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Biomedical subjects

L Hilakivi-Clarke

Publications and source records attributed to L Hilakivi-Clarke.

At least 19 recordsLinked to original sources
PubMed2007

Preventing excessive weight gain during pregnancy - a controlled trial in primary health care.

OBJECTIVE: To investigate whether individual counselling on diet and physical activity during pregnancy can have positive effects on diet and leisure time physical activity (LTPA) and prevent excessive gestational weight gain. DESIGN: A controlled trial. SETTING: Six maternity clinics in primary health care in Finland. The clinics were selected into three intervention and three control clinics. SUBJECTS: Of the 132 pregnant primiparas, recruited by 15 public health nurses (PHN), 105 completed the study. INTERVENTIONS: The intervention included individual counselling on diet and LTPA during five routine visits to a PHN until 37 weeks' gestation; the controls received the standard maternity care. RESULTS: The counselling did not affect the proportion of primiparas exceeding the weight gain recommendations or total LTPA when adjusted for confounders. The adjusted proportion of high-fibre bread of the total weekly amount of bread decreased more in the control group than in the intervention group (difference 11.8%-units, 95% confidence interval (CI) 0.6-23.1, P=0.04). The adjusted intake of vegetables, fruit and berries increased by 0.8 portions/day (95% CI 0.3-1.4, P=0.004) and dietary fibre by 3.6 g/day (95% CI 1.0-6.1, P=0.007) more in the intervention group than in the control group. There were no high birth weight babies (>or=4000 g) in the intervention group, but eight (15%) of them in the control group (P=0.006). CONCLUSIONS: The counselling helped pregnant women to maintain the proportion of high-fibre bread and to increase vegetable, fruit and fibre intakes, but was unable to prevent excessive gestational weight gain.

Adult↗
PubMed2004

In utero alcohol exposure increases mammary tumorigenesis in rats.

Findings in humans and animal models suggest that in utero hormonal and dietary exposures increase later breast cancer risk. Since alcohol intake by adult women consistently increases their breast cancer risk, we wondered whether maternal alcohol consumption during pregnancy increases female offspring's mammary tumorigenesis. In our study, pregnant female rats were pair-fed isocaloric diets containing either 0 (control), 16 or 25 g alcohol kg(-1) feed between days 7 and 19 of gestation. These alcohol exposures generate blood alcohol levels that correspond to low and moderate alcohol consumption and are lower than those that induce foetal alcohol syndrome. Serum oestradiol levels were elevated in pregnant rats exposed to alcohol (P<0.003). When adult, female offspring of alcohol-exposed dams developed significantly more 7,12-dimethylbenz[a]anthracene -induced mammary tumours, compared to the controls (tumour multiplicity; mean+/-s.e.m., controls: 2.0+/-0.3, 16 g alcohol: 2.7+/-0.4 and 25 g alcohol: 3.7+/-0.4; P<0.006). In addition, the mammary epithelial tree of the alcohol-exposed offspring was denser (P<0.004) and contained more structures that are susceptible for the initiation of breast cancer (P<0.001). Immunohistochemical assessment indicated that the mammary glands of 22-week-old in utero alcohol-exposed rats contained elevated levels of oestrogen receptor-alpha (P<0.04) that is consistent with the changes in mammary gland morphology. In summary, maternal alcohol intake during pregnancy increases female offspring's mammary tumorigenesis, perhaps by programming the foetal mammary gland to exhibit persistent alterations in morphology and gene expression. It remains to be determined whether an increase in pregnancy oestradiol levels mediated alcohol's effects on offspring's mammary tumorigenesis.

Animals↗
PubMed2004

Trimester-specific reference intervals for thyroxine and triiodothyronine in pregnancy in iodine-sufficient women using isotope dilution tandem mass spectrometry and immunoassays.

BACKGROUND: Accurate assessment of the pregnant woman's thyroid status is critical, for both the initiation of thyroid hormone therapy and for the adjustment of thyroid hormone dose in those already receiving thyroid hormone. Trimester-specific intervals are especially important during pregnancy when thyroid insufficiency may be associated with adverse obstetric outcome and fetal neurodevelopmental deficits. We defined pregnancy-specific reference intervals for thyroxine (T4) and 3,5,3'-triiodothyronine (T3). We used a novel isotope dilution tandem mass spectrometry (LC/MS/MS) method, and compare these to reference intervals obtained by immunoassays (IAs) performed on the same samples. METHODS: Concentrations of circulating T4 and T3 were measured simultaneously during first, second and third trimesters and postpartum in iodine-sufficient, healthy, singleton pregnancies using API-3000 LC/MS/MS with deuterium-labeled internal standard (L-thyroxine-d2). Immunoassays were conducted on the same samples (T4 Dade Behring RxL, T3 DPC-Immunolite). RESULTS: Linear regression is reported for method comparisons; for T4, the slope decreased from r=0.900 in nonpregnant women to 0.802-0.820 during pregnancy. For T3, correlations between LC/MS/MS and immunoassays were weaker in all cases (r=0.407-0.574). CONCLUSION: In this longitudinal study, we established trimester-specific reference intervals for T4 and T3 by LC/MS/MS and compare these to intervals obtained by immunoassays.

