Biomedical subjects

I Pollard

Publications and source records attributed to I Pollard.

At least 19 recordsLinked to original sources

PubMed2001

Effects of caffeine and its reactive metabolites theophylline and theobromine on the differentiating testis.

A previous study in the rat (Pollard et al. 1990) established that caffeine, when administered during pregnancy, significantly inhibited the differentiation of the seminiferous cords and subsequent Leydig cell development in the interstitium. However, that study could not distinguish between the direct effects of caffeine and/or the intermediary secondary toxic effects of metabolites such as theophylline and theobromine. Because the fetus lacks the appropriate enzyme systems, clearance of toxic substances takes place via the placenta and maternal liver. Thus, a suitable in vitro system can effectively differentiate between primary and secondary drug effects. In the present study, 13-day-old fetal testis, at the stage of incipient differentiation, were cultured for 4 days in vitro in the presence of graded doses of caffeine, theophylline or theobromine. It was found that explants exposed to caffeine or theobromine differentiated normally, developing seminiferous cords made up of Sertoli and germ cells, soon followed by the differentiation of functionally active Leydig cells appearing in the newly formed interstitium. However, explants exposed to theophylline failed to develop seminiferous cords and, as a consequence, Leydig cells. In conclusion, insights obtained from different experimental methods, such as organ culture or whole organism studies, are not always identical. It may be prudent, therefore, to take into account that certain experimental techniques, despite providing valuable information, may require confirmation by other test methods in order to obtain an in-depth understanding of mechanisms of action involved.

Animals↗

PubMed2000

Substance abuse and parenthood: biological mechanisms--bioethical challenges.

This review catalogues the long-term health effects of parental recreational drug abuse on the fetus and the subsequent well-being of the child. It is hard to conceive that parents would knowingly harm the health of their children, yet toxic effects resulting from ignorance, addiction or any of a number of socioeconomic factors are still responsible for handicapping countless potentially healthy offspring. The negative effects of female recreational drug and alcohol abuse during pregnancy are well documented, but exposure prior to conception and male-mediated effects are less well publicized. Abnormalities in the sperm are prevalent among men who consume recreational drugs, and birth defects are more often linked with paternal than with maternal DNA damage. This review is divided into three parts. Part I describes the biology and potential mechanisms of adverse alterations in reproductive potential, Part II explores the socioeconomic determinants of substance use, and raises the question of poverty. Drug-induced disability is not evenly distributed among the population as there are ethnic and socioeconomic disparities of infant mortality, childhood morbidity and reproductive dysfunction. Part III describes the author's conclusion that fundamental social change is needed to protect future children without threatening parents' basic freedom, and real change requires new beliefs and prioritics that must evolve from the ground up. An ecological model of care concentrating on health issues is described. Such an ecological model of care is in tune with the fundamental principles of bioscience ethics and emphasises that high quality education, health and good preconceptional/prenatal care are essentials in the search for greater equity in standard of living across a population.

Abnormalities, Drug-Induced↗

PubMed1999

Maternal caffeine consumption during pregnancy does not affect preimplantation development but delays early postimplantation growth in rat embryos.

Models for studying prenatal drug-induced intrauterine growth retardation (IUGR) have, without exception, measured growth-related factors in the postimplantation embryo, fetus or neonate. Therefore, it is not known whether effects of drug exposure on growth and metabolism begin early in the preimplantation embryo, or whether IUGR is exclusively a postimplantation phenomenon. The present study investigates whether caffeine, a drug known to induce a dose-dependent fetal IUGR, affects embryo development before and/or after implantation or is exclusively a fetal phenomenon. Preimplantation embryo assessment (with treatment from Days 2 to 4 of pregnancy) included glucose utilization, cell number evaluation and stage of development (morula to hatched blastocyst); whereas, postimplantation embryo assessment (treatment from Days 2 to 10, 10.5 or 11 of pregnancy) included somite number evaluation and extent of neural tube closure, as seen using scanning electron microscopy. Comparing control preimplantation embryos with those exposed to 30 and 60 mg kg(-1) caffeine did not reveal any effects of caffeine exposure, as assessed on Day 5 of gestation. However, postimplantation embryo development assessed on Day 12 of gestation revealed that caffeine exposure of 15 and 30 mg kg(-1) significantly reduced, at both dosage levels, somite number and the extent of neural tube closure. In addition, comparisons of control and experimental groups revealed that in the high-dose caffeine group the forebrain cavity was significantly enlarged and bounded by a reduced, irregularly aligned neuroepithelium. The findings suggest that IUGR is a phenomenon first identifiable during late postimplantation embryogenesis and continues in fetal life.

