In the ventral tegmental area, cyclic AMP mediates the actions of progesterone at dopamine type 1 receptors for lordosis of rats and hamsters.

Progesterone-facilitated lordosis is enhanced by activation of, and inhibited by antagonism of, dopamine type 1 receptors (D1) in the ventral tegmental area (VTA). Given that D1 activation leads to increases in cyclic AMP (cAMP), we hypothesised that, in the VTA, progesterone's actions on lordosis that involve D1 are mediated, in part, by cAMP. In Experiment 1, naturally receptive rats and hamsters were pretested for lordosis, infused with the cAMP analogue 8-bromo-cAMP (200 ng) or vehicle to the VTA, and tested again 30 min later. In Experiments 2 and 3, ovariectomised, oestradiol (10 microg) + progesterone (0 or 100 microg)-primed rats and oestradiol (10 microg) + progesterone (0 or 200 microg)-primed hamsters were pretested for lordosis and infused with 8-bromo-cAMP (200 ng), the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine (12 microM) or vehicle to the VTA. Subjects were tested again 30 min later. In Experiment 4, oestradiol + progesterone-primed rats and hamsters were pretested and infused with the D1 agonist SKF38393 (0 or 100 ng) to the VTA. Thirty minutes later, subjects were tested again and infused with 2',5'-dideoxyadenosine (12 microM) or vehicle. Subjects were tested again 30 min later. VTA infusions of 8-bromo-cAMP enhanced lordosis of naturally receptive or hormone-primed rats and hamsters and 2',5'-dideoxyadenosine decreased lordosis of oestradiol + progesterone-primed rats and hamsters. D1-mediated increases in progesterone-facilitated lordosis were reduced by 2',5'-dideoxyadenosine. These data suggest that progesterone-facilitated lordosis of rats and hamsters may be modulated by D1 and cAMP activity in the VTA.

Mitochondrial benzodiazepine receptors in the ventral tegmental area modulate sexual behaviour of cycling or hormone-primed hamsters.

Hamsters are highly dependent upon the central actions of progesterone (P4) for facilitation of sexual behaviour. In the ventral tegmental area (VTA), P4 has actions through its neurosteroid metabolite 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). The effects of enhancing or inhibiting neurosteroidogenesis (and thereby 3alpha,5alpha-THP concentrations), through manipulations of mitochondrial benzodiazepine receptors, in the VTA on socio-sexual behaviour of female hamsters were examined. Intact, naturally receptive hamsters and ovariectomized (OVX), hormone-primed hamsters were unilaterally infused via chronic guide cannula to the VTA with the mitochondrial benzodiazepine receptor antagonist 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboximide (PK-11195) or the mitochondrial benzodiazepine receptor agonist, N,N-dihexyl-2-(4-fluorophenyl)indole-30-acetamide (FGIN 1-27) and tested for sexual responsiveness and lordosis. PK-11195 (5.6, 11.2 or 22.4 nm) to the VTA attenuated sexual responsiveness of naturally receptive or oestradiol benzoate (EB) + P4-primed hamsters compared to vehicle. In addition, FGIN 1-27 (11.4 nm) infusions to the VTA increased sexual responsiveness and lordosis of cycling or OVX, EB + P4-primed hamsters, compared to vehicle infusions. In OVX, EB + P4-primed hamsters, decrements in sexual responsiveness produced by VTA infusions of PK-11195 (5.6 nm) were attenuated by VTA infusions of 3alpha,5alpha-THP. VTA infusions of PK-11195 (5.6 nm) or FGIN 1-27 (11.4 nm), respectively, decreased and increased midbrain levels of 3alpha,5alpha-THP compared to each other. Together, these findings indicate that manipulating actions of mitochondrial benzodiazepine receptors in the VTA can augment and inhibit neurosteroidogenesis and sexual responsiveness of hormone-primed and naturally receptive hamsters.

The photochemistry of flutamide and its inclusion complex with beta-cyclodextrin. Dramatic effect of the microenvironment on the nature and on the efficiency of the photodegradation pathways.