Adult↗
PubMed2004

Nutritional modulation of the cell cycle and breast cancer.

In the USA, breast cancer accounts for approximately 30% of all cancers diagnosed in women and is the second leading cause of cancer death in women. An understanding of the molecular genetic events governing breast cancer lead to both prevention and intervention strategies in an attempt to reduce mortality and morbidity from breast cancer. The last three decades of medical research examining the molecular pathogenesis of cancers have provided compelling evidence for the universal disruption of the cell cycle in human tumors. The importance of cell cycle control in human cancer was recognized by the recent award of the Nobel Prize to Drs Nurse and Hartwell for their discovery of the cyclins. More recent studies have demonstrated a critical interface between hormonal signaling and the cell cycle. In parallel, epidemiological studies have identified as being associated with breast cancer important dietary and environmental components that regulate hormonal signaling. This review describes the intersection of these two fields of study, which together imply a role for dietary prevention and intervention in human breast cancer perhaps through altering cell cycle components.

Androgens↗
PubMed2001

Tallness and overweight during childhood have opposing effects on breast cancer risk.

Using birth and school health records we studied how weight and height during childhood affect breast cancer risk among 3447 women born during 1924-33 at the University Hospital of Helsinki, Finland. Through linkages with the National Hospital Discharge Registry and the Cause of Death Registry we identified 177 women who during 1971-1995 had been admitted to hospital with breast cancer, of whom 49 had died from the disease. Of these, 135 (76%) were aged 50 years or more at the time of diagnosis, and therefore likely to have been post-menopausal. Hazard ratios for breast cancer rose with increasing weight and length at birth, though neither trend was statistically significant. At each age, from 7 to 15 years, the girls who later developed breast cancer were on average taller and had lower body mass than the other girls. Unadjusted hazard ratios rose across the range of height (P = 0.01 at age 7 years) and fell across the range of body mass index (P = 0.009 at age 7 years). In a simultaneous analysis the hazard ratio for breast cancer was 1.27 (95% CI 0.97-1.78, P = 0.08) for every kilogram increase in birth weight and 1.21 (95% CI 1.06-1.38, P = 0.004) for every kg/m(2) decrease in body mass index at 7. Our findings indicate that tallness in childhood is associated with increased risk of developing breast cancer. One possible explanation is persisting high plasma concentrations of insulin-like growth factors in tall women. In contrast, we found that being overweight in childhood reduces breast cancer risk. The increased adipose tissue-derived oestrogen levels in overweight children could induce early breast differentiation and eliminate some targets for malignant transformation.

Adolescent↗
PubMed2001

Maternal and prepubertal diet, mammary development and breast cancer risk.

At present, we do not know what causes sporadic breast cancer. Environmental factors,particularly diet, appear to explain at least 70% of newly diagnosed breast cancers, but it is not clear what these factors are. We propose that the lack of progress in this area is due to a lack of considering the effect of timing of environmental and dietary exposures on the breast. The evidence provided above suggests that an in utero exposure to an estrogenic environment-including that caused by diet [high (n-6) PUFA or genistein]-increases breast cancer risk. This increase may be mediated by an increased presence of TEB in the mammary epithelial tree and increased ER-alpha levels, reduced ER-beta levels or both. Prepubertal estrogenic exposure, in contrast, reduces later risk of developing breast cancer. The protective effect of estrogens may be mediated by early epithelial differentiation, reduced presence of ER-alpha and increased levels of ER-beta in the mammary gland. The challenge we are now facing is to determine whether the data obtained mainly through the use of animal models is relevant to women and if so, how we might be able to modulate pregnancy and childhood estrogenic exposure by appropriate dietary modifications to reduce breast cancer risk in women.

Breast↗
PubMed2001

Breast cancer: dietary and environmental oestrogens.

Breast cancer is among the most common of the cancers that occur in women living in western societies. It is a much-feared disease and the risks are confusing and often badly reported. Oestrogen levels are a known risk factor. But is it possible to lower the risk? And where are all the oestrogens coming from?

