17beta-estradiol and ICI-182780 regulate the hair follicle cycle in mice through an estrogen receptor-alpha pathway.

Estradiol (E(2)) applied topically twice weekly to mouse skin at doses as low as 1 nmol inhibited hair growth by blocking the transition of the hair follicle from the resting phase (telogen) to the growth phase (anagen). In contrast, application of

Perinatal exposure to estrogenic compounds and the subsequent effects on the prostate of the adult rat: evaluation of inflammation in the ventral and lateral lobes.

Although the effects of estrogenic compounds administered during the perinatal period on the size and morphology of the prostate have been well documented, the effects of such exposures on inflammatory changes in the prostate have not been well characterized. Since neonatal estradiol exposure has been shown to cause periods of hyperprolactinemia later in life and a relationship exists between high prolactin levels and rat lateral prostate inflammation, we hypothesized that an exposure to environmental compounds with estrogenic activity could result in an increase in lateral prostate inflammation in adulthood. To investigate this possibility and compare differences between estrogen agonists and antagonists, we examined the effect of a perinatal exposure to 17beta-estradiol, the insecticide methoxychlor, the partial estrogen agonist tamoxifen, and the pure antiestrogen ICI 182,780. Dams were dosed from gestation day (GD)18 to parturition and then the pups were dosed from postnatal day (PND) 1 to 5 with 0.1 mL of a solution of 0.355 mM and .0178 mM by sc injection, respectively, of all compounds in sesame oil, except for methoxychlor, which was administered only to the dam by gavage from GD 18 through PND 5 at a dose of 50 mg/kg in sesame oil. At 90 d of age, the weight of the lateral and ventral prostate in the estradiol group was significantly decreased. Tamoxifen caused a decrease in the weight of the lateral prostate, whereas the ventral lobe was not affected. ICI 182,780 did not alter prostate weight. The methoxychlor exposure increased the lateral lobe weight, but the ventral lobe weight was not affected. In the estradiol and tamoxifen groups, an inflammatory infiltrate was observed in the ventral prostates in 45.0 and 27.8% of the animals, respectively. There was a significant increase in the percent and severity of inflammation in the lateral prostate (as determined by a myeloperoxidase or neutrophil quantification assay) in the estradiol, tamoxifen, and methoxychlor groups as compared to controls. The ICI group was comparable to the controls in both ventral and lateral lobes. This study demonstrates that perinatal exposure to estrogenic compounds can result in alterations in the size of the adult prostate and increase the incidence of prostatitis.

Maternal exposure to atrazine during lactation suppresses suckling-induced prolactin release and results in prostatitis in the adult offspring.

The availability of prolactin (PRL) to the neonatal brain is known to affect the development of the tuberoinfundibular (TIDA) neurons and, as a consequence, lead to alterations in subsequent PRL regulation. Without early lactational exposure to PRL (derived from the dam's milk), TIDA neuronal growth is impaired and elevated PRL levels are present in the prepubertal male. These observations, combined with the finding that alterations in PRL secretion (i.e., hyperprolactinemia) in the adult male rat have been implicated in the development of prostatitis, led us to hypothesize that early lactational exposure to agents that suppress suckling-induced PRL release would lead to a disruption in TIDA development, altered PRL regulation, and subsequent prostatitis in the male offspring. To test this hypothesis, suckling-induced PRL release was measured in Wistar dams treated twice daily with the herbicide atrazine (ATR, by gavage, on PND 1-4 at 0, 6.25, 12.5, 25, and 50 mg/kg body weight), or twice daily with the dopamine receptor agonist bromocriptine (BROM, sc, at 0.052, 0.104, 0.208, and 0.417 mg/kg); BROM is known to suppress PRL release. Similarly, atrazine has also been reported to suppress PRL in adult females. Serum PRL was measured on PND 3 using a serial sampling technique and indwelling cardiac catheters. A significant rise in serum PRL release was noted in all control females within 10 min of the initiation of suckling. Fifty-mg/kg ATR inhibited suckling-induced PRL release in all females, whereas 25 and 12.5 mg/kg ATR inhibited this measure in some dams and had no discernible effect in others. The 6.25 mg/kg dose of ATR was without effect. BROM, used here as a positive control, also inhibited suckling-induced PRL release at doses of 0.104 to 0.417 mg/kg, with no effect at 0.052 mg/kg. To examine the effect of postnatal ATR and BROM on the incidence and severity of inflammation (INF) of the lateral prostate of the offspring, adult males were examined at 90 and 120 days. While no effect was noted at 90 days of age, at 120 days, both the incidence and severity of prostate inflammation was increased in those offspring of ATR-treated dams (25 and 50 mg/kg). The 12.5 mg/kg ATR and the two highest doses of BROM increased the incidence, but not the severity, of prostatitis. Combined treatment of ovine prolactin (oPRL) and 25 or 50 mg/kg ATR on PND 1-4 reduced the incidence of inflammation observed at 120 days, indicating that this increase in INF, seen after ATR alone, resulted from the suppression of PRL in the dam. To determine whether or not there is a critical period for these effects, dams were dosed with 25 and 50 mg/kg on PND 6-9 and PND 11-14. Inflammation was increased in those offspring from dams treated on PND 6-9, but this increase was not significant. Dosing on PND 11-14 was without effect. These data demonstrate that ATR suppresses suckling-induced PRL release and that this suppression results in lateral prostate inflammation in the offspring. The critical period for this effect is PND 1-9.