The photochemistry of the anticancer drug flutamide (FM), 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide, in homogeneous media and in the beta-cyclodextrin (beta-CD) cavity has been investigated. The photoreactivity of the free molecule has been rationalized on the basis of an intramolecular nitro to nitrite rearrangement followed by cleavage of the nitrite intermediate. The twisted geometry of the nitro group with respect to the aromatic plane plays a key role in triggering such a photoprocess. Incorporation of FM in the beta-CD cavity leads to dramatic effects on both the efficiency and the nature of the photochemical deactivation pathways of the guest molecule. A 20-fold increase in the FM photodecomposition quantum yield and the formation of photoproducts originated by both reduction of the nitro group and cleavage of the amide bond were observed in the presence of the macrocycle. Such a behavior cannot be attributed exclusively to the micropolarity of beta-CD and/or to its role as a reactant. The induced circular dichroism spectra and the nature of the photoproducts formed in these experimental conditions provide indications that the photoreactivity in the beta-CD microenvironment could likely be mediated by structural changes of FM upon complexation.

Mortality among workers exposed to cutting oil mist: update of previous reports.

BACKGROUND: Earlier reports of the mortality experience of this cohort of automotive workers followed from 1938 to 1967 who were exposed to cutting oil mist noted an excess of gastrointestinal cancer. The present report describes the mortality experience of these workers followed for mortality through 1980. METHODS: Cause-specific standardized mortality ratios were calculated by comparing the observed number of deaths to the expected numbers based on rates for the U.S. male population. RESULTS: The SMRs for liver and biliary tract, and testicular cancers were significantly elevated. Among the subset of workers with heavy oil mist exposure, SMRs were significantly elevated for cancers of the lung and testis, and for Hodgkin's disease. The risk of death due to lung cancer was greatest among workers with heavy exposure to oil mist employed for 15 or more years. Mortality due to stomach cancer was in excess among workers with heavy exposure to oil mist who were employed for 5 or more years. There were significant excesses of deaths due to asthma and emphysema. CONCLUSIONS: Further studies with information on the presence of contaminants and additives in oil mists will help elucidate the relationship between oil mist exposure and cancer.

Estrous cycle and sex differences in performance on anxiety tasks coincide with increases in hippocampal progesterone and 3alpha,5alpha-THP.

Sex differences and estrous cycle variations in anxiolytic-like behaviors and progestin concentrations were examined. Proestrous (n=22), estrous (n=19), diestrous (n=20), and male (n=18) Long-Evans rats were tested in horizontal crossing, open field, elevated plus-maze, emergence, holeboard, social interaction, tailflick, pawlick, and defensive burying tasks. Concentrations of plasma and hippocampal progesterone and 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) were measured by radioimmunoassay in behaviorally tested (proestrus n=11, estrus n=8, diestrus n=9, male n=7) and yoked non-tested rats (proestrus n=11, estrus n=8, diestrus n=10, male n=8). Proestrous females exhibited more anxiolytic-like behavior than all other groups on the elevated plus-maze, social interaction, and defensive burying tasks. Proestrous females had significantly shorter latencies to emerge from a cylinder than did estrous and diestrous females, but not males. Proestrous and estrous females entered significantly more peripheral and total squares in a brightly-lit open field than did males. While proestrous females had a tendency to make more beam breaks than did males in the horizontal crossing task, there were no differences between groups on the holeboard task. There was a tendency for proestrous females to have longer tailflick latencies than diestrous and male rats; however, on the pawlick task there were no differences among the groups. Plasma and central progesterone and 3alpha,5alpha-THP of tested and non-tested rats were not different. Proestrous females had significantly higher plasma and hippocampal progesterone and 3alpha,5alpha-THP levels than all other groups. These data demonstrate that proestrous increases in anxiolytic-like behavior coincide with elevated circulating and hippocampal progestin concentrations.

Risk of premenopausal breast cancer in association with occupational exposure to polycyclic aromatic hydrocarbons and benzene.

OBJECTIVES: This study examined the relationship between risk of premenopausal breast cancer and occupational exposure to benzene and polycyclic aromatic hydrocarbons (PAH) and whether the proposed relationship between PAH and breast cancer differed by tumor estrogen receptor (ER) status. METHODS: In a case-referent study of premenopausal breast cancer, occupational histories and other information were obtained through interviews, and job-exposure matrices were used to assess exposure to PAH and benzene. RESULTS: A dose-response relationship for the probability of exposure to benzene [low: odds ratio (OR) 1.64, 95% confidence interval (95% CI) 0.64-4.21; high: OR 1.95, 95% CI 1.14-3.33) and to PAH (low: OR 1.56, 95% CI 0.78-3.12; high: OR 2.40, 95% CI 0.96-6.01). Risk increased with duration of exposure to benzene, but not to PAH. A dose-response relationship was not evident for the intensity of exposure to benzene or to PAH. When analyses were stratified by tumor ER status, PAH exposure was related to a greater increase in the risk of ER-positive (OR 2.27, 95% CI 1.14-4.54) than ER-negative (OR 1.12, 95% CI 0.47-2.64) breast cancer. Risk of ER-positive, but not ER-negative, tumors increased with the probability of exposure to PAH. CONCLUSIONS: The findings suggest an association between risk and occupational exposure to benzene. Although it was difficult to study PAH independently of benzene, there was some suggestion of an association between PAH exposure and ER-positive tumors. These data should be interpreted with caution because of the limitations of this study, including low-response rates and small numbers of exposed persons.

Cancer mortality in women with probable exposure to silica: a death certificate study in 24 states of the U.S.

BACKGROUND: Silica exposure is known to cause an increased risk of pneumoconiosis and some types of cancers. Exposure to silica is becoming an increasingly common occupational hazard for women. Studies contradict each other on whether or not women suffer more occupational pneumoconiosis than men, but no studies have evaluated cancer risks among women exposed to silica. METHODS: Death certificate data on occupation and industry from 24 states in the U.S. between 1984 and 1993 were used to calculate proportional mortality ratios (PMRs) for workers exposed to silica. RESULTS: Over 20,000 deaths (4% of all deaths in persons with possible work-related silica-exposure) occurred among women. The PMR for pneumoconiosis among women working in occupations or industries with possible silica exposure was 13.6 (95% CI: 7.2-23.2), for men 3.8 (CI: 3.7-4.0). Both men and women had higher than expected PMRs for respiratory diseases, lung and esophageal cancers, and external causes of death. In the group with probable silica exposure (both occupation and industry associated with silica), women had elevated PMRs for thyroid cancer (PMR = 5.5), multiple myeloma (PMR = 1.3), digestive organ cancers (PMR = 1.2), whereas men had no increased PMRs for these cancers. Both genders had significantly decreased PMRs for breast cancer, cerebrovascular diseases, nervous system diseases, and brain and other central nervous system cancers. CONCLUSIONS: An in depth look at the types of silica exposures (specific work duties) and adjustment for confounders is warranted to determine the importance of these gender-specific excess mortalities associated with possible silica exposure.

Cancer mortality among women employed in health care occupations in 24 U.S. states, 1984-1993.

BACKGROUND: Health care workers are potentially exposed to a number of carcinogens. Studies among women in this field have focused on white nurses; however, workers in many health care occupations share exposures experienced by nurses. METHODS: Cancer mortality was examined among female health care workers using death certificate data collected in 24 U.S. states from 1984 through 1993. Cancer mortality odds ratios (MORs) were calculated by race (white, black) and age group. RESULTS: White nurses had a 30% elevation of mortality due to liver cancer and myeloid leukemia. White registered nurses (RNs) had a small excess and white licensed practical nurses (LPNs) had a small deficit of mortality due to breast cancer. Ovarian cancer was in excess among RNs, but decreased among LPNs. Among black nurses, excesses of death due to kidney cancer (MOR = 1.7) and multiple myeloma (MOR = 1.3), and a significant 50% deficit in mortality due to cancer of the esophagus were found. Black RNs, but not LPNs, had an excess of breast cancer (MOR = 1.3; 95% CI = 1.0-1.5). Ovarian cancer was elevated by 30% in both RNs and LPNs. Excess deaths due to cancers of the breast, ovary, and uterus occurred among white physicians. Among black physicians, lung cancer was significantly elevated (MOR = 2.8). White pharmacists had significant excesses of breast (MOR = 1.5) and ovarian (MOR = 2.4) cancers, and myeloid leukemia (MOR = 2.0). White clinical laboratory technicians had excess deaths from several cancers. The greatest excess was for myeloid leukemia (MOR = 2.3; 95% CI = 1.5-3.4). Excesses among radiologic technologists included cancers of the lung, pancreas, breast, uterus, and ovary. CONCLUSION: Several findings reported here warrant further investigation. In particular, excesses of myeloid leukemia among nurses, pharmacists, and clinical laboratory technicians and liver cancer among nurses should be investigated in studies with data on occupational and other exposures. Patterns of mortality from breast and ovarian cancer found in this study must be evaluated further in studies with data on reproductive history.

Risk of premenopausal breast cancer and patterns of established breast cancer risk factors among teachers and nurses.

BACKGROUND: Contrasting results have been published regarding the risk of breast cancer among teachers and nurses. Confounding by reproductive factors may explain the increased risk observed among women in these occupations as information on those factors were not available in most studies. METHODS: We examined the risk of premenopausal breast cancer among teachers and nurses using occupational histories in a case-control study where information on established risk factors was available. RESULTS: Having ever held a teaching job was not related to breast cancer (OR = 0.74, 95% CI = 0.44-1.28) and women who worked for 10 years or less in this occupation had a non-significant deficit of risk (OR = 0.52, 95% CI = 0.27-1.02). No elevation in risk was found in association with having ever been a nurse (OR = 0.85, 95% CI = 0.45-1.61) or with duration of nursing. Although direct comparison of established risk factors among teachers and nurses and other women in the study showed some evidence of differential distribution, especially when comparing teachers to other women, adjustment for reproductive variables and other breast cancer risk factors did not change the results of this study. CONCLUSION: These findings suggest that teachers and nurses are not at an increased risk of breast cancer. This study also suggests that established risk factors for premenopausal breast cancer may not explain the elevation of risk found in other studies of teachers and nurses. However, this conclusion is limited by the fact that in the present study teachers and nurses had lower than expected breast cancer risk with or without adjustment for established risk factors. Limitations of this study such as low response rates and limited statistical power should be considered in the interpretation of these findings.

Occupational risk factors for breast cancer among women in Shanghai.

Although female breast cancer rates are lower in China than in Western countries, rates have been rising rapidly in China. This increase may be due to changes in established breast cancer risk factors, but it is possible that exposure to occupational and environmental carcinogens in Shanghai also have contributed to the rise in incidence. We used data collected by the Shanghai Cancer Registry and the Chinese Third National Census to study the risk of breast cancer by occupation and by occupational exposures. Standardized incidence ratios (SIRs) were used to compare observed cases to expected numbers of cases, based on the incidence rates for Shanghai and the number of women in each occupation according to the 1982 census. Statistically elevated SIRs for breast cancer were seen for a number of professional occupational categories, with the greatest risk seen among scientific research workers (SIR = 3.3). Administrative clerks, political and security personnel, and makers of rubber and plastics products also had significant excesses. Significant deficits of risk were seen for the categories of production and related workers, construction workers, and transportation equipment operators. For specific occupations, the highest SIRs were observed among doctors of Chinese-Western medicine (SIR = 14.7, 95% CI = 5.9-30.3) and doctors of Chinese medicine (SIR = 7.2, 95% CI = 4.4-11.4). We also found excesses among teachers at each level of education, librarians, clerical workers, electrical and electronic engineers, nurses, lab technicians, accountants and bookkeepers, rubber manufacturing products makers, weavers, and knitters. SIRs were significantly elevated for high probability of exposure to organic solvents (SIR = 1.4). For benzene exposure, we found significant excesses for overall exposure (SIR = 1.1) and for medium level of exposure (SIR = 1.3). There was no evidence of an association between risk and electromagnetic fields (EMF) exposure. Based on a small number of exposed, SIRs were elevated for both medium probability and high level of exposure to pesticides. The elevations in occupations reported here support some previous reports. Our finding of an increased risk associated with benzene also has been reported previously; the finding for organic solvents is new. However, the literature on the risk of breast cancer related to occupational exposures is limited and there is no consistent body of literature for any of the exposures studied here. Further, many comparisons were made and the problem of multiple hypothesis testing cannot be ignored in a survey such as ours.

Environmental risk factors of breast cancer.

Breast cancer is women's most ubiquitous cancer. The role of dietary factors is controversial, but there is limited evidence for such occupational risk factors as employment in the pharmaceutical industry and as a beautician. Ionizing radiation probably increases the risk. Exposure to chlorinated hydrocarbon pesticides, chlorinated solvents, and polychlorinated biphenyls may be risk factors, although the evidence is insufficient. Data on low-frequency electromagnetic fields are inconclusive. Tobacco smoking may be a risk factor, but the effect may depend on N-acetyltransferase 2 genetic polymorphisms. There are yet unidentified determinants, probably environmental, that may act via estrogenic activity or through other mechanisms. The etiology may vary according to the joint estrogen and progesterone receptor status of the tumor. P53 mutation frequency varies considerably in breast cancer populations, which may reflect variation in exogenous exposures. Epidemiology research on breast cancer needs to consider subtypes of the disease, lifetime exposure assessment, host susceptibility, and adjustment for reproductive and menstrual history.

Breast cancer risk and lifetime occupational history: employment in professional and managerial occupations.

OBJECTIVE: In this case-control study, occupational histories were used to assess the relation between risk of breast cancer and employment in professional and managerial occupations while adjusting for reproductive and other risk factors. METHODS: Incident, primary, female cases of breast cancer diagnosed between 1986 and 1991, and randomly selected controls were interviewed to obtain detailed medical, reproductive, and occupational histories. Mantel-Haenszel crude odds ratios (OR) and 95% confidence intervals (95% CIs) were used to estimate risk of breast cancer related to the job of longest duration. Unconditional logistic regression was used to estimate crude and adjusted ORs and 95% CIs associated with having ever been employed and duration of employment in a professional or managerial occupation. RESULTS: A non-significant threefold increase in risk was found among premenopausal women whose major job was in the occupational category of precision production, craft, and repair (95% CI 0.90 to 20.35). No increase in risk was found for premenopausal women whose major job was a managerial or professional occupation. However, an inverse relation between risk of premenopausal breast cancer and having ever held a professional or managerial job was observed (OR 0.53, 95% CI 0.34 to 0.82). This relation was strongest for women who worked one to 10 years (OR 0.47, 95% CI 0.29 to 0.77). Postmenopausal breast cancer was not related to professional and managerial employment. CONCLUSIONS: In this population, employment in professional and managerial occupations is not associated with postmenopausal risk of breast cancer, but seems to be related to a reduction in risk of premenopausal breast cancer. Methodological limitations of this study including response rates are discussed.

Mortality of a police cohort: 1950-1990.

This study presents findings from an updated retrospective cohort mortality study of male police officers from January 1, 1950 to December 31, 1990 (n = 2,593; 58,474 person-years; 98% follow-up). Significantly higher than expected mortality rates were found for all cause mortality (Standardized mortality ratio [SMR] = 110; 95% confidence interval [95% CI] = 1.04-1.17), all malignant neoplasms (SMR = 125; 95% CI = 1.10-1.41), cancer of the esophagus (SMR = 213; 95% CI = 1.01-3.91), cancer of the colon (SMR = 187; 95% CI = 1.29-2.59), cancer of the kidney (SMR = 2.08, 95% CI = 100-3.82), Hodgkin's disease (SMR = 313; 95% CI = 1.01-7.29), cirrhosis of the liver (SMR = 150; 95% CI = 1.00-2.16), and suicide (SMR = 153; 95% CI = 1.00-2.24). All accidents were significantly lower (SMR = 53; 95% CI = 0.34-0.79). Mortality by years of police service showed higher than expected rates for (1) all malignant neoplasms in the 1- to 9-years-of-service group; (2) all causes, bladder cancer, leukemia, and arteriosclerotic heart disease in the 10 to 19-year group; and (3) colon cancer and cirrhosis of the liver in the over 30 years of service group. Hypotheses for findings are discussed.

Pituitary adenylate cyclase activating polypeptide prevents apoptosis in cultured cerebellar granule neurons.

The two forms of pituitary adenylate cyclase-activating polypeptide, PACAP27 and PACAP38, are two neuropeptide hormones related to the vasoactive intestinal peptide/secretin/ glucagon family of peptides. PACAP receptors that are positively coupled to adenylyl cyclase and phospholipase C have been identified in cultured cerebellar granule cells. Using the reverse transcription-polymerase chain reaction methodology, we demonstrated the expression of the PACAP-R and PACAP-R-hop mRNAs in cultured granule cells. When grown in the absence of serum or in low K+ concentrations, these neurons underwent apoptosis, a naturally occurring process characterized by cell shrinkage and internucleosomal DNA cleavage. We used these models of programmed cell death to study the relationship between PACAP receptor activation and neuronal apoptosis. Treatment with PACAP27 and PACAP38 reduced the development of apoptosis in a dose-dependent manner. The neuroprotective activity of PACAP was mimicked by high concentrations of vasoactive intestinal peptide or forskolin but not by carbamylcholine. Thus, we suggest that the activation of type I PACAP receptors may contribute to the survival of cerebellar granule neurons.

Women in the public sector: cancer mortality.

Very few mortality occupational studies of female workers have been published, even though the number of women in the workforce has increased dramatically to reach more than 45%. Public sector employees comprise 12% of the female workforce. This article reports the findings of a retrospective cohort mortality study of 1371 full-time female employees of the city of Buffalo, New York, who were employed between January 1, 1950, and October 1, 1979, and have worked a minimum of 5 years. The majority of women were hired in the 1940s and early 1950s and began employment after age 30. This predominantly white-collar, service-oriented female cohort demonstrated significantly lower all-cause mortality than that expected based on US mortality rates for white females. The highest observed numbers of cancer deaths were for breast, digestive, and respiratory cancers. The majority of person-years were accrued in clerical and service occupations. Higher-than-expected mortality was shown for reproductive and respiratory cancers among professional employees; digestive cancers, diseases of the nervous system, and pneumonia among clerical workers; and cancers of the lung and brain and diseases of the digestive system, especially ulcers, among service employees. Because these results are based on few observed cases, they must be interpreted cautiously.

Constitutively expressed c-myb abrogates the requirement for insulinlike growth factor 1 in 3T3 fibroblasts.

The proto-oncogene c-myb, whose expression is usually limited to cells of the hematopoietic lineages, can be expressed in fibroblasts if placed under the control of a constitutive promoter, such as the simian virus SV40 early promoter. 3T3 cells carrying a constitutively expressed human c-myb were found to grow in 1% serum or in a serum-free, platelet-derived growth factor-supplemented medium, whereas the parent cell line, BALB/c 3T3, needed insulinlike growth factor 1 (IGF-1) in addition to platelet-derived growth factor for growth. myb-carrying cells, however, could not grow in platelet-poor plasma. In fibroblasts, therefore, a constitutively expressed c-myb can abrogate the requirement for platelet-poor plasma or IGF-1. When 3T3 cells constitutively expressed both c-myc and c-myb, they could grow in serum-free medium without added growth factors. The ability of c-myb to abrogate in fibroblasts the IGF-1 requirement seems to be due to its ability to induce overexpression of IGF-1, as indicated by an increase in steady-state levels of IGF-1 mRNA. These results have some important implications; for instance, they suggest a commonality of pathways for entry into S phase in different cell types and the possibility of a myb-like or myb-equivalent gene product of critical importance for entry of fibroblasts into S phase.

Oncogenes in growth and development.

Oncogenes play a major role in the control of proliferation in animal cells. Because the growth of cell populations is regulated by the stimulatory and inhibitory growth factors in the environment, we have attempted in this review to relate the function of oncogenes to the mechanism of action of growth factors. This correlation allows a description of the cell cycle that rests on a molecular basis and in which protooncogenes figure prominently as the cellular messengers of the environmental growth stimuli.