Atrazine and reproductive function: mode and mechanism of action studies.

Atrazine, a chlorotriazine herbicide, is used to control annual grasses and broadleaf weeds. In this review, we summarize our laboratory's work evaluating the neuroendocrine toxicity of atrazine (and related chlorotriazines) from an historic perspective. We provide the rationale for our work as we have endeavored to determine: 1) the underlying reproductive changes leading to the development of mammary gland tumors in the atrazine-exposed female rat; 2) the cascade of physiological events that are responsible for these changes (i.e., the mode of action for mammary tumors); 3) the potential cellular mechanisms involving adverse effects of atrazine; and 4) the range of reproductive alterations associated with this pesticide.

[1]  C. Finch,et al.  Transient shortening of estrous cycles in aging C57BL/6J mice: effects of spontaneous pseudopregnancy, progesterone, L-dihydroxyphenylalanine, and hydergine. , 1987, Biology of reproduction.

[2]  S. Safe,et al.  Failure of chloro-S-triazine-derived compounds to induce estrogen receptor-mediated responses in vivo and in vitro. , 1996, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[3]  R. Cooper,et al.  Maternal exposure to atrazine during lactation suppresses suckling-induced prolactin release and results in prostatitis in the adult offspring. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[4]  C. Breckenridge,et al.  A risk characterization for atrazine: oncogenicity profile. , 1999, Journal of toxicology and environmental health. Part A.

[5]  W. Modic The Role of Testicular Aromatase in the Atrazine Mediated Changes of Estrone and Estradiol in the Male Wistar Rat. , 2004 .

[6]  J T Stevens,et al.  Chloro-s-triazine antagonism of estrogen action: limited interaction with estrogen receptor binding. , 1994, Journal of toxicology and environmental health.

[7]  J. Meites Relation of prolactin and estrogen to mammary tumorigenesis in the rat. , 1972, Journal of the National Cancer Institute.

[8]  S. Miller,et al.  Levodopa, fertility, and longevity. , 1977, Science.

[9]  R. Cooper,et al.  Potential mechanisms responsible for chlorotriazine-induced alterations in catecholamines in pheochromocytoma (PC12) cells. , 2003, Life sciences.

[10]  R. Cooper,et al.  Strain comparisons of atrazine-induced pregnancy loss in the rat? 1 1 ? Disclaimer: The information , 2000 .

[11]  Robert J. Kavlock,et al.  Endocrine-Disrupting Chemicals: Prepubertal Exposures and Effects on Sexual Maturation and Thyroid Activity in the Female Rat. A Focus on the EDSTAC Recommendations , 2000, Critical reviews in toxicology.

[12]  R. Sheaves,et al.  Hypothalamic adrenergic activity precedes the preovulatory luteinizing hormone surge in the rat , 1983, Neuroscience Letters.

[13]  R. Cooper,et al.  Atrazine disrupts the hypothalamic control of pituitary-ovarian function. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  J T Stevens,et al.  Chronic effects of atrazine on estrus and mammary tumor formation in female Sprague-Dawley and Fischer 344 rats. , 1994, Journal of toxicology and environmental health.

[15]  R. Cooper,et al.  Differential modulation of catecholamines by chlorotriazine herbicides in pheochromocytoma (PC12) cells in vitro. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[16]  Robert I. Krieger,et al.  HANDBOOK OF PESTICIDE TOXICOLOGY , 2001 .

[17]  C. Breckenridge,et al.  Hypothesis for mammary tumorigenesis in Sprague-Dawley rats exposed to certain triazine herbicides. , 1994, Journal of toxicology and environmental health.

[18]  A. Herbison Noradrenergic regulation of cyclic GnRH secretion. , 1997, Reviews of reproduction.

[19]  A. Sahu Absence of increased hypothalamic nitric oxide synthase gene expression during the preovulatory LH surge in middle‐aged rats , 1998, NeuroReport.

[20]  M. Ching Correlative surges of LHRH, LH and FSH in pituitary stalk plasma and systemic plasma of rat during proestrus. Effect of anesthetics. , 1982, Neuroendocrinology.

[21]  D. Cory-Slechta,et al.  Sustained Exposure to the Widely Used Herbicide Atrazine: Altered Function and Loss of Neurons in Brain Monoamine Systems , 2005, Environmental health perspectives.

[22]  H. Nagasawa,et al.  Prophylaxis of spontaneous mammary tumorigenesis by temporal inhibition of prolactin secretion in rats at young ages. , 1981, Cancer research.

[23]  H. Nagasawa,et al.  Increased incidence of spontaneous mammary tumors in female rats with induced hypothalamic lesions. , 1970, Cancer research.

[24]  R E Harlan,et al.  Steroid regulation of luteinizing hormone secretion in normal and androgenized rats at different ages. , 1977, Endocrinology.

[25]  R. Cooper,et al.  Pubertal development in female Wistar rats following exposure to propazine and atrazine biotransformation by-products, diamino-S-chlorotriazine and hydroxyatrazine. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[26]  P. MohanKumar,et al.  Cyclic and age-related changes in norepinephrine concentrations in the medial preoptic area and arcuate nucleus , 1995, Brain Research Bulletin.

