dione, BaP-3,6-dione, and BaP-6,12-dione. Of interest was the presence of DNA-reactive metabolites such as BaP-3,6-dione, BaP-6,12-dione, and BaP 7,8-diol, which have been implicated in the causation of infertility and cancer. Our results indicate that women who are exposed to BaP via cigarette smoke, occupational settings, and diet are more likely at a larger risk of this toxicant-induced infertility and cancer than others.