Animals↗

PubMed1997

The circulating concentrations of FSH, LH and prolactin in the oestradiol-implanted ovariectomized ewe treated with caffeine.

Caffeine, a trimethylxanthine alkaloid, is a psycho-active drug that effects a wide range of physiological systems, including the reproductive system. Reports of infants with intra-uterine growth retardation and lowered birth weight as a result of in utero exposure to caffeine, are increasing. The drug is also known to alter steroidogenesis but it is not certain whether this is a direct and/or an indirect effect with the involvement of the central nervous system. Thus, an experiment was designed to determine the effect of acute caffeine administration on the circulating concentrations of gonadotrophins and prolactin in the ovariectomized oestradiol-implanted ewe. A single intravenous dose of caffeine (20 mg kg-1 bodyweight) did not affect circulating gonadotrophin concentrations with the parameters for the pulsatile secretion of luteinizing hormone (LH) and the mean concentration of follicle stimulating hormone (FSH) being similar in both experimental and control groups. Circulating prolactin levels, on the other hand, were significantly (P < 0.01) elevated following intravenous treatment with caffeine. The effect was immediate following caffeine administration with elevated concentrations being maintained over the next 3 h before their return to pre-treatment concentrations. The response was bi-phasic with peaks of prolactin concentrations at 1 and 3 h. The results of this experiment show that acute caffeine exposure does not affect the secretion of gonadotrophins from the anterior pituitary gland. Furthermore, they show that acute administration of caffeine stimulates prolactin secretion via an action that is independent of oestradiol feedback and which we suggest, may involve the ACTH/adrenal axis.

Animals↗

PubMed1996

Preconceptual programming and sexual orientation: a hypothesis.

To date, biological explanations of sexual orientation have broadly focused on genes and/or prenatal hormonal environments which are thought to act on the brain to provide the neural circuitry on which sexual orientation is inscribed. The proposed models are open to criticism when applied to a healthy population at large because of the implied reference to developmental anomalies. For this reason the present paper challenges the traditional viewpoint and hypothesizes that the foundation of adult sexual orientation may be the result of adaptive programming beginning before conception. According to this hypothesis the continuum spanning human sexuality has its etiology defined in terms of male and female-mediated forms of selective preconceptual marking. The hypothesis also assumes that, via the mechanism of genomic imprinting, the imprinted gene is able to switch through different states of potential activity from the incomplete to the fully penetrant state resulting in a continuum of orientations ranging from asexual, through graded bisexual to homosexual. An adaptive preconceptual program has biological significance as it ensures a generational preparedness for the prevailing conditions. The physiological aspects and circumstantial evidences which were important in developing the new hypothesis are also described.

Adaptation, Physiological↗

PubMed1996

Pharmacokinetics of caffeine in the oestrogen-implanted ovariectomized ewe.

The disposition kinetics of caffeine and its metabolites theophylline, theobromine and paraxanthine in the oestrogen-implanted ovariectomized ewe following single intravenous doses of 5, 10, 15 or 20 mg/kg caffeine are described in this paper. Blood was collected at 5, 30 and 60 min, and at 3, 6, 8, 12, 24, 48, 72, 96, 120, 144, 192 and 240 h after dosing. Caffeine concentrations peaked within 30 min of administration but remained in a plateau phase for 3-6 h before declining over a prolonged period of time. For caffeine the mean elimination half-life was calculated to be 47 h. Detectable caffeine concentrations remained for 10 days after administration in all groups. The area under the plasma concentration-time curve (AUC) values were used to compare tissue caffeine exposure and were, approximately, linearly related to dose. Metabolite concentrations were maintained at peak and near peak concentrations for 6-24 h after caffeine administration followed by prolonged elimination. Because of significant species differences in drug elimination rates, it is concluded that the ewe is not a suitable animal model in the clinical context. However, the sheep may well provide insights into caffeine's mechanism of action of relevance to veterinary drug research.

Animals↗

PubMed1996

Case report: pneumomediastinum and pneumothorax complicating colonoscopy.

Colonic perforation is potentially the most serious complication of colonoscopy. Both the clinical manifestation and rapidity of onset of symptoms can vary depending on whether the perforation occurs directly into the peritoneal cavity or into the retroperitoneal space. Colonic perforation is often associated with abdominal pain, although more uncommon presentations have been documented. A case report of a unilateral pneumothorax and pneumomediastinum complicating colonoscopy is described, which responded well to conservative measures without recourse to surgical intervention, antibiotic therapy or parenteral alimentation.

Aged↗

PubMed1994

In utero exposure to caffeine causes delayed neural tube closure in rat embryos.