Breast Neoplasms↗
PubMed2000

Estrogens, BRCA1, and breast cancer.

Findings obtained in in vitro assays and animal studies indicate that estrogens might influence the activity of the tumor suppressor gene BRCA1, and BRCA1 in turn may suppress the activity of the estrogen receptor. This review will discuss the possibility that interactions between estrogens and BRCA1 partly explain why elevated circulating estrogen levels appear to increase breast cancer risk among postmenopausal women but not among young women. A hypothesis is proposed that estrogens have a dual role in affecting breast cancer risk. In young women whose breasts have not yet accumulated critical mutations required for cancer initiation and promotion, activation of BRCA1 by estrogens helps to maintain genetic stability and induce differentiation, and therefore estrogens do not increase breast cancer risk. Breasts of older women, in contrast, are likely to contain transformed cells whose growth is stimulated by estrogens. Although BRCA1 is also probably activated by estrogens in older women, its function may have been impaired, for example, due to increased methylation associated with aging. Estrogen exposure in women who carry germ-line mutations in BRCA1 may always increase breast cancer risk because estrogens would be able to cause DNA damage and increase genetic instability without being opposed by BRCA1-induced repair activity. This might lead to an increase in the number of overall mutations, including those that initiate breast cancer. In addition to increasing genetic instability, reduced BRCA1 activity may also be linked to changes in the mammary gland morphology that predispose individuals to breast cancer. For example, a persistent presence of lobules type 1, which are the least differentiated lobular structures in the human breast, is seen in the BRCA1 mutation carriers. The aim of this review is to discuss the role of premenopausal estrogens in breast cancer and to initiate more research that would lead to novel means of reducing breast cancer risk, particularly among BRCA1 mutation carriers.

Animals↗
PubMed2000

Genistein: does it prevent or promote breast cancer?

Diet is estimated to contribute to approximately 50% of all newly diagnosed breast cancers. As such, a search for dietary factors differentially consumed among populations with increased breast cancer risk (e.g., Caucasians) compared to those with low risk (e.g., Asians) has become a priority. One such dietary component, which is typical to the Asian but not the Caucasian diet, is soy. We review data relevant to attempts to determine whether soy, and more specifically genistein, is a dietary component that may help to explain the dramatic disparity in breast cancer risk among these populations.

Asia↗
PubMed1999

The influence of maternal diet on breast cancer risk among female offspring.

The induction of breast cancer is a long process, containing a series of biological events that drive a normal mammary cell towards malignant growth. However, it is not known when the initiation of breast cancer occurs. One hypothesis is that a high estrogenic environment during the perinatal period increases subsequent breast cancer risk. There are many sources of extragonadal estrogens, particularly in the diet. The purpose of this paper is to review the evidence that a high maternal intake of dietary fats increases serum estrogens during pregnancy and increases breast cancer risk in daughters. Our animal studies show that a high maternal consumption of corn oil consisting mainly of linoleic acid (omega-6 polyunsaturated fatty acid, PUFA), increases both circulating estradiol (E2) levels during pregnancy and the risk of developing carcinogen-induced mammary tumors among the female rat offspring. A similar increase in breast cancer risk occurs in female offspring exposed to injections of E2 through their pregnant mother. Our data suggest that the mechanisms by which an early exposure to dietary fat and/or estrogens increases breast cancer risk is related to reduced differentiation of the mammary epithelial tree and increased number of mammary epithelial cell structures that are known to the sites of neoplastic transformation. These findings may reflect our data of the reduced estrogen receptor protein levels and protein kinase C activity in the developing mammary glands of female rats exposed to a high-fat diet in utero. In summary, a high dietary linoleic acid intake can elevate pregnancy estrogen levels and this, possibly by altering mammary gland morphology and expression of fat- and/or estrogen-regulated genes, can increase breast cancer risk in the offspring. If true for women, breast cancer prevention in daughters may include modulating the mother's pregnancy intake of some dietary fats.

Animals↗
PubMed1999

Prepubertal exposure to zearalenone or genistein reduces mammary tumorigenesis.

