Mary Perrