Effect of atrazine on ovarian function in the rat

… Research Part B: …, 2007

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. Birth Defects Res (Part B) 80: 98-112, 2007. Published 2007 Wiley-Liss, Inc. w

Reproductive Toxicology, 1999

An increased incidence or earlier onset of mammary tumors (MT) has been associated with lifetime feeding of atrazine, an agricultural herbicide, to Sprague-Dawley (SD) female rats. Because MT occur spontaneously in this strain, along with episodes of persistent estrus and acyclic estrogen secretion, it was proposed that atrazine may act to promote this process. SD female rats, 7 to 8 wks old, were administered atrazine while vaginal cytology was monitored. At 200 mg/kg/d by gavage, which clearly exceeded the maximum tolerated dose (MTD), the predominant early response was prolonged vaginal diestrus. Persistent estrous episodes were seen, but less commonly. When atrazine was added to the diet, there was likewise an initial appearance of prolonged diestrus at 400 ppm, but by 13 to 14 wks on test (20 to 21 wks of age), persistent estrus was predominant, rising to Ͼ50% of animals by 26 wks on test. Age-matched controls also displayed persistent estrus, but to a lesser degree. At 400 ppm atrazine for 6 mo, animals displayed vaginal estrus for a mean of 62.8% of all days, versus 47.3% in age-matched controls, and 20 to 25% in young animals. The 400 ppm dose also exceeded the MTD. Observed no-effect levels for estrous cycling and body weight change were 50 ppm. Significant effects on estrous cycling occurred only at levels previously associated with enhanced or premature MT formation, and suggest that the tumor response in aging SD female rats can be manipulated by factors controlling the internal estrogen milieu. Because atrazine has no intrinsic estrogenic activity, it is more likely that high-level dosing to a susceptible animal model alters control of ovulation and normal cycling. The requirement of excessive dosing levels, as well as differences in neuroendocrine senescence, makes a risk to human health from this mode of action essentially nonexistent.

Micron, 2008

Fertility in female mammals may be affected by a variety of endocrine disrupters present in the environment. Herbicide atrazine is an example of endocrine disrupter employed in agriculture, which disrupts estrous cyclicity in rats. Aiming to characterize morphologically the effect of low and sublethal doses of atrazine on the ovaries of Wistar rats, in an effort to determine the possible intrafollicular target site through which this herbicide acts adult females were submitted to both subacute and subchronic treatments. Additionally, immunocytochemical labeling of 90 kDa heat shock protein (HSP90) was performed in order to evaluate the role played by this protein in the ovary, under stressed conditions induced by herbicide exposure. The results indicated that atrazine induced impaired folliculogenesis, increased follicular atresia and HSP90 depletion in female rats submitted to subacute treatment, while the subchronic treatment with low dose of atrazine could compromise the reproductive capacity reflected by the presence of multioocytic follicle and stress-inducible HSP90. #

Bulletin of Environmental Contamination and Toxicology, 2008

The aim of this study was to determine the toxic effect of atrazine at the ovarian cellular level. Chinese Hamster Ovary (CHO-K1) cell line was used to evaluate the degree of in vitro atrazine cytotoxicity and the morphological changes were followed during the cell death. Application of four bioassays confirmed that atrazine decreases ovarian cell proliferation and IC 50 were determined with each assay after 72 h of exposure. The level of apoptosis in atrazine treated cells was low.

Birth Defects Research Part B: Developmental and Reproductive Toxicology, 2014

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. Birth Defects Res (Part B) 101:262-275, 2014. C 2014 Wiley Periodicals, Inc.

Birth Defects Research Part B: Developmental and Reproductive Toxicology, 2015

Atrazine (ATZ) was administered daily by gavage to pregnant female Sprague Dawley rats at doses of 0, 6.25, 25 or 50 mg/kg/day, either during gestation, lactation and post-weaning (G/L/PW cohort) to F 1 generation female offspring or only from postnatal day (PND 21) until five days after sexual maturation (vaginal opening) when the estrogen-primed, luteinizing hormone (LH) surge was evaluated (PW cohort). Additional subgroups of F 1 females received the vehicle or ATZ from PND 21-133 or from PND 120-133. Slight reductions in fertility and the percentage of F 1 generation pups surviving to PND 21 in the gestationally exposed 50 mg/kg dose group were accompanied by decreased food intake and body weight of dams and F 1 generation offspring. The onset of puberty was delayed in of the F 1 generation G/L/PW females at doses of 25 and 50 mg/kg/day. F 1 generation females in the PW high-dose ATZ group also experienced a delay in the onset of puberty. ATZ had no effect on peak LH or LH AUC in ovariectomized rats 5 days after sexual maturation, irrespective of whether the F 1 generation females were treated from gestation onward or only peripubertally. There was no effect of ATZ treatment on the estrous cycle, peak LH or LH AUC of F 1 generation females exposed from gestation through to PND 133 or only for two weeks from PND 120-133. These results indicate that developing females exposed to ATZ are not more sensitive compared to animals exposed to ATZ as young adults. Birth Defects Res (Part B) 00:1-14,

ijppsjournal.com

Atropine sulphate at the dose level of 0.1mg & 0.2mg/100gm body weight administration for 30 days to the cycling albino rats, caused decrease in the ovarian weight, showing a decreasing number of developing follicles, Graafian follicles and corpora lutea, and an increased number of atretic follicles in histological sections. The estrous cycles of these rats were irregular with prolonged diestrus and reduced proestrus, estrus and metaestrus phases also support the decreased estrogen synthesis. Responsible for cornification of vaginal smear in Atropine sulphate treated rats. The hisometric changes of diameter of the ovarian follicles are reduced significantly. The total cholesterol content of the ovary was increased; protein and glycogen content were decreased.

