Strain comparisons of atrazine-induced pregnancy loss in the rat☆11☆Disclaimer: The information in this document has been funded wholly by the US Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

Narotsky, Michael G.; Best, Deborah S.; Guidici, Dorothy L.; Cooper, Ralph L.

doi:10.1016/s0890-6238(00)00111-8

Cited by 65 publications

(14 citation statements)

References 32 publications

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“…Experimental evidence obtained from animal studies demonstrated that ATR could be an endocrine disrupter, which influences hormone production and, subsequently, reproduction [3,4,5,6,7]. As hormones play a major role in the development of the central nervous system (CNS), recent research has suggested that ATR is a dopaminergic system toxicant.…”

Section: Introductionmentioning

confidence: 99%

Developmental Exposure to Atrazine Impairs Spatial Memory and Downregulates the Hippocampal D1 Dopamine Receptor and cAMP-Dependent Signaling Pathway in Rats

et al. 2018

IJMS

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Atrazine (ATR) is a widely used herbicide that has been implicated as a neurotoxicant. Recent experimental evidence has implicated that ATR exposure also appears to have adverse effects on the hippocampus, which is a critical region for learning and memory. The aim of the present study was to investigate the effects of ATR toxicity on the hippocampus of developing rats. Postnatal day (PND) 28 male Sprague–Dawley (SD) rats received ATR by oral gavage at 10 or 100 mg/kg bodyweight (BW) for 30 consecutive days and were sacrificed at PND 90. Behavioral test results indicated that spatial learning and memory were affected by ATR treatment. Electron microscopy analysis showed that the ultrastructures of the hippocampus were altered in the ATR-treated groups, as compared to the control group. Additionally, ATR treatment impacted dopamine and D1 dopamine receptor (D1DR) contents through different mechanisms. Reduced mRNA and protein expression levels of factors involved in the cAMP-dependent signaling pathway were also detected. These results indicate that the developmental exposure of rats to ATR can damage the hippocampus and spatial memory, which might be related to the downregulation of expression levels of the D1DR and its downstream signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Developmental Exposure to Atrazine Impairs Spatial Memory and Downregulates the Hippocampal D1 Dopamine Receptor and cAMP-Dependent Signaling Pathway in Rats

et al. 2018

IJMS

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“…Hence, the equivalent daily dietary administration of ATR was distributed across the day based upon the pattern of food intake and body weight during a pretest period. By examining the effect of bolus and distributed doses of ATR on multiple measures of reproductive outcome, the threshold ATR dose needed to suppress the LH surge and/or inhibit ovulation was determined for two strains of rats that have been previously shown to be sensitive to ATR (Cooper et al, 1996, 2000; Cummings et al, 2000; Narotsky et al, 2001). Furthermore, the relationship between the effects of ATR on the LH surge and the biology of reproduction in intact, normally cycling, female rats was characterized and compared to results obtained in traditional reproduction studies that were conducted by administering ATR in diet (DeSesso et al, accepted -companion article).…”

Section: Introductionmentioning

confidence: 99%

The Effect of Atrazine Administered by Gavage or in Diet on the LH Surge and Reproductive Performance in Intact Female Sprague‐Dawley and Long Evans Rats

Foradori

Coder

Tisdel

et al. 2014

Birth Defects Research Pt B

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Atrazine (ATR) blunts the hormone-induced luteinizing hormone (LH) surge, when administered by gavage (50–100 mg/kg/day for 4 days), in ovariectomized rats. In this study, we determined if comparable doses delivered either by gavage (bolus dose) or distributed in diet would reduce the LH surge and subsequently affect fertility in the intact female rat. ATR was administered daily to intact female Sprague-Dawley (SD) or Long Evans (LE) rats by gavage (0, 0.75 1.5, 3, 6, 10, 12, 50, or 100 mg/kg/day) or diet (0, 30, 100, 160, 500, 660, or 1460 ppm) during one complete 4-day estrous cycle, starting on day of estrus. Estrous status, corpora lutea, ova, and LH plasma concentrations were evaluated. A second cohort of animals was mated on the fourth treatment day. Fertility metrics were assessed on gestational day 20. A higher portion of LE rats had asynchronous estrous cycles when compared to SD rats both during pretreatment and in response to ATR (≥50 mg/kg). In contrast, bolus doses of ATR (≥50 mg/kg) inhibited the peak and area under the curve for the preovulatory LH surge in SD but not LE animals. Likewise, only bolus-treated SD, not LE, rats displayed reduced mean number of corpora lutea and ova. There were no effects of ATR administered by gavage on mating, gravid number, or fetus number. Dietary administration had no effect on any reproductive parameter measured. These findings indicate that short duration, high-bolus doses of ATR can inhibit the LH surge and reduce the number of follicles ovulated; however, dietary administration has no effect on any endocrine or reproductive outcomes