[27]  R. Cooper,et al.  The dithiocarbamate fungicide thiram disrupts the hormonal control of ovulation in the female rat. , 1993, Reproductive toxicology.

[28]  M. Andersen,et al.  Evidence that atrazine and diaminochlorotriazine inhibit the estrogen/progesterone induced surge of luteinizing hormone in female Sprague-Dawley rats without changing estrogen receptor action. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[29]  F. Naftolin,et al.  Ovary-dependent degeneration in the hypothalamic arcuate nucleus. , 1980, Endocrinology.

[30]  R. Cooper,et al.  Suppression of the luteinizing hormone surge by chlordimeform in ovariectomized, steroid-primed female rats. , 1991, Pharmacology & toxicology.

[31]  P. Wise,et al.  Age-related changes in pulsatile luteinizing hormone release precede the transition to estrous acyclicity and depend upon estrous cycle history. , 1990, Endocrinology.

[32]  K. Berhane,et al.  Failure of Chloro-S-triazine-Derived Compounds to Induce Estrogen Receptor-Mediated Responses in Viv , 1996 .

[33]  R. Cooper,et al.  The effect of atrazine on puberty in male wistar rats: an evaluation in the protocol for the assessment of pubertal development and thyroid function. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[34]  S. Ojeda,et al.  A rapid and simple procedure for chronic cannulation of the rat jugular vein. , 1974, Journal of applied physiology.

[35]  R. Cooper,et al.  Effect of atrazine on implantation and early pregnancy in 4 strains of rats. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[36]  R. Steger,et al.  Patterns of sex steroid and gonadotropin secretion in aging female rats. , 1978, Endocrinology.

[37]  P. Wise,et al.  The role of the hypothalamus in aging of the female reproductive system. , 1987, Journal of steroid biochemistry.

[38]  L. Wetzel,et al.  Toxicity Characteristics of the 2-Chlorotriazines Atrazine and Simazine , 1998 .

[39]  N. Miki,et al.  Maintenance by L-DOPA treatment of estrous cycles and LH response to estrogen in aging female rats. , 1980, Experimental aging research.

[40]  P. Wise Estradiol-induced daily luteinizing hormone and prolactin surges in young and middle-aged rats: correlations with age-related changes in pituitary responsiveness and catecholamine turnover rates in microdissected brain areas. , 1984, Endocrinology.

[41]  J. Meites,et al.  Effects of L-dopa and methyldopa on growth of mammary cancers in rats. , 1973, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[42]  R. Cooper,et al.  Blockade of ovulation in the rat by the fungicide sodium N-methyldithiocarbamate: relationship between effects on the luteinizing hormone surge and alterations in hypothalamic catecholamines. , 1994, Neurotoxicology and teratology.

[43]  T. Horvath,et al.  Estrogen, synaptic plasticity and hypothalamic reproductive aging , 2003, Experimental Gerontology.

[44]  J. C. Eldridge,et al.  Short-term effects of chlorotriazines on estrus in female Sprague-Dawley and Fischer 344 rats. , 1994, Journal of Toxicology and Environmental Health, Part A.

[45]  R. Cooper,et al.  Effect of atrazine on ovarian function in the rat. , 1996, Reproductive toxicology.

[46]  H. Huang,et al.  Reproductive capacity of aging female rats. , 1975, Neuroendocrinology.

[47]  J. Meites,et al.  Increased incidence of mammary tumors in the female rat grafted with multiple pituitaries. , 1970, Cancer research.

[48]  R. Cooper,et al.  The effects of atrazine on female wistar rats: an evaluation of the protocol for assessing pubertal development and thyroid function. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[49]  R. Cooper,et al.  The effects of atrazine metabolites on puberty and thyroid function in the male Wistar rat. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[50]  L. Doncarlos,et al.  Sex hormones and brain aging , 2004, Experimental Gerontology.

[51]  L. Tyrey,et al.  Estrous cycle patterns of Sprague-Dawley rats during acute and chronic atrazine administration. , 1999, Reproductive toxicology.

[52]  R. Cooper,et al.  Neuroendocrine Control of Reproductive Function in the Aging Female Rodent , 1986, Journal of the American Geriatrics Society.

[53]  R. Cooper,et al.  Characterization of the LH surge in middle-aged female rats. , 1980, Biology of reproduction.

[54]  J. Anselmo-Franci,et al.  Luteinizing hormone and luteinizing hormone-releasing hormone secretion is under locus coeruleus control in female rats , 2002, Brain Research.

[55]  R. Cooper,et al.  Alteration of catecholamines in pheochromocytoma (PC12) cells in vitro by the metabolites of chlorotriazine herbicide. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[56]  P. Wise,et al.  Aging abolishes the estradiol-induced suppression and diurnal rhythm of proopiomelanocortin gene expression in the arcuate nucleus. , 1992, Endocrinology.

[57]  Q. Zheng,et al.  Modeling and predicting immunological effects of chemical stressors: characterization of a quantitative biomarker for immunological changes caused by atrazine and ethanol. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[58]  D. McKay,et al.  L-Dopa effects on serum LH and prolactin in old and young female rats. , 1975, Neuroendocrinology.

[59]  R. Cooper,et al.  Potential Therapeutic Consequences of Age-Dependent Changes in Brain Physiology1 , 1979 .