Prepubertal exposure to a pharmacological dose (500 mg kg(-1)) of the phyto-oestrogen genistein can reduce the incidence and multiplicity of carcinogen-induced mammary tumours in rats. However, such an exposure also disrupts the function of the hypothalamic-pituitary-gonadal axis, making it unsuitable for breast cancer prevention. We studied whether prepubertal exposure to genistein at a total body dose broadly comparable to the level typical of Oriental countries, approximately 1 mg kg(-1) body weight, affects mammary tumorigenesis. We also studied whether prepubertal exposure to zearalenone, a major source for phyto-oestrogens in the USA, influences breast cancer risk. Prepubertal rats were treated between postnatal days 7 and 20, with 20 microg (approximately 1 mg kg(-1) body weight) of either genistein or zearalenone. Zearalenone exposure significantly reduced both the incidence and multiplicity of mammary tumours induced by 7,12-dimethylbenz(a)anthracene (DMBA). Genistein exposure significantly reduced tumour multiplicity, but not tumour incidence, when compared with vehicle-treated animals. Furthermore, 60% of the tumours in the genistein group were not malignant, while all the tumours analysed for histopathology in the vehicle and zearalenone groups were adenocarcinomas. A higher number of differentiated alveolar buds, and lower number of terminal ducts, were present in the DMBA-treated mammary glands of the phyto-oestrogen exposed rats. The concentration of oestrogen receptor (ER) binding sites after the DMBA treatment was low in the mammary glands of all groups but a significantly higher proportion of the glands in the zearalenone exposed rats were ER-positive (i.e. ER levels > or = 5 fmol mg(-1) protein) than the glands of the vehicle controls. Our data suggest that a prepubertal exposure to a low dose of either zearalenone or genistein may protect the mammary gland from carcinogen-induced malignant transformation, possibly by increasing differentiation of the mammary epithelial tree.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Hypomethylation of an exon I estrogen receptor CpG island in spontaneous and carcinogen-induced mammary tumorigenesis in the rat.

Loss of methylation at a CpG island in exon I of the rat ER gene was observed in 48% of the spontaneous mammary tumors in old female Wistar rats and 22% of the contralateral normal mammary tissues. The majority of the methylation losses were total. Similarly, 50% of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in young Sprague-Dawley rats exhibited a partial or total loss of methylation at this site, while all normal mammary tissues in young rats were fully methylated. Loss of ER methylation also increased with age in normal mammary tissues of tumor-free rats approaching 12.5% in middle-aged and 43% in old rats. In addition, 66% of mammary glands obtained from young rats that are subsequently at an increased risk to develop breast cancer due to manipulation of in utero dietary fat intake, exhibited methylation loss while no methylation changes were observed in rats at no increased risk for breast cancer. Therefore, the loss of ER methylation is more extensive in mammary glands of rats at high than low breast cancer risk, in old than young, and in mammary tumors than in normal tissues. The data suggest that hypomethylation of a growth-associated ER gene may be a common event in mammary tumorigenesis in the rat and may be of predictive value as a marker of increased breast cancer risk in aged individuals.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Consumption of a high-fat diet alters estrogen receptor content, protein kinase C activity, and mammary gland morphology in virgin and pregnant mice and female offspring.

Previous studies have shown that a diet high in polyunsaturated fatty acids increases mammary tumor incidence in adult and pregnant mice and rats and in the female offspring. The present study investigated whether a high-fat diet alters the number of estrogen receptor (ER) binding sites and protein kinase C (PKC) activity in the mammary gland of these animals. In the female offspring, the effects of maternal exposure to a high-fat diet during pregnancy on development of the mammary epithelial tree were studied also. BALB/c mice were kept on a diet containing either 43% (high-fat) or 16% (low-fat) calories from corn oil, which consists mostly of n-6 polyunsaturated fatty acids, for 1 month. In adult female mice, a 6-fold increase in the number of ER binding sites and 2-fold increase in PKC activity were found in the mammary glands of the high-fat mice when compared with the low-fat mice. In pregnant mice, a high-fat diet increased ER binding sites by 61% and PKC activity by 51%. In contrast to adult and pregnant mice, females exposed to a high-fat diet only in utero through their pregnant mother exhibited a significantly reduced number of mammary ER binding sites by age 45 days (78% decrease) and a reduction in PKC activity by ages 30 and 100 days (44 and 20% decrease, respectively). The mammary epithelial tree of the high-fat offspring contained more terminal end buds and was less differentiated than that of the low-fat offspring. These findings show that consumption of a high-fat diet increases ER and PKC in the adult and pregnant mouse mammary gland, perhaps contributing to the fat-induced promotion of mammary tumorigenesis. In contrast, reduced ER and PKC following a high-fat exposure in utero may be associated with increased susceptibility to carcinogenesis, possibly due to an increased number of terminal end buds that are the sites of neoplastic transformation in the mammary gland.

Animals↗
PubMed1998

High maternal intake of polyunsaturated fatty acids during pregnancy in mice alters offsprings' aggressive behavior, immobility in the swim test, locomotor activity and brain protein kinase C activity.

Populations in Western countries consume an excess of polyunsaturated fatty acids (PUFA), even during pregnancy. Since (n-6) PUFA is critical for brain development, we studied whether a high maternal consumption of this fatty acid alters offsprings' affective-like behaviors and (n-6) PUFA-induced protein kinase C (PKC) activity in the brain. Three different strains of pregnant mice were fed isocaloric diets containing either 16% (control) or 43% (high) energy derived from fat high in (n-6) PUFA (corn oil: Balb/c and CD-1 mice, or soybean oil: C3H mice) throughout gestation. From birth onward dams and offspring were fed a nonpurified diet containing 12% energy from a variety of fats. Two- to 12-month-old female and male offspring of dams exposed to a high (n-6) PUFA diet during pregnancy were significantly more active in an open field, more aggressive in the resident-intruder test and spent less time immobile in the swim test than offspring of dams exposed to a control (n-6) PUFA diet. Significantly greater PKC activity in the hypothalamus and moderately less PKC activity in the whole brain (P = 0.10) were seen in the 2-month-old female and male high (n-6) PUFA offspring compared to controls. Our findings indicate that in utero exposure to a high (n-6) PUFA diet subsequently increases locomotor activity and aggression, and reduces immobility in the swim test. The mechanism mediating these effects may be linked to an increased PKC activity in the hypothalamus.

Aggression↗
PubMed1998

Timing of dietary fat exposure and mammary tumorigenesis: role of estrogen receptor and protein kinase C activity.

The possible association between a high fat diet and increased breast cancer risk has remained controversial. This largely reflects the conflicting data obtained from migrant, case control and animal studies, which generally support this association, and cohort studies which often fail to show a link between fat and breast cancer. The mammary gland is particularly sensitive to estrogens during fetal development, leading us to hypothesize that dietary fat levels during this period may significantly influence breast cancer risk. Using chemically-induced mammary tumors in rats as our experimental model, we have demonstrated the ability of a maternal diet, high in the polyunsaturated fatty acid (PUFA) linoleic acid, to alter mammary gland differentiation, accelerate the onset of sexual maturation, and increase breast cancer risk. The mammary glands of female rats exposed to a high-fat diet in utero have more of the undifferentiated structures (terminal end buds) and fewer of the differentiated structures (alveolar buds) than the glands of rats exposed to a low-fat diet in utero. Furthermore, these mammary glands contain lower levels of total estrogen receptors and have reduced total protein kinase C activity. These effects appear to be mediated by an increase in the serum estradiol levels of pregnancy, which are elevated at least 30% in pregnant dams fed a high-fat diet. Furthermore, the administration of estradiol to pregnant dams produces effects on mammary gland development, onset of puberty and sensitivity to chemical carcinogenesis comparable to those seen in the offspring of rats fed a high fat diet during pregnancy. Our results, thus, support the hypothesis based on epidemiological data that high maternal estrogen levels increase daughters' breast cancer risk. The results also suggest that a high-fat diet may be an important factor in increasing pregnancy estrogenic activity.

Animals↗
PubMed1997

A maternal diet high in n - 6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring.

We hypothesized that feeding pregnant rats with a high-fat diet would increase both circulating 17beta-estradiol (E2) levels in the dams and the risk of developing carcinogen-induced mammary tumors among their female offspring. Pregnant rats were fed isocaloric diets containing 12% or 16% (low fat) or 43% or 46% (high fat) of calories from corn oil, which primarily contains the n - 6 polyunsaturated fatty acid (PUFA) linoleic acid, throughout pregnancy. The plasma concentrations of E2 were significantly higher in pregnant females fed a high n - 6 PUFA diet. The female offspring of these rats were fed with a laboratory chow from birth onward, and when exposed to 7,12-dimethylbenz(a)anthracene had a significantly higher mammary tumor incidence (60% vs. 30%) and shorter latency for tumor appearance (11.4 +/- 0.5 weeks vs. 14.2 +/- 0.6 weeks) than the offspring of the low-fat mothers. The high-fat offspring also had puberty onset at a younger age, and their mammary glands contained significantly higher numbers of the epithelial structures that are the targets for malignant transformation. Comparable changes in puberty onset, mammary gland morphology, and tumor incidence were observed in the offspring of rats treated daily with 20 ng of E2 during pregnancy. These data, if extrapolated to humans, may explain the link among diet, early puberty onset, mammary parenchymal patterns, and breast cancer risk, and indicate that an in utero exposure to a diet high in n - 6 PUFA and/or estrogenic stimuli may be critical for affecting breast cancer risk.

Animals↗