Florida red tides are a natural phenomenon caused by dense aggregations of single cell or several species of unicellular organisms. Patches of discolored water, dead or dying fish, and respiratory irritants in the air often characterize these algal blooms. In humans, two distinct clinical entities, depending on the route of exposure, are associated with exposure to the Florida red tide toxins (particularly the brevetoxins). With the ingestion of brevetoxin-contaminated shellfish, neurotoxic shellfish poisoning (NSP) presents as a milder gastroenteritis with neurologic symptoms compared with other marine toxin diseases such as paralytic shellfish poisoning (PSP) or ciguatera fish poisoning. With the inhalation of the aerosolized red tide toxins (especially the brevetoxins) from the sea spray, respiratory irritation and possibly other health effects are reported in both humans and other mammals (Baden 1995, Fleming 1998a, Fleming 1998b, Fleming 1999a, Bossart 1998, Asai 1982, Eastaugh 1989, Pierce 1986, Music 1973, Temple 1995, Anderson 1994).This paper reviews the literature on the known and possible human health effects of exposure to the Florida red tides and their toxins. The review includes discussion of the red tide organisms and their toxins, as well as the effects of these toxins on both wild and laboratory animals as they relate to possible human health effects and exposures.

This article is available online at http://www.jlr.org is of grave consequence to human health. In fact, cardiovascular diseases, mostly as a result of long-standing metabolic dysregulations, are the leading cause of morbidity and mortality in many parts of the world.The pathogenesis of obesity-linked insulin resistance is only partially understood. Accumulating evidence has revealed a strong association between obesity-linked insulin resistance and infl ammation ( 2 ). Tumor necrosis factor-a (TNF-a ), a prototypical pro-infl ammatory cytokine, was upregulated in the epididymal fat of obese rodents, and neutralization of TNF-a ameliorated insulin resistance ( 3 ). Moreover, obese mice lacking TNF-a demonstrated improved insulin sensitivity ( 4 ). In addition, increased numbers of macrophages and their transcripts were reported in the epididymal fat of genetically and dietinduced obese (DIO) mice ( 5, 6 ). These adipose tissue macrophages (ATM) were found scattered between adipocytes (herein referred to as solitary ATM ) or forming clusters around adipocytes. Based on ultrastructural and immunohistochemical alterations, it was argued that most ATM in obese mice and humans surround dead adipocytes, forming so-called crown-like structures (CLS) ( 7 ). Subsequently, we reported that CLS were distributed differentially in abdominal fat depots of DIO mice ( 8 ). Consistent with our fi ndings, it was recently reported that CLS were also more prevalent in visceral than subcutaneous fat of leptin-defi cient ob/ob and leptin receptor-defi cient db/db mice ( 9 ).Although macrophages are critical in innate and adaptive immunity, most immune responses are the result of interplay between multiple cell types and mediators of the immune system ( 10 ). Therefore, it comes as no surprise to learn that regulatory T cells ( 11 ), CD8+ effector T cells Over the past several decades a steady increase in the prevalence of obesity across the continents, especially in the US, has been observed ( 1 ). Increased caloric intake, mostly due to consumption of a high-fat diet, and decreased physical activity seem to be major contributors. Insulin resistance, hypertension, and dyslipidemia often accompany obesity. The constellation, referred to as metabolic syndrome, This work was supported by generous funds from the Katz Family Foundation.

This paper reviews the literature describing research performed over the past decade on the known and possible exposures and human health effects associated with Florida red tides. These harmful algal blooms are caused by the dinoflagellate, Karenia brevis, and similar organisms, all of which produce a suite of natural toxins known as brevetoxins. Florida red tide research has benefited from a consistently funded, long term research program, that has allowed an interdisciplinary team of researchers to focus their attention on this specific environmental issue—one that is critically important to Gulf of Mexico and other coastal communities. This long-term interdisciplinary approach has allowed the team to engage the local community, identify measures to protect public health, take emerging technologies into the field, forge advances in natural products chemistry, and develop a valuable pharmaceutical product. The Review includes a brief discussion of the Florida red tide organisms and their toxins, and then focuses on the effects of these toxins on animals and humans, including how these effects predict what we might expect to see in exposed people.

Florida red tides annually occur in the Gulf of Mexico, resulting from blooms of the marine dinoflagellate Karenia brevis. K. brevis produces highly potent natural polyether toxins, known as brevetoxins, that activate voltage-sensitive sodium channels. In experimental animals, brevetoxins cause significant bronchoconstriction. A study of persons who visited the beach recreationally found a significant increase in self-reported respiratory symptoms after exposure to aerosolized Florida red tides. Anecdotal reports indicate that persons with underlying respiratory diseases may be particularly susceptible to adverse health effects from these aerosolized toxins. Fifty-nine persons with physician-diagnosed asthma were evaluated for 1 hr before and after going to the beach on days with and without Florida red tide. Study participants were evaluated with a brief symptom questionnaire, nose and throat swabs, and spirometry approved by the National Institute for Occupational Safety and Health. Environmental monitoring, water and air sampling (i.e., K. brevis, brevetoxins, and particulate size distribution), and personal monitoring (for toxins) were performed. Brevetoxin concentrations were measured by liquid chromatography mass spectrometry, high-performance liquid chromatography, and a newly developed brevetoxin enzyme-linked immunosorbent assay. Participants were significantly more likely to report respiratory symptoms after Florida red tide exposure. Participants demonstrated small but statistically significant decreases in forced expiratory volume in 1 sec, forced expiratory flow between 25 and 75%, and peak expiratory flow after exposure, particularly those regularly using asthma medications. Similar evaluation during nonexposure periods did not significantly differ. This is the first study to show objectively measurable adverse health effects from exposure to aerosolized Florida red tide toxins in persons with asthma. Future studies will examine the possible chronic effects of these toxins among persons with asthma and other chronic respiratory impairment.