The Effect of Atrazine on Puberty in Male Wistar Rats: An Evaluation in the Protocol for the Assessment of Pubertal Development and Thyroid Function

Abstract

Since atrazine (ATR), a chlorotriazine herbicide, has been shown previously to alter the secretion of luteinizing hormone (LH) and prolactin (PRL) through a direct effect on the central nervous system (CNS), we hypothesized that exposure to ATR in the EDSTAC male pubertal protocol (juvenile to peripubertal) would alter the development of the male rat reproductive system. We dosed intact male Wistar rats from postnatal day (PND) 23 to 53 and examined several reproductive endpoints. ATR (0, 12.5, 25, 50, 100, 150, or 200 mg/kg) was administered by gavage and an additional pair-fed group was added to compare the effects of any decreased food consumption in the high dose group. Preputial separation (PPS) was significantly delayed in the 12.5, 50, 100, 150, and 200 mg/kg ATR dose groups. PPS was also delayed in the pair-fed group, although significantly less than in the high dose-ATR group. The males were killed on PND 53 or 54, and pituitary, thyroid, testes, epididymides, seminal vesicles, and ventral and lateral prostates were removed. ATR (50 to 200 mg/kg) treatment resulted in a significant reduction in ventral prostate weights, as did the reduced food consumption of the pair-fed group. Testes weights were unaffected by atrazine treatment. Seminal vesicle and epididymal weights were decreased in the high dose-ATR group and the control pair-fed group. However, the difference in epididymal weights was no longer significantly different when body weight was entered as a covariable. Intratesticular testosterone was significantly decreased in the high dose-ATR group on PND 45, but apparent decreases in serum testosterone were not statistically significantly on PND 53. There was a trend for a decrease in luteinizing hormone (LH) as the dose of ATR increased; however, dose group mean LH was not different from controls. Due to the variability of serum prolactin concentrations on PND 53, no significant difference was identified. Although prolactin is involved in the maintenance of LH receptors prior to puberty, we observed no difference in LH receptor number at PND 45 or 53. Serum estrone and estradiol showed dose-related increases that were significant only in the 200 mg/kg-ATR group. No differences were observed in thyroid stimulating hormone (TSH) and thyroxine (T4) between the ATR groups and the control; however triiodothyronine (T3) was elevated in the high dose-ATR group. No differences in hormone levels were observed in the pair-fed animals. These results indicate that ATR delays puberty in the male rat and its mode of action appears to be altering the secretion of steroids and having subsequent effects on the development of the reproductive tract, which appear to be due to ATR's effects on the CNS. Thus, ATR tested positive in the pubertal male screen that the Endocrine-Disrupter Screening and Testing Advisory Committee (EDSTAC) is considering as an optional screen for endocrine disrupters.

Interpreting histopathology in the epididymis

“…56,57 Many of these substances interfere with androgen production or signaling and can delay the development of the male genital system, with effects being dependent on the time of exposure. 58 Exposure to chemical agents that can alter reproductive function during this period is highly important to reproductive toxicology, 59 given that changes in puberty can also alter reproductive function during sexual maturity.…”

Atrazine induces complete feminization and chemical castration in male African clawed frogs (Xenopus laevis)

“…In addition to its persistence, mobility, and widespread contamination of water, atrazine is also a concern because several studies have shown that atrazine is a potent endocrine disruptor active in the ppb (parts per billion) range in fish (4, 5), amphibians (6)(7)(8)(9)(10)(11)(12), reptiles, and human cell lines (5,(13)(14)(15), and at higher doses (ppm) in reptiles (16)(17)(18), birds (19), and laboratory rodents (20)(21)(22)(23)(24)(25)(26)(27)(28). Atrazine seems to be most potent in amphibians, where it is active at levels as low as 0.1 ppb (6)(7)(8)(9)(10).…”

A Daubert Motion: A Legal Strategy to Exclude Essential Scientific Evidence in Toxic Tort Litigation

“…29 However, endocrine disruption by environmental agents has been studied and reported for over 25 years, and the following definition of an endocrine disruptor has been established: an "endocrine disruptor is an exogenous agent (synthetic or natural) that interferes with the production, release, transport, metabolism, binding action or elimination of natural hormones in the body responsible for maintaining homeostasis and regulation of developmental processes." 30 Thus, the published findings that atrazine produced sexual deformities, including hermaphroditism in male frogs, as well as other studies showing delayed puberty 31 and direct inhibition of Leydig cell testosterone production 32 in male rats clearly demonstrate the endocrine-disrupting effects of this agent. Furthermore, because hormones and hormone receptor systems are phylogenetically similar, the effects observed in one mammalian species raise concern about the potential effects in other mammalian species, including humans.…”