We have investigated the effect of caffeine on embryo growth and development. Caffeine (25 mg/kg) was administered on gestation day (g.d.) 8-9 and the embryos examined histologically 24 h after the final dose. The crown-rump length of caffeine treated embryos (1.92 +/- 0.08 mm) was significantly smaller (P < 0.001) than the controls (2.91 +/- 0.26 mm) as was the circumferential length (caffeine vs. controls, 3.79 +/- 0.16 mm vs. 6.03 +/- 0.61 mm; P < 0.001). Additional measures, such as development of the heart, eye, and limb buds, were also reduced in the caffeine treated embryos. The most striking difference between the control and caffeine treated embryos was the larger proportion of treated embryos with regions of open neural tube. This was most marked in the caudal region of the embryos where 91% of treated embryos had regions of open neural tube compared with 14% of controls. The amount of open neural tube in any individual caffeine treated embryo did not relate to the crown-rump or circumferential length of that embryo nor was the effect restricted to particular litters. These results indicate that caffeine had a significant effects on embryonic growth and development.

Animals↗

PubMed1993

Accumulation of theophylline, theobromine and paraxanthine in the fetal rat brain following a single oral dose of caffeine.

This paper describes the disposition of caffeine and its metabolites, theophylline, theobromine and paraxanthine in the 20-day fetal and adult brains following a single maternal dose of 5 or 25 mg/kg caffeine. Brains and plasma were collected 5 and 30 min, and 1, 3, 8 and 24 h after dosing. It was found that fetal and adult caffeine AUC (area under the concentration-time curve) values did not differ between the brain and plasma at either dose. Caffeine's primary metabolites theophylline, theobromine and paraxanthine did, however, accumulate in the fetal brain at both doses resulting in a 3-fold increase in brain metabolite exposure compared to fetal circulatory levels. In contrast to the fetus, metabolite AUC values after a dose of 25 mg/kg were found to be lower in the brains of adults compared with plasma. This suggests that caffeine's primary metabolites might be selectively excluded from the adult brain. In conclusion we have shown that, unlike the adult, the fetal rat brain accumulates theophylline, theobromine and paraxanthine when exposed to caffeine doses comparable to those attainable by normal human consumption. Since many aspects of caffeine metabolism are similar in the rat and human, we suggested that particular attention should be paid to the consumption of caffeine during pregnancy.

Animals↗

PubMed1993

Immunohistochemical localisation of the 25 kDa heat shock protein in unstressed rats: possible functional implications.

The distribution of the 25 kDa heat shock protein (hsp 25) in a number of tissue types from unstressed rats was investigated. Immunohistochemical analysis showed that hsp 25 was not found in the thymus, brain (cerebral cortex and cerebellum), testis, adrenal, liver, spleen, or kidney. A number of cells in the anterior pituitary showed strong staining. These cells were tentatively identified as being either gonadotropes or thyrotropes. Strong staining was also observed in the blood vessels within these tissues. Hsp 25 was found to be localised predominantly to intestinal smooth muscle of the duodenum and colon and to vascular smooth muscle. Smooth muscle from other sites, such as the trachea, was also intensely stained. Lower and more variable amounts of staining were observed in cardiac and skeletal muscle. These observations suggest that hsp 25 is associated with cytoskeletal elements in muscle, and that the high staining intensity in smooth muscle might be due to the lack of internal architecture present in this muscle type.

Animals↗

PubMed1993

Caffeine does not increase synthesis of heat shock proteins in rat embryos.

Caffeine exposure in utero in rats is known to result in intrauterine growth retardation and lowered birth weight as well as changes to behaviour and brain biochemistry. We have investigated whether caffeine's embryotoxicity is a result of the events associated with increased hsp synthesis, i.e., disruption to normal protein synthesis. Caffeine (30 mg/kg) was administered orally to pregnant rats as single or repeated doses. Embryos were removed 3 h after dosing on gestation day (GD) 9, 10, 11 and 12 and total embryonic protein and RNA analysed. There was no change in the mRNA or protein levels of hsp 88, 71/73, and 25 after acute or chronic treatment. To separate the direct effect of caffeine from those mediated through the mother, whole rat embryo culture was used. Caffeine (50 micrograms/ml) for 90 min did not increase hsp 88, 73 or 25 mRNA levels in 9.5, 10.5 and 11.5 GD cultured embryos. We conclude that in vivo or in vitro treatment of 9-12 GD rat embryos with moderate to high doses of caffeine does not increase the synthesis of the major mammalian hsps. Hence, hsp induction is unlikely to play a role in the embryotoxic actions of caffeine.

