Novel molecular events associated with altered steroidogenesis induced by exposure to atrazine in the intact and castrate male rat.

Toxicology is increasingly focused on molecular events comprising adverse outcome pathways. Atrazine activates the hypothalamic-pituitary adrenal axis, but relationships to gonadal alterations are unknown. We characterized hormone profiles and adrenal (intact and castrate) and testis (intact) proteomes in rats after 3 days of exposure.

Atrazine-induced elevation or attenuation of the LH surge in the ovariectomized, estrogen-primed female rat: role of adrenal progesterone.

Multiple exposures to the herbicide atrazine (ATRZ) were shown to suppress the LH surge in both cycling female rats and those ovariectomized (OVX) and primed with estradiol (E2). A single ATRZ administration was found to induce a prompt and marked increase in progesterone (P4). As exogenous P4 is known to have a differential effect on the LH surge depending on its temporal relationship with the surge, it was hypothesized that a single treatment in an OVX, E2-primed rat would augment the surge, whereas several exposures would cause a decrease.

Atrazine does not induce pica behavior at doses that increase hypothalamic-pituitary-adrenal axis activation and cause conditioned taste avoidance.

Previous work has shown that a single oral administration of atrazine (ATR), a chlorotriazine herbicide, causes rapid increases in plasma adrenocorticotropic hormone (ACTH), serum corticosterone (CORT) and progesterone. The mechanism for these effects is unknown. To test whether administration of ATR causes hypothalamic-pituitary-adrenal (HPA) axis activation through the production of a generalized stress response resulting from gastrointestinal distress, we conducted both conditioned taste avoidance (CTA) and pica behavior experiments.

Gestational atrazine exposure: effects on male reproductive development and metabolite distribution in the dam, fetus, and neonate.

Few studies have investigated the long-term effects of atrazine (ATR) following in utero exposure. We evaluated the effects of gestational exposure of Sprague Dawley dams to ATR (0, 1, 5, 20, or 100mg/kg-d) on the reproductive development of male offspring. We also quantified the distribution of ATR and its chlorinated metabolites in maternal, fetal, and neonatal fluid and tissue samples following gestational and/or lactational exposure.

The effects of prenatal exposure to atrazine on pubertal and postnatal reproductive indices in the female rat.

Atrazine (ATR) is an herbicide that exerts negative reproductive effects. We examined the effects of vehicle or ATR (1, 5, 20 and 100mg/kg-d), administered to Sprague-Dawley rats on gestational days 14-21, once daily or divided into two doses per day, on female offspring reproductive indices. Offspring body weights at birth were reduced and mortality increased in the 100mg/kg-d group shortly after birth; by PND 21 there were no significant effects.

Understanding the effects of atrazine on steroidogenesis in rat granulosa and H295R adrenal cortical carcinoma cells.

Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) was introduced in the 1950s as a broad spectrum herbicide, and remains one of the most widely used herbicides in the United States. Several studies have suggested that atrazine modifies steroidogenesis and may disrupt reproductive function and development in a variety of species. A primary concern has been whether atrazine increases the synthesis of estrogens, perhaps by enhancing aromatase gene expression and activity.

Characterization of the hypothalamic-pituitary-adrenal axis response to atrazine and metabolites in the female rat.

Atrazine (ATR) has recently been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis in rodents. The current study investigated the effect of ATR and two of its chlorinated metabolites, desisopropylatrazine (DIA) and diamino-s-chlorotriazine (DACT), on the HPA axis in the Long-Evans female rat. A single oral gavage administration of 75 mg/kg ATR or 60.

Current developments in reproductive toxicity testing of pesticides.

A protocol to evaluate the potential developmental and reproductive effects of test chemicals has been developed by the Life Stages Task Force of the International Life Sciences Institute (ILSI)/Health and Environmental Sciences Institute (HESI) Agricultural Chemical Safety Assessment (ACSA) Technical Committee. Since the original publication, several international groups have provided public comment on conducting the test. The extended one-generation reproductive toxicity test is now under consideration as a potential test guideline.

The effects of triclosan on puberty and thyroid hormones in male Wistar rats.

Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a potent antibacterial and antifungal compound that is widely used in personal care products, plastics, and fabrics. Recently triclosan has been shown to alter endocrine function in a variety of species. The purpose of this study was to determine effects of triclosan on pubertal development and thyroid hormone concentrations in the male rat.

Suppression of the steroid-primed luteinizing hormone surge in the female rat by sodium dimethyldithiocarbamate: relationship to hypothalamic catecholamines and GnRH neuronal activation.

In female rodents, hypothalamic norepinephrine (NE) has a role in stimulating the secretion of gonadotropin-releasing hormone (GnRH) that triggers the ovulatory surge of luteinizing hormone (LH). NE synthesis from dopamine (DA) is catalyzed by dopamine-beta-hydroxylase (DbetaH) which contains a copper cofactor. Sodium dimethyldithiocarbamate (DMDC) is a pesticide with metal chelating properties that has been found to reduce DbetaH activity.

Effects of altered food intake during pubertal development in male and female wistar rats.

The U.S. Environmental Protection Agency is currently validating assays that will be used in a Tier I Screening Battery to detect endocrine disrupting chemicals.

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.

Moderating influence of the drinking water disinfection by-product dibromoacetic acid on a dithiocarbamate-induced suppression of the luteinizing hormone surge in female rats.

The disinfection by-product dibromoacetic acid (DBA) has been found in female rats to increase circulating concentrations of both estradiol (E2) and estrone (E1). This effect is apparently due, at least in part, to a suppression in hepatic catabolism. The present study investigated whether DBA, by increasing sex steroid levels, is able either to augment the hypothalamic up-regulation involved in triggering a luteinizing hormone (LH) surge, or to affect the ability of the neurotoxicant sodium dimethyldithiocarbamate (DMDC) to block the surge.

Distribution of 14C-atrazine following an acute lactational exposure in the Wistar rat.

The purpose of the present study was to examine the distribution of atrazine in the lactating dam and suckling neonate following an acute exposure to either 2 or 4mg/kg 14C-atrazine (14C-ATR) by gavage. 14C-ATR was administered to the nursing dam on postnatal day 3 by oral gavage. Two and a half hours after exposure of the mother to 14C-ATR, the pups were allowed to nurse for 30min.

The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies.

While an evaluation of the estrous cycle in laboratory rodents can be a useful measure of the integrity of the hypothalamic-pituitary-ovarian reproductive axis, it can also serve as a way of insuring that animals exhibiting abnormal cycling patterns are disincluded from a study prior to exposure to a test compound. Assessment of vaginal cytology in regularly cycling animals also provides a means to establish a comparable endocrine milieu for animals at necropsy. The procedure for obtaining a vaginal smear is relatively non-invasive and is one to which animals can become readily accustomed.

Reproductive functions and hypothalamic catecholamines in response to the soil fumigant metam sodium: adaptations to extended exposures.

Metam sodium (MS) is a soil fumigant and Category II pesticide with a relatively low toxicity in mammals. Previous data have shown an ability to impair reproductive mechanisms in ovariectomized, estradiol-primed rats. A single i.

Nature of the binding interaction for 50 structurally diverse chemicals with rat estrogen receptors.

This study was conducted to characterize the estrogen receptor (ER)-binding affinities of 50 chemicals selected from among the high production volume chemicals under the U.S. EPA's (U.

Agricultural chemical safety assessment: A multisector approach to the modernization of human safety requirements.

Better understanding of toxicological mechanisms, enhanced testing capabilities, and demands for more sophisticated data for safety and health risk assessment have generated international interest in improving the current testing paradigm for agricultural chemicals. To address this need, the ILSI Health and Environmental Sciences Institute convened a large and diverse group of international experts to develop a credible and viable testing approach that includes scientifically appropriate studies that are necessary without being redundant, and that emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Benefits of the proposed approach include improved data for risk assessment, greater efficiency, use of fewer animals, and better use of resources.

Acute exposure to molinate alters neuroendocrine control of ovulation in the rat.

Molinate, a thiocarbamate herbicide, has been reported to impair reproductive capability in the male rat and alter pregnancy outcome in a two-generation study. Published data are lacking on the effects of acute exposure to molinate in the female. Based on this work and our previous observations with related dithiocarbamate compounds, we hypothesized that a single exposure to molinate during the critical window for the neural trigger of ovulation on the day of proestrus (PRO) would block the luteinizing hormone (LH) surge and delay ovulation.

Assessment of DE-71, a commercial polybrominated diphenyl ether (PBDE) mixture, in the EDSP male and female pubertal protocols.

DE-71, a commercial mixture, was used to test the sensitivity of the female and male pubertal protocol to detect thyroid active chemicals. These protocols are being evaluated for the U.S.

Potential mechanisms responsible for chlorotriazine-induced alterations in catecholamines in pheochromocytoma (PC12) cells.

Chlorotriazines interact with undifferentiated PC12 cells in vitro to modulate catecholamine synthesis and release, but the mechanism(s) responsible for this effect had not been determined. In this study we evaluated the effect of atrazine, simazine and cyanazine on the protein expression of the enzymes responsible for the synthesis of dopamine [tyrosine hydroxylase (TH)] and norepinephrine [dopamine-beta-hydroxylase (DbetaH)]. We also examined the possible intracellular pathway associated with chlorotriazine-induced changes in catecholamine synthesis and release.

Pubertal development in female Wistar rats following exposure to propazine and atrazine biotransformation by-products, diamino-S-chlorotriazine and hydroxyatrazine.

We showed previously that the chlorotriazine herbicide, atrazine (ATR), delays the onset of pubertal development in female rats. ATR and its biotransformation by-products are present in soil and groundwater. Since current maximum contaminant levels are set only for ATR, it is important to determine whether these by-products can also alter pubertal development and possibly pose a cumulative exposure hazard.

Abnormal fertilization is responsible for reduced fecundity following thiram-induced ovulatory delay in the rat.

Brief exposure to some pesticides, applied during a sensitive window for the neural regulation of ovulation, will block the preovulatory surge of LH and, thus, delay ovulation. Previously, we have shown that a single i.p.

Single or group housing altered hormonal physiology and affected pituitary and interstitial cell kinetics.

A significant negative correlation between testicular interstitial cell tumors and pituitary tumors in control male F344 rats has been reported associated with the number of animals per cage. Change in numbers of animals per cage may cause stress and increased serum corticosteroids that can impair testosterone synthesis by interstitial cells. Eventual atrophy of interstitial cells may result in pituitary hyperfunction and tumor development.