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

Endocrine Toxicology Branch, Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Reproductive Toxicology (Impact Factor: 3.23). 04/2011; 32(1):43-51. DOI: 10.1016/j.reprotox.2011.04.004
Source: PubMed


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. Vaginal opening was delayed in this group, indicating delayed puberty. No significant differences in mammary gland development were apparent at PND 45, or estrous cyclicity through PND 272. There were no differences between dosing regimens. Lower ATR doses (0-20mg/kg-d) showed few effects in females prenatally exposed to ATR, while the high dose (100mg/kg-d) reduced offspring body weight and delayed vaginal opening. Nonetheless, it is unlikely that environmental exposure comparable to the high dose would be encountered.

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Available from: Jerome Goldman, Oct 13, 2015
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    • "The no observed effect level (NOEL) based upon sexual maturation delay observed in this study was greater in F 1 progeny administered ATZ only PW (NOEL = 25 mg/kg) compared to animals exposed to ATZ during gestation, lactation , and PW (NOEL = 6.5 mg/kg/day). However, these NOELs were similar to those reported by other investigators who evaluated the effects of ATZ on sexual maturation when administered either during gestation, lactation, and PW (NOEL = 20 mg/kg/day) (Davis et al., 2011) or only PW (NOEL = 10–12.5 mg/kg/day) (Laws et al., 2000; Ashby et al., 2002). "
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    ABSTRACT: 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 F1 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 F1 females received the vehicle or ATZ from PND 21-133 or from PND 120-133. Slight reductions in fertility and the percentage of F1 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 F1 generation offspring. The onset of puberty was delayed in of the F1 generation G/L/PW females at doses of 25 and 50 mg/kg/day. F1 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 F1 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 F1 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 Research Part B Developmental and Reproductive Toxicology 10/2015; DOI:10.1002/bdrb.21154 · 0.77 Impact Factor
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    • "Most studies on ATZ toxicity to rodents during gestation/lactation were carried out on doses much higher than the dose characterized as the " acceptable daily intake, ADI " (0.005 mg kg −1 food per day). Examples for the doses used in this respect were 1, 5, 20 and 100 mg kg −1 /day [20] [21] [34] [35]; 100 mg kg −1 /day [36]; 50–100 mg kg −1 /day [37]; and 50–200 mg kg −1 /day [18]. "
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    ABSTRACT: Either during gestation or lactation, the experimental mouse dams received one of the following treatments: (a) diet free of pesticide; (b) diet enriched with atrazine (ATZ); 31.0 μg kg−1; (c) diet free of pesticide + oral vitamin E (α-tocopherol; 200 mg kg−1 per mouse); and (d) diet enriched with ATZ (31.0 μg kg−1) + oral vitamin E (200 mg kg−1 per mouse). At the weaning, pups and dams were killed and selected organs and blood samples were collected for analyses. Compared with the control results, ATZ induced alteration in a number of biochemical and histopathological parameters either in the dams or their offspring. The ameliorative effect of vitamin E, based on estimating the “Ameliorative Index; AI” to malondialdehyde (MDA) and superoxide dismutase (SOD) ranged between 0.95 and 1.06 (≈1.0) for the dams and the pups either in gestational or lactational exposure routes. In general, the mouse pups were more vulnerable to ATZ toxicity than their mothers and exposure during gestation was suggested to be more effective than during lactation. The findings may support the need to further investigating the adverse effects of exposure to low doses of commonly used pesticides, especially during pregnancy and breast-feeding as well as effects on newborn child.
    Toxicology Reports 12/2014; 1:53–68. DOI:10.1016/j.toxrep.2014.04.001
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    • "Delay in sexual maturation is known to affect mammary gland development because growth during puberty is allometric and sensitive to hormonal changes during the estrous cycle (Hovey et al., 2002). The results from a second laboratory confirmed the absence of an atrazine effect on postnatal mammary gland development at doses as high as 100 mg/kg/day (Davis et al., 2011). In addition, female SD rats exposed to atrazine in utero and throughout life did not have an increased incidence of mammary tumors compared with controls, suggesting that in utero exposure to atrazine did not contribute to an increased risk of developing mammary tumors later in life (Stevens et al., 1999). "
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    ABSTRACT: The causal relationship between atrazine exposure and the occurrence of breast cancer in women was evaluated using the framework developed by Adami et al. (2011) wherein biological plausibility and epidemiological evidence were combined to conclude that a causal relationship between atrazine exposure and breast cancer is "unlikely". Carcinogenicity studies in female Sprague-Dawley (SD) but not Fischer-344 rats indicate that high doses of atrazine caused a decreased latency and an increased incidence of combined adenocarcinoma and fibroadenoma mammary tumors. There were no effects of atrazine on any other tumor type in male or female SD or Fischer-344 rats or in three strains of mice. Seven key events that precede tumor expression in female SD rats were identified. Atrazine induces mammary tumors in aging female SD rats by suppressing the luteinizing hormone surge, thereby supporting a state of persistent estrus and prolonged exposure to endogenous estrogen and prolactin. This endocrine mode of action has low biological plausibility for women because women who undergo reproductive senescence have low rather than elevated levels of estrogen and prolactin. Four alternative modes of action (genotoxicity, estrogenicity, upregulation of aromatase gene expression or delayed mammary gland development) were considered and none could account for the tumor response in SD rats. Epidemiological studies provide no support for a causal relationship between atrazine exposure and breast cancer. This conclusion is consistent with International Agency for Research on Cancer's classification of atrazine as "unclassifiable as to carcinogenicity" and the United States Environmental Protection Agency's classification of atrazine as "not likely to be carcinogenic."
    Toxicological Sciences 07/2011; 123(2):441-59. DOI:10.1093/toxsci/kfr176 · 3.85 Impact Factor
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