Imprinting and Reproductive Health: A Toxicological Perspective.

This overview discusses the role of imprinting in the development of an organism, and how exposure to environmental chemicals during fetal development leads to the physiological and biochemical changes that can have adverse lifelong effects on the health of the offspring. There has been a recent upsurge in the use of chemical products in everyday life. These chemicals include industrial byproducts, pesticides, dietary supplements, and pharmaceutical products. They mimic the natural estrogens and bind to estradiol receptors. Consequently, they reduce the number of receptors available for ligand binding. This leads to a faulty signaling in the neuroendocrine system during the critical developmental process of 'imprinting'. Imprinting causes structural and organizational differentiation in male and female reproductive organs, sexual behavior, bone mineral density, and the metabolism of exogenous and endogenous chemical substances. Several studies conducted on animal models and epidemiological studies provide profound evidence that altered imprinting causes various developmental and reproductive abnormalities and other diseases in humans. Altered metabolism can be measured by various endpoints such as the profile of cytochrome P-450 enzymes (CYP450's), xenobiotic metabolite levels, and DNA adducts. The importance of imprinting in the potentiation or attenuation of toxic chemicals is discussed.

Vehicle-dependent disposition kinetics of fluoranthene in Fisher-344 rats.

The objective of this study was to evaluate how the vehicles of choice affect the pharmacokinetics of orally administered Fluoranthene [FLA] in rats. Fluoranthene is a member of the family of Polycyclic Aromatic Hydrocarbon chemicals. Fluoranthene exposure to humans may occur as a result of cigarette smoking, consumption of contaminated food and water, heating woods in stoves and boilers, industrial sources such as coal gasification, carbon and graphite electrode manufacturing. Adult male Fisher-344 rats were given single oral doses of 25 and 50 microg/kg FLA in tricaprylin, peanut oil, cod liver oil, Tween 80/isotonic saline (1:5) and 2% Alkamuls-EL620 through gavage. After administration, the rats were housed individually in metabolic cages and sacrificed at 2, 4, 6, 8, 10 and 12 hours post FLA exposure. Blood, lung, liver, small intestine, adipose tissue samples, urine, and feces were collected at each time point. Samples were subjected to a liquid-liquid extraction using methanol, chloroform, and water. The extracts were analyzed by a reverse-phase HPLC, equipped with a fluorescence detector. The results revealed a dose-dependent increase in FLA concentrations in plasma and tissues for all the vehicles used. Plasma and tissue FLA concentrations were greater for peanut oil; cod liver oil, and tricaprylin vehicles compared to Alkamuls (p < 0.05), and Tween 80/isotonic saline (1:5). Most of the FLA administered through peanut oil, cod liver oil and tricaprylin was cleared from the body by 8 hours (90%) and 12 hours (80%) post administration for the 25 microg/kg and 50 microg/kg dose groups, respectively. With both doses employed, the metabolism of FLA was highest when cod liver oil was used as a vehicle and lowest in vehicles containing detergent/water [cod liver oil > peanut oil > tricaprylin > alkamuls > Tween 80/isotonic saline (1:5)]. These findings suggest that uptake and elimination of FLA is accelerated when administered through oil-based vehicles. The low uptake of FLA from Alkamuls and Tween 80/isotonic saline may have been a result of the poor solubility of the chemical. In summary, our findings reiterate that absorption characteristics of FLA were governed by the dose as well as the dosing vehicle. The vehicle-dependent bioavailability of FLA suggests a need for the judicious selection of vehicles in evaluating oral toxicity studies for risk assessment purposes.

Acute and subchronic oral toxicity of fluoranthene in F-344 rats.

We have studied the acute and subchronic oral toxicity of fluoranthene (FLA) in male and female F-344 rats. Single acute FLA doses of 0, 1000, 2000, and 3000 mg/kg body weight (BW) dissolved in peanut oil were administered daily by oral gavage. Subchronic doses of 0, 150, 750, and 1500 mg FLA/kg BW/day were administered for 90 days in the rats' diet. The toxicological endpoints examined included rat body and organ weights, as well as histopathological examinations of liver, kidney, stomach, prostate, testes, and ovaries; hematological parameters including red blood cell (RBC) counts, white blood cell (WBC) counts, hemoglobin (Hgb) concentration, hematocrit (Hct) concentration, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC); blood chemistry including alanine amino transferase (ALT), aspartate amino transferase (AST), blood urea nitrogen (BUN); and urine chemistry including glucose, bilirubin, specific gravity, pH, protein, urobilinogen, nitrite, occult blood, and leukocytes. In acute toxicity studies, WBC counts were significantly decreased and MCHC was significantly increased in both males and females at all doses. In the subchronic study, several of the blood cell parameters were significantly decreased in males and females after 90 days; RBCs (< or = 10877;12%), WBCs (< or = 10877;40%), Hct (< or = 10877;9%), and Hgb (< or = 10877;12%). Only BUN in males was significantly increased in the high-dose group (1500 mg FLA/kg BW/day) at the 90-day time point. None of the other clinical chemistry parameters were affected. The histopathological examinations showed significant abnormalities (tubular casts) only in the male kidney at the two highest doses after 90 days. We propose a subchronic oral no-observed-adverse-effect level (NOAEL) of 150 mg/kg BW/day for FLA in rats, based on the hematological and renal changes. Overall, our findings indicate that FLA affects specific hematological parameters and kidneys, and has a greater effect on males than females.