Atrazine interaction with estrogen expression systems

Aquatic Toxicology, 2005

… 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

Endocrine Disruptors, 2015

Atrazine (ATZ) is an endocrine disruptor that increases aromatase activity. In viviparous (live-bearing) vertebrates, embryos may be exposed to endocrine disruptors via the placenta. Studies of the effects of ATZ in viviparous amniotes have focused on rodents, which are relatively insensitive to ATZ: studies on other viviparous amniotes are therefore required. We aimed to determine the effects of gestational exposure to a single dose of ATZ at 10 ppb on gonadal development in a viviparous skink, Niveoscincus metallicus. Pregnant skinks were exposed to ATZ, the synthetic estrogen diethylstilbestrol (DES) (positive control), vehicle solvent or no treatment. Gonads were examined histologically at birth. Females born to ATZ and DES exposed mothers were more likely to exhibit ovaries with abnormal oocytes than were females whose mothers received vehicle solvent or no treatment. Males born to ATZ and DES exposed mothers were equally more likely to exhibit testes devoid of germ cells with reduced organization of seminiferous tubules (ST) compared to males born to mothers receiving vehicle solvent or no treatment. However, ATZ treatment significantly increased the number of male neonates born with testicular lesions compared to males born to mothers in any other group. We conclude that atrazine disrupts gonadal differentiation in the viviparous lizard, N. metallicus. The similar effects of DES and ATZ suggest that the developmental effects of ATZ in N. metallicus reflect increased estrogen signaling. Atrazine should be used with caution as exposure of wildlife to this EDC is likely to have adverse effects on reproductive health.

Reproductive Toxicology, 1996

The effect of the chlorotriazine herbicide, atrazine, on ovarian function was studied in Long-Evans hooded (LE-hooded) and Sprague-Dawley (SD) rats. Atrazine was administered by gavage for 21 d to females displaying regular 4-d estrous cycles. In both strains, 75 mg/kg/d disrupted the 4-d ovarian cycle; however, no distinct alteration (i.e., irregular cycles but not persistent estrus or diestrus) was apparent

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.

Environmental Health Perspectives, 2015

Environmental Health Perspectives, 2007

The Journal of Steroid Biochemistry and Molecular Biology, 2011

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 socalled "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 mammalsrepresent 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".

2004

High oral doses of atrazine (ATRA) disrupt normal neuroendocrine function, resulting in suppression of the luteinizing hormone (LH) surge in adult, ovariectomized (OVX) estrogen-primed female rats. While the mechanism by which ATRA inhibits LH secretion is not known, current data indicate that ATRA does have anti-estrogenic properties in vitro and in vivo. In the body, ATRA is rapidly converted to diaminochlorotriazine (DACT). The present study was conducted to investigate the effects of ATRA and DACT on the estradiol benzoate (EB)/progesterone (P) induced LH surge and to determine if such changes correlate with impaired estrogen receptor (ER) function. ATRA, administered by gavage for five consecutive days to adult OVX, female Sprague-Dawley rats, caused a dose-dependent suppression of the EB/P induced LH surge. Although to a lesser degree than ATRA, DACT significantly suppressed total plasma LH and peak LH surge levels in EB/P primed animals by 60 and 58%, respectively. DACT treatment also decreased release of LH from the pituitary in response to exogenous gonadotropin releasing hormone (GnRH) by 47% compared to control. Total plasma LH secretion was reduced by 37% compared to control, suggesting that in addition to potential hypothalamic dysfunction, pituitary function is altered. To further investigate the mechanism by which hypothalamic function might be altered, potential anti-estrogenicity of ATRA and DACT were assessed by evaluating ER function treated rats. Using an in vitro receptor binding assay, ATRA, but not DACT, inhibited binding of [ 3 H]-estradiol to ER. In contrast, ATRA, administered to female rats under dosing conditions which suppressed the LH surge, neither changed the levels of unoccupied ER nor altered the estrogen induced up-regulation of progesterone receptor mRNA. Collectively, these results indicate that although ATRA is capable of binding ER in vitro, the suppression of LH after treatment with high doses of ATRA is not due to alterations of hypothalamic ER function.

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,