ROLE OF PROLACTIN IN CHLORO-S-TRIAZINE RAT MAMMARY TUMORIGENESIS

Abstract

Chloro-S-triazine herbicides [cyanazine (CZ), atrazine (AZ), simazine (SZ)] increase mammary tumors in Crl:CD BR rats but not in F-344 rats or in mice. A nongenotoxic mechanism was investigated since the chloro-S-triazines are negative in short-term tests for genotoxicity. An in vivo battery was used to assess the chloro-S-triazines for estrogenic activity or for their ability to increase prolactin (PRL) levels, both of which play important roles in enhancing mammary gland tumorigenesis in rodents. Ovariectomized (OVX) female rats were treated with AZ, CZ, SZ, or three CZ metabolites for 4 days via intraperitoneal injection. The pattern of responses between the chloro-S-triazines and four controls (estradiol, estriol, haloperidol, reserpine) was compared. For the 6 end-points examined, the responses from rats treated with AZ, CZ, SZ, and the metabolites of CZ most closely matched the responses from the reserpine-treated rats (a PRL rather than estrogenic mechanism). In addition, AZ, CZ, and SZ were tested in several other in vitro models (estrogen/biogenic amine receptor competition assays and a yeast-expressed human estrogen receptor transcription assay) as well as an in vivo 24 h time-course experiment to characterize the CZ-induced increases in PRL levels. AZ, CZ, and SZ are not estrogen receptor (ER) activating compounds based on yeast transactivation and receptor competition data. CZ and AZ demonstrated marginal competition (at mM levels) to the D and alpha2 adrenergic receptors. Ligands to the D2 receptor, but not the alpha2 adrenergic receptor, are known to induce mammary tumors. CZ was also found to produce elevated PRL levels in a time-course similar to that seen with reserpine and haloperidol. Overall, the pattern of responses obtained with the chloro-S-triazines most closely matched the responses observed for reserpine. Taken together, these data suggest chloro-S-triazine-induced mammary tumors in rats are mediated through a PRL mechanism, which is thought to be of low relevance to humans.

Possible enhancing effects of atrazine and nonylphenol on 7,12‐dimethylbenz[a]anthracene‐induced mammary tumor development in human c‐Ha‐ras proto‐oncogene transgenic rats

“…10) Chloro-S-triazine herbicides, such as cyanazine (CZ), atrazine (AZ), simazine (SZ), increased mammary tumors in Crl:CD BR rats, but not in F344 rats or in mice, but this is mediated through a prolactin mechanism not relevant to humans. 49) While one study suggested a link between agricultural exposure to atrazine and non-Hodgkins lymphomas, 50) the epidemiological evidence regarding triazines points to a null association for breast cancer across all exposure indices and an inverse association with ovarian cancer. 51) Individual population groups may show associations with specific cancers and atrazine contami- nation levels (range 50-649 ng/liter, maximum acceptable concentration [MAC]=60,000 ng/liter) were positively associated (P<0.05) with stomach cancer incidence and negatively associated with colon cancer incidence in one study, 52) but an earlier review of the literature, with a pooled analysis of three of the case-control studies and the combined analysis of two retrospective follow-up studies, did not demonstrate the types of dose-response or induction time patterns that would be expected if triazines were causal factors.…”

Human relevance of rodent prolactin-induced non-genotoxic mammary carcinogenesis: prolactin involvement in human breast cancer and significance for toxicology risk assessments

“…Interestingly, in a study by O'Connor et al (2000) in which ovariectomized rats were treated intraperitoneally with atrazine, cyanazine or simazine, the responses were stated to resemble most closely those of the positive control reserpine in a battery of tests examining prolactin activity or oestrogenicity in vivo (i.e. the compounds produced a prolactin response rather than an oestrogenic response).…”

Assessment of Circulating Hormones in Regulatory Toxicity Studies II. Male Reproductive Hormones

“…However, these amounts of T will be insufficient to maintain spermatogenesis, which apparently depends on normally high levels. This decrease will produce the low-T effects in the testis: stage-specific (stage VII/VIII and XIV) germ cell death, spermatid retention, and decreased/degenerating elongating spermatids in the testes (O'Connor, Davis et al 2000;Sun et al 1989). Accessory sex organs will generally appear normal, since they will be maintained by the exogenous androgen stimulation.…”

“…In addition, a detailed review of how the pathologist can recognize endocrine disruption in the male reproductive system and the critical aspects of that evaluation and interpretation can be found in a guidance document published by the Organization for Economic Co-operation and Development (Creasy 2008). Also, there is a series of publications that describe the signature hormonal and morphologic profiles of various endocrine-disrupting substances on the male reproductive system (O'Connor, Cook et al 1998;O'Connor et al 1999;O'Connor et al 2000a;O'Connor, Davis et al 2000;2000c;O'Connor, Frame et al 2002a, 2002bO'Connor, Cook et al 2002).…”