Prepubertal exposure to compounds that increase prolactin secretion in the male rat: effects on the adult prostate.

To test the hypothesis that a transient increase in prolactin (PRL) secretion prior to puberty can result in an alteration of the adult prostate, male rats were exposed from postnatal Days (PND) 22 to 32 to compounds that increase PRL secretion. These compounds included pimozide (a dopamine antagonist), estradiol-17beta, and bisphenol A (a monomer of polycarbonate plastics reported to have weak estrogenic activity). During dosing, pimozide (PIM), bisphenol A (BPA), and estradiol-17beta (E(2)) stimulated an increased secretion of PRL. At 120 days of age, the lateral prostate weight was increased in the PIM and BPA groups as compared to the vehicle-injected controls. Examination of the prostates revealed inflammation in the lateral lobes of all treated groups. Results of a myeloperoxidase assay, a quantitative assay to assess acute inflammation, indicated an increase in the percentage of males with neutrophil infiltrate in the lateral prostates of the PIM and E(2) treatment groups compared to their respective controls. The histological evaluations of these tissues confirmed an increase in luminal polymorphonuclear cells and interstitial mononuclear cells of the lateral prostates in all treatment groups. Administration of the dopamine agonist, bromocriptine, to the estradiol-implanted males from PND 22 to 32 reversed the induction of lateral prostate inflammation by estradiol, suggesting that PRL was necessary for the inflammatory effect. This study demonstrates that prepubertal exposures to compounds that increase PRL secretion, albeit through different mechanisms, can increase the incidence of lateral prostate inflammation in the adult.

Effects of 17-beta-estradiol and ICI 182 780 on hair growth in various strains of mice.

17-beta-Estradiol (10 nmol per 200 microl acetone) applied topically twice weekly to the clipped dorsal surface of C57BL/6 or C3H female mouse skin prevented hair growth, as previously described in the CD-1 mouse strain. Twice weekly topical application of the estrogen receptor antagonist, ICI 182 780 (10nmol per 200microl acetone), induced the telogenanagen transition and produced early pigmentation appearance in skin and hair growth in C57BL/6 and C3H female mice. Whereas twice weekly topical application of 10nmol 17-beta-estradiol blocked hair growth, the intraperitoneal administration of this dose twice weekly did not block hair growth, suggesting a direct cutaneous effect of 17-beta-estradiol. We also evaluated the effect of 17-alpha-estradiol, 17-beta-estradiol, and ICI 182 780 on hair growth in male mice. As observed in female mice, 17-beta-estradiol was a potent inhibitor of hair growth and ICI 182 780 stimulated hair growth; however, unlike the results previously observed in female mice, 17-alpha-estradiol was a potent inhibitor of hair growth in male mice. These results demonstrate that (i) the route of administration of 17-beta-estradiol is critical for its ability to block hair growth; (ii) C57BL/6 and C3H mice, two commonly employed mouse strains for hair growth studies, responded to 17-beta-estradiol and ICI 182 780 in a manner similar to that described in CD-1 mice; and (iii) the hair follicles of male and female mice respond similarly to 17-beta-estradiol and ICI 182 780, but display striking sex differences in the response to 17-alpha-estradiol on hair growth.

Characterization of skin tumor promotion by mirex: structure-activity relationships, sexual dimorphism and presence of Ha-ras mutation.