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“…Multiple mechanisms likely account for the decreased androgens and decreased androgen activity (summarized in Fig. 4): (1) atrazine inhibits luteinizing hormone (LH) and follicle stimulating hormone (FSH) peaks and surges by inhibiting pulsatile release of gonadotropin releasing hormone (GnRH) from the hypothalamus which leads to decreased androgen synthesis [24,62-66]; (2) atrazine inhibits LH release from the pituitary directly which leads to decreased androgen production [62,64,67,68]; (3) atrazine inhibits the enzyme 5α reductase which leads to decreased levels of the potent androgen dihydrotestosterone (DHT) and leaves more testosterone as substrate for aromatase to convert to estradiol which negatively feeds back on the hypothalamus and pituitary [69,70]; (4) atrazine inhibits binding of DHT to the androgen binding protein [71]; (5) atrazine inhibits interactions between DHT and the androgen receptor(AR) [69,70,72] but perhaps not by directly binding to the receptor [73], but perhaps not by directly inhibiting binding to the receptor (see [78]); (6) atrazine inhibits androgen synthesis in the testes [60,74,75]; (7) atrazine decreases prolactin secretion [63,78,79]. Prolactin promotes LH receptor expression, and thus a decrease in prolactin would lead to a decrease in LH receptors, impairing normal LH-stimulation of testosterone production; (8) atrazine increases adreno-corticotropic hormone (ACTH) secretion from the pituitary leading to increased progesterone and increased corticosteroid (cortisol or corticosterone) secretion [76,77].…”

Section: Introductionmentioning

confidence: 99%

Demasculinization and feminization of male gonads by atrazine: Consistent effects across vertebrate classes

Hayes

Anderson

Beasley

et al. 2011

The Journal of Steroid Biochemistry and Molecular Biology

301

161

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Atrazine is the most commonly detected pesticide contaminant of ground water, surface water, and precipitation. Atrazine is also an endocrine disruptor that, among other effects, alters male reproductive tissues when animals are exposed during development. Here, we apply the nine so-called “Hill criteria” (Strength, Consistency, Specificity, Temporality, Biological Gradient, Plausibility, Coherence, Experiment, and Analogy) for establishing cause–effect relationships to examine the evidence for atrazine as an endocrine disruptor that demasculinizes and feminizes the gonads of male vertebrates. We present experimental evidence that the effects of atrazine on male development are consistent across all vertebrate classes examined and we present a state of the art summary of the mechanisms by which atrazine acts as an endocrine disruptor to produce these effects. Atrazine demasculinizes male gonads producing testicular lesions associated with reduced germ cell numbers in teleost fish, amphibians, reptiles, and mammals, and induces partial and/or complete feminization in fish, amphibians, and reptiles. These effects are strong (statistically significant), consistent across vertebrate classes, and specific. Reductions in androgen levels and the induction of estrogen synthesis – demonstrated in fish, amphibians, reptiles, and mammals – represent plausible and coherent mechanisms that explain these effects. Biological gradients are observed in several of the cited studies, although threshold doses and patterns vary among species. Given that the effects on the male gonads described in all of these experimental studies occurred only after atrazine exposure, temporality is also met here. Thus the case for atrazine as an endocrine disruptor that demasculinizes and feminizes male vertebrates meets all nine of the “Hill criteria”.

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Cited by 65 publications

References 32 publications

Developmental Exposure to Atrazine Impairs Spatial Memory and Downregulates the Hippocampal D1 Dopamine Receptor and cAMP-Dependent Signaling Pathway in Rats

Developmental Exposure to Atrazine Impairs Spatial Memory and Downregulates the Hippocampal D1 Dopamine Receptor and cAMP-Dependent Signaling Pathway in Rats

The Effect of Atrazine Administered by Gavage or in Diet on the LH Surge and Reproductive Performance in Intact Female Sprague‐Dawley and Long Evans Rats

Demasculinization and feminization of male gonads by atrazine: Consistent effects across vertebrate classes

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