Animals↗

PubMed1993

Immunohistochemical localisation of the 90, 70 and 25 kDa heat shock proteins in control and caffeine treated rat embryos.

Human and animal experimental data demonstrate that in utero exposure to caffeine results in intrauterine growth retardation and long-term behavioural and reproductive effects. We have suggested that the disruption of normal transcription and translation associated with the initiation of the heat shock response may be a possible mechanism of action of caffeine. This hypothesis was investigated using immunohistochemistry to determine whether an acute (3 h) dose of 30 mg/kg caffeine alters the distribution of hsp 90, 70 and 25 in 10.5-12.5 g.d. rat embryos. In the control embryos hsps 90 and 70 were distributed throughout the embryo with no areas of specific accumulation. Hsp 25 was localised to the developing myocardium of 10.5, 11.5 and 12.5 g.d. embryos and the myotome of 11.5 and 12.5 g.d. embryos. The appearance of hsp 25 was correlated with the onset of muscle fibre differentiation and it is suggested that hsp 25 is associated with cytoskeletal proteins. Following dosing with caffeine no change in the distribution of staining for hsp 90, 70 and 25 was found. These results strongly suggest that caffeine's mechanism of action does not involve initiation of the heat shock response.

Animals↗

PubMed1993

Placental transfer and foetal disposition of caffeine and its immediate metabolites in the 20-day pregnant rat: function of dose.

1. The dispositions of caffeine and its immediate dimethylxanthine metabolites, theobromine, theophylline and paraxanthine were studied after a single oral dose of 5 and 25 mg/kg caffeine administered to 20-day pregnant and non-pregnant rats, respectively. 2. Peak plasma levels were reached between 1 and 3 h in all fluids and tissues studied. 3. The elimination phase, however, differed significantly between the pregnant and non-pregnant groups. For 25 mg/kg the plasma half-life (t1/2) of caffeine was significantly longer in the pregnant than the non-pregnant group; for 5 mg/kg the elimination rate of caffeine was similar in both groups. 4. AUC values were used to compare caffeine and metabolite exposure in foetal tissues. At 5 mg/kg, peak concentrations for amniotic fluid, foetal blood, liver and kidney were not significantly different from one another. At 25 mg/kg peak levels in foetal liver and kidney were significantly less than those of foetal blood, amniotic fluid or placenta. 5. Because of the observed increase in maternal t1/2 at high dosage, a cautionary note is sounded about caffeine intake in pregnancy.

Amniotic Fluid↗

PubMed1992

Caffeine-mediated effects on reproductive health over two generations in rats.

The present study was designed to investigate the mechanism(s) underlying previously observed birth weight differences found in the first litter of the second (F2) generation bred from caffeine-exposed F1 females. The effect of exposure to caffeine in utero on subsequent sexual receptivity, fertility, gestation length, parturition, nesting activity, maternal behaviour, and reproductive senescence in the F1 mothers, and the viability of the F2 offspring was investigated. This information was collected by breeding control or caffeine exposed females for 8 consecutive litters. It was demonstrated that exposure to caffeine did not affect the sexual receptivity, fertility, gestation length, or maternal behaviour of the F1 females, but parturition was prolonged and the viability of the F2 generation was seriously jeopardized. Many F2 pups were born significantly larger than their control counterparts and a significant proportion of litters (after the first two litters) were wholly stillborn. It was concluded that a changed genetic program, mediated via the F2 fetus, delayed the normal progression of parturition. This, in turn, compromised the F1 mothers and caused increased mortality of their offspring. The severity of the outcome was dose dependent.

Animals↗

PubMed1990

Influence of caffeine administered during pregnancy on the early differentiation of fetal rat ovaries and testes.

In this manuscript it is demonstrated that caffeine when administered to the rat (30 mg/kg per day) during pregnancy affected certain aspects of normal sexual differentiation of the fetal gonads. In the male fetus caffeine was shown to significantly inhibit differentiation of the interstitial tissue and Leydig cells. A significant decrease in the number of Leydig cells exhibiting 3 beta-hydroxysteroid dehydrogenase activity, and consequent reduction in testosterone biosynthesis in the fetal testes at day 15 and day 16 of gestation was found. While the beginnings of Leydig cell function was first seen in the afternoon of the 14th day of gestation in both the experimental and control groups, the adverse effects became marked by 15 days and extreme by 16 days. With the aid of the scanning electron microscope it was observed that caffeine also had an effect on the earlier morphogenic organisation of the seminiferous cords at 13 days of gestation where the aggregation of the Sertoli cells forming the seminiferous cords, was marginally advanced in the control group. However the treated group had caught up by 14 days of gestation. In the female fetus scanning electron microscope studies revealed that in the control and caffeine treated groups the early phase of ovarian differentiation and the later 20 day ovaries were similar in morphology, tissue arrangement and overall appearance. It was also seen that chronic caffeine exposure did not affect the rate of early mitotic proliferation of germ cells, nor later in development the numbers entering meiosis. At 20 days of gestation the numbers and proportion of meiotic to atretic oocytes were comparable in the control and treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxysteroid Dehydrogenases↗

PubMed1988

Increases in plasma concentrations of steroids in the rat after the administration of caffeine: comparison with plasma disposition of caffeine.

It was demonstrated that the altered endocrine environment caused by caffeine consumption could be equated with a stress-like pattern of response. A single acute treatment with caffeine (30 or 60 mg/kg) to male rats approximately 85 days old caused plasma concentrations of corticosterone, progesterone, testosterone and Na+ to rise significantly above control values. These changes were evident 3 min after caffeine administration and were maintained for 1-4 h before returning to normal. In animals exposed to daily chronic caffeine treatment for 10 days or more the levels of progesterone fell and Na+ rose significantly compared with control values at 24 h after administration. Following a single treatment of 30 mg/kg, caffeine was detected in blood plasma after 3 min, and reached peak levels by 1 h. After 24 h, less than 2% of the peak levels of caffeine remained. Metabolites of caffeine were detectable within 6 min and reached their peak levels 4 and 12 h later for theophylline and theobromine respectively. It is suggested that high steroid levels may in the long-term cause an altered hepatic clearance pattern affecting both steroid metabolism and caffeine elimination. A preliminary study of the morphology of livers from males chronically exposed to caffeine revealed that the hepatic cells lost cytoplasmic matrix, and that the sinusoids did not show up as clear spaces, compared with those in the controls.

Animals↗

PubMed1988

Male mediated caffeine effects over two generations of rats.

Caffeine exposure of a male rat prior to mating affected his progeny and the progeny of a second generation. The dose chosen, 30 mg/kg per day given orally, was approximately equivalent to a caffeine intake of 10-12 cups of brewed coffee daily. In the first (F1) generation caffeine consumption of the sires for a minimum period of 15 days prior to mating with drug naive females, caused significant fetal growth retardation of both sexes and an increased postnatal mortality of pups between weeks 1 and 2, many of which displayed characteristics of runts. Persistent caffeine effects were also found in a second (F2) generation obtained by back breeding male and female F1 offspring from control and treated groups. The F2 pups of both sexes, from the female breeding line, were born significantly heavier when compared with their control counterparts. In the male breeding line, 33% of the litters conceived were aborted in utero, and among the young F2 pups born runts were again evident. At the conclusion of the breeding for the first generation the testes of the FO sires were studied after they received caffeine for 38 consecutive days. The experimental testes showed a marked degeneration characterized by significant overall size reduction, breakdown of the germinal epithelium, accumulation of cellular debris in the lumen of the seminiferous tubules, and significant reduction in the abundance of mature spermatozoa. On ultrastructural examination there appeared to be genetic damage to the spermatozoa where nucleic cysts and pouches were seen.

Animals↗

PubMed1987

Effects of caffeine administered during pregnancy on fetal development and subsequent function in the adult rat: prolonged effects on a second generation.

Caffeine, when administered in moderate (30 mg/kg X d) or high (60 mg/kg X d) doses during pregnancy, was shown to cause significant fetal growth retardation of both sexes. Mortality rate at or soon after birth was significantly higher and litter size significantly lower in the litters treated with 60 mg. The subsequent growth rates were also affected. The experimental pups grew more slowly, with growth plateauing at the same age resulting in smaller adults. The male offspring when subjected to short-term stress (one session) in adulthood showed an intact emergency response, demonstrating an adequate ability to react to a sudden environmental change. A significant decrease in 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity, and consequent reduction in testosterone biosynthesis, in the fetal testes at d 18 and 20 of gestation was also found for both doses of caffeine. Low 3 beta-HSD activity persisted to adulthood in the group receiving 60 mg. Lingering effects were observed in a second litter bred 8 wk after the discontinuation of caffeine consumption. In this second breeding, the offspring of both sexes from both caffeine doses were born significantly smaller when compared to the controls. Persistent effects of caffeine were also found in second-generation rats bred from females who were exposed to caffeine in utero. The pups of both sexes were born significantly heavier after a significantly longer gestation. The subsequent growth did not differ from that of the controls. It was suggested that a changed genetic program in the ovarian germ cells of the first generation and/or a changed uterine environment in the second generation may be implicated.

3-Hydroxysteroid Dehydrogenases↗