In the present study we have compared the tumor-promoting activity of the non-phorbol ester-type skin tumor promoter, mirex, a halogenated cycloalkane pesticide, to the following: (i) chlordane, a halogenated cycloalkane pesticide; (ii) 1,1-bis (4-chlorophenyl)-2,2,2-trichlorethane (DDT), a halogenated bridged aromatic pesticide; and (iii) kepone, a halogenated cycloalkane pesticide, which only differs from mirex by the substitution of two chlorine atoms with an oxygen atom. Topical application of 200 nmol mirex three times weekly for 20 weeks to 7,12-dimethylbenz[a]anthracene (DMBA)-initiated female mouse skin produced approximately 16 tumors/mouse with a 96% incidence of tumor bearing mice. Neither chlordane (2 mumol) or DDT (5 mumol) promoted tumors in DMBA-initiated mouse skin after three times weekly application for 20 weeks. Unexpectedly, DMBA-initiated mice treated with 250 nmol kepone three times weekly for 20 weeks did not develop any tumors, demonstrating that the replacement of two chlorine atoms by an oxygen atom results in loss of the skin tumor-promoting activity of mirex. To further characterize mirex-induced skin tumor promotion, male mice were initiated with a single topical application of 200 nmol DMBA and promoted topically three times weekly for 20 weeks with 200 nmol mirex. As compared to female mice, male mice demonstrated (i) 70% fewer tumors/mouse, (ii) decreased incidence of tumor bearing mice, (iii) increased time to first tumor and (iv) increased latency. To determine the role of ovarian hormones in the increased sensitivity of female mice, mice were initiated with DMBA, ovariectomized (OVX) 2 weeks later and then promoted with mirex. OVX mice exhibited 70% fewer tumors/mouse and a 40% decrease in incidence of tumor-bearing mice as compared to controls. Finally, > 90% of DMBA-initiated/mirex-promoted papillomas from male mice and female mice demonstrated a mutated Ha-ras gene with an A-->T transversion in the middle base of the 61st codon. Collectively, these data indicate that the tumor-promoting ability of mirex is highly structure specific, and ovarian hormones are a factor in the increased sensitivity of female mice to the skin tumor-promoting ability of mirex. Furthermore, mirex appears to clonally expand epidermal cells with a mutated Ha-ras oncogene.

Prolactin mediates estradiol-induced inflammation in the lateral prostate of Wistar rats.

Inflammation was induced in the lateral prostate of castrated Wistar rats by exposure to a sc implant of estradiol-filled Silastic tubing, followed by the addition of a dihydrotestosterone implant to restore prostatic wet weight. The presence of inflammation was correlated with increased serum PRL, elevated pituitary weight, and a greater than 2-fold increase in the lateral prostate DNA concentration. The administration of bromocriptine (4 mg/kg.day) to these animals was effective in suppressing pituitary weight and hyperprolactinemia and mitigated the lateral prostate inflammatory response. Inflammation was restored in the bromocriptine-treated hormone-implanted rats by administering exogenous ovine PRL at a dose of 2 mg/kg twice a day. The results indicate that estradiol-induced inflammation in the rat lateral prostate is mediated at least in part by the release of PRL from the pituitary.

Toxicology of selected pesticides, drugs, and chemicals. Zinc.

Zinc poisoning in small animals has been described in dogs, cats, birds, and ferrets, but the dog appears to be the species most often affected. Ingestion of zinc-containing metallic objects, including pennies, and zinc oxide ointments has been associated with the majority of the toxicoses. Clinical signs include anorexia, vomiting, diarrhea, hemolytic anemia, kidney dysfunction, and possible liver and pancreatic abnormalities. Treatments that have proven efficacious include fluid diuresis, blood transfusions as needed, general supportive care, and removal of the source of zinc. Further evaluation of the benefit of chelation therapy is urgently needed.

Sex-hormone-induced inflammation and fibromuscular proliferation in the rat lateral prostate.

The subacute administration of estradiol-17 beta was shown to be a potent inducer of an inflammatory response specific to the lateral prostate of the castrated Wistar rat. The subsequent administration of dihydrotestosterone restored the wet weight of the gland while maintaining the inflammation established with estrogen treatment. These changes are histologically similar to a spontaneously arising nonbacterial prostatitis previously reported by others in the aging rat lateral prostate. When the same hormones were administered on a chronic basis, the intensity of the inflammation increased with time and was accompanied by a fibromuscular proliferation that consisted of fibroblasts, smooth muscle cells, and collagen. These chronic changes correlated well with studies by other investigators on human benign prostatic hyperplasia (BPH) where certain forms of BPH were associated with a significant degree of inflammation and fibromuscular growth. The present studies therefore establish a model system for the hormonal induction of an inflammatory reaction in the rat lateral prostate that precedes and could be causally related to proliferative responses in the fibromuscular stroma. The potentially important similarities that exist between these experimental findings and the human problems of nonbacterial prostatitis and benign prostatic hyperplasia warrant additional study.

Pathogenesis of giant colonic diverticula.

The clinical, radiographic, and pathologic findings of 3 patients with giant colonic diverticula are presented. Although several theories have been proposed for the formation of these diverticula, they have not been fully documented. One of our cases illustrates the evolution of this disorder following typical colonic diverticulitis. The pathogenesis and differential diagnosis of this unusual entity are discussed.