Toxicological …, 2010

Atrazine is currently one of the most widely used herbicides in the United States and elsewhere. Here we examined 24 h in vitro and in vivo effects of atrazine on androgen production and on expression and activity of steroidogenic enzymes and regulatory proteins involved in cyclic adenosine monophosphate (cAMP)signaling pathway in peripubertal rat Leydig cells. When in vitro added, 1-50mM atrazine increased basal and human chorion gonadotropin-stimulated testosterone production and accumulation of cAMP in the medium of treated cells. The stimulatory action of atrazine on androgen production but not on cAMP accumulation was abolished in cells with inhibited protein kinase A. Atrazine also stimulated the expression of mRNA transcripts for steroidogenic factor-1, steroidogenic acute regulatory protein, cytochrome P450 (CYP)17A1, and 17b-hydroxysteroid dehydrogenase (HSD), as well as the activity of CYP17A1 and 17bHSD. The stimulatory effects of atrazine on cAMP accumulation and androgen production were also observed during the first 3 days of in vivo treatment (200 mg/kg body weight, by gavage) followed by a decline during further treatment. These results indicate that atrazine has a transient stimulatory action on cAMP signaling pathway in Leydig cells, leading to facilitated androgenesis.

Egyptian Academic Journal of Biological Sciences, B. Zoology, 2021

The aim of this study was to examine the cytotoxicity of the herbicide atrazine on the reproductive system. 48 male and 48 female albino rats were treated with atrazine daily for two different durations (15 and 30 days). Reproductive system toxicity was monitored by quantitative analysis of the serum Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), Prolactin (PRL), Estrogen (E2), Progesterone (Prog) and Testosterone (Testo). On the other hand, the reproductive organs were collected for histopathology study. The study showed a significant elevation of estrogen, progesterone hormones with a significant decrease in testosterone hormone in male groups while in female groups there was a significant decrease in estrogen, progesterone & hormones with a significant increase in testosterone hormone. But there was no effect on PRL and LH hormones in both male and female groups toxified by ATZ, in comparison to the control groups. In addition to that, the Light microscopic examination of the seminiferous tubule cells (st) showed vacuolations within seminiferous tubules (V), degeneration of spermatozoa formation and hemorrhage (hg) in the interstitial tissue. These effects were increased by increasing the dose or the time of exposure. By using ascorbic acid in the treatment of those effects, we find a significant improvement and detoxification of the atrazine effects on both hormonal tests and histological sections. From our study results, we concluded that there is a potential contribution of herbicide mixtures in the etiology of somebody's diseases, while ascorbic acid has beneficial effects as it tends to dampen atrazine toxicity, in albino rats.

Regulatory Toxicology and Pharmacology, 2002

The mammalian hazard assessment of the herbicide atrazine (ATR) has focused on the induction of mammary tumors and accelerated reproductive aging of adult rats, and the relationship of these effects to the inhibition of leutinizing hormone (LH) release from the pituitary, an effect itself caused by inhibition of GnRH signaling by the adult rat hypothalamus. In earlier studies, Laws et al. (Toxicol. Sci., 58, 366-376, 2000) demonstrated a delay in female rat sexual maturation induced by ATR, effects that could equally have been caused by inhibition of hypothalamic GnRH release. The present studies were designed to compare the doses that interfere with GnRH signaling seen in previous studies in adult Sprague-Dawley (SD) rats (LH surge suppression) with doses that impair GnRH signaling in peripubertal rats, as indicated by delayed sexual maturation. The studies evaluated the effects of ATR treatment on the timing of uterine growth and vaginal opening (VO) in peripubertal female Wistar (Alderley Park, AP) and SD rats. Doses of 10, 30, and 100 mg/kg ATR were administered daily from postnatal day (pnd) 21 to up to pnd 46. Determinations of uterine weight were made at pnd 30, 33, 43 (AP), and 46 (SD) and the timing of VO was also assessed in the last two of these experiments. The centrally acting GnRH antagonist Antarelix (ANT) was used as a positive control agent as it has previously been shown to prevent uterine growth and to delay VO in peripubertal AP rats. Uterine growth and VO were completely prevented in AP rats exposed to ANT. Uterine growth was delayed at pnd 30 and 33 in AP rats exposed to 100 mg/kg ATR, but this growth inhibition had been overcome by pnd 43. VO was significantly delayed in AP rats for the 100 mg/kg ATR dose. By pnd 46, VO was significantly delayed in SD rats exposed to both 30 and 100 mg/kg ATR, but uterine weights were unaffected by that time (as for AP rats). It is concluded that the no-effect level for the effects of ATR on sexually immature rats (10 mg/kg in SD; 30 mg/kg AP) is approximately the same as reported previously by Laws et al. in peripubertal Wistar rats (25 mg/kg). However, the no-effect level in peripubertal female SD rats is nearly an order of magnitude greater than the no-observed effect level observed in female SD rats fed ATR for 6 months (1.8 mg/kg) where LH suppression was used as an indicator of effect on the pituitary/hypothalamic axis (USEPA, Atrazine-DACT Fourth Report of the Hazard Identification and Review Committee, April 5, 2002). These results support the conclusion that the pituitary/hypothalamic axis in peripubertal female SD rats is less sensitive than that in adult female SD rats. C 2002 Elsevier Science (USA) Key Words: delayed sexual maturation; GnRH inhibition; no observed adverse effect level (NOAEL). 468 0273-2300/02 $35.00 C 2002 Elsevier Science (USA) All rights reserved.