Testosterone and progesterone titers were determined by RIA in the plasma of pregnant rats and their male and female fetuses from day 17 of gestation through the day of birth and in male and female neonates on days 3 and 5 post partum. Males had significantly higher mean testosterone levels than females from day 18 of gestation through day 5 post partum. Sex differences in plasma testosterone concentrations were greatest in the fetuses on days 18 and 19 of gestation when testosterone levels peaked in the males. Instances in which female fetuses had testosterone titers equal to or greater than their male littermates were found on every day of gestation except day 18. Mean testosterone concentrations in plasma of female fetuses were high throughout gestation (greater than 1000 pcg/ml). Testosterone concentrations decreased in both sexes after birth. Differences between the sexes remained significant, and although there was an overlap in the values for males and females, testosterone concentrations in females exceeded those of their male littermates in only one out of nine pairs of samples on day 5 and in none of seven pairs on day 3 post partum. There were no significant differences in progesterone levels in plasma of males and females, either pre- or postnatally. Progesterone titers changed as a function of days post conception in both the fetuses and their mothers. In the fetuses, progesterone levels declined progressively from day 18 post conception through the day of birth, while in the mother they rose from days 18 to 19 then declined between days 20 and 21 of pregnancy. Fetuses had lower progesterone titers than their mothers. From these data, we conclude that day 18 and possibly day 19 post conception represent a critical period during which the central nervous system of the male is primed by high levels of testosterone. Thereafter, the process of masculinization is completed by exposure to testosterone levels that are relatively low and need not be consistently higher than those of female littermates.

No abstract

Testosterone, progesterone, and corticosterone titers were measured by RIA in plasma of stressed and control pregnant rats and their male and female fetuses on days 17, 18, 19, and 21 of gestation and on the day of birth. The regimen of stress used (three 45-min periods of restraint under intense illumination daily from days 14-21 of pregnancy) causes failure of masculinization and defeminization of behavioral potentials in male offspring. In fetuses of both sexes, corticosterone titers increased sharply between days 17 and 18 postconception (pc) to a peak that was maintained through day 19 and then declined. This pattern resembled that obtained for testosterone in control male fetuses in which the levels of testosterone also rose sharply between days 17 and 18 pc. Corticosterone titers were elevated in samples obtained during the middle of the stress session from both the mothers (serum) and their male and female fetuses (plasma). Increased corticosterone levels were no longer evident in samples obtained from fetuses 75-165 min after the end of a stress session. Testosterone titers were altered by stress only in male fetuses. Their testosterone levels were elevated on day 17 pc, and the surge on days 18 and 19 pc, characteristic of control males, was absent in samples obtained 75-165 min after termination of stress. Progesterone titers were not affected by stress in either mothers or their fetuses. In both stressed and control groups, progesterone concentrations were identical in male and female fetuses, were higher in mothers than in fetuses, and declined in both fetuses and mothers between days 19 and 21 pc. Thus, a persistent effect of stress was observed only on testosterone and only in males.

SummaryLow-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.

Titers of testosterone in plasma were determined by radioimmunoassay in male rat fetuses of stressed and control mothers on days 17, 18, 19, 21, and 23 (the day of birth) after conception. In fetuses of stressed mothers, testosterone concentrations were highest on day 17, declined on days 18 and 19, and then remained unchanged. In the control fetuses, testosterone increased from relatively low concentrations on day 17 to the highest amounts on days 18 and 19, and then declined. Thus, the persistence of feminine and impaired masculine sexual behavior in male offspring of stressed mothers could be due to the absence of a surge of circulating testosterone during days 18 and 19 after conception, a period postulated to be critical in the development of the central nervous system in the rat.

Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested.

Summary Surfactant protein A (SP‐A), first identified as a component of the lung surfactant system, is now recognized to be an important contributor to host defence mechanisms. SP‐A can facilitate phagocytosis by opsonizing bacteria, fungi and viruses, stimulate the oxidative burst by phagocytes and modulate pro‐inflammatory cytokine production by phagocytic cells. SP‐A can also provide a link between innate and adaptive immune responses by promoting differentiation and chemotaxis of dendritic cells. Because of the obvious relevance of these mechanisms to the host defence and ‘gate keeping’ functions of the lower genital tract, we examined human vaginal mucosa for SP‐A protein and transcripts and analysed vaginal lavage fluid for SP‐A. By immunocytochemistry, SP‐A was identified in two layers of the vaginal epithelium: the deep intermediate layer (the site of newly differentiated epithelial cells); and the superficial layer (comprising dead epithelial cells), where SP‐A is probably extracellular and associated with a glycocalyx. Transcripts of SP‐A were identified by Northern blot analysis in RNA isolated from vaginal wall and shown, by sequencing of reverse transcription–polymerase chain reaction products, to be derived from each of the two closely related SP‐A genes, SP‐A1 and SP‐A2. SP‐A was identified in vaginal lavage fluid by two‐dimensional gel electrophoresis, and confirmed by mass spectrometry. This study provides evidence, for the first time, that SP‐A is produced in a squamous epithelium, namely the vaginal mucosa, and has a localization that would allow it to contribute to both the innate and adaptive immune response. The findings support the hypothesis that in the vagina, as in lung, SP‐A is an essential component of the host‐defence system. A corollary hypothesis is that qualitative and quantitative alterations of normal SP‐A may play a role in the pathogenesis of lower genital tract inflammatory conditions.

The expression of aromatase by breast cancer cells and the role of locally produced estrogen in the stimulation of tumor growth has been controversial. The present study was performed to determine the site of aromatization in human breast cancers, using both immunocytochemistry and in situ hybridization. The functional significance of locally produced estrogens on growth of the tumor was addressed by measuring aromatase activity and a marker of proliferation (PCNA score). In addition, histocultures of some tumors were carried out to investigate whether testosterone aromatization could stimulate tumor proliferation. Of the 19 tumors investigated, 10 (52.6%) showed significant immunoreactivity to antiaromatase antibody in the cytoplasm of tumor epithelial cells and in surrounding stromal cells. The presence of aromatase mRNA detected by ISH was also located in tumor epithelial cells and stromal cell, and the pattern of expression was the same as with immunocytochemistry. In the ten tumors that showed immunoreaction to aromatase, the average aromatase activity measured in cryosections was 286.5 +/- 18.6 (SE) fmol estrogen/mg protein.h, whereas in nine tumors with weak aromatase immunoreaction, the enzyme activity was 154.7 +/- 19.3 (SE) fmol estrogen/mg protein-h (P < 0.05). The mean PCNA score was 33.8 +/- 5.1 (SE)% in strongly stained tumors and 20.8 +/- 2.0 (SE)% in weakly stained tumors (P < 0.05). Aromatase activity level and PCNA score were significantly correlated. In histoculture of four tumors, estradiol increased the incorporation of [3H]-thymidine into DNA. In two of these tumors, aromatase activity was high and [3H]-thymidine incorporation into DNA was also stimulated by testosterone. In the other two tumors that had low aromatase activity, no such stimulation occurred with testosterone. The results indicate that aromatase is expressed mainly in tumor epithelial cells and that sufficient amounts of estrogen are synthesized by the tumor to produce a proliferative response. It is concluded that estrogen synthesis by cancer cells could play a important role in promoting growth in a significant proportion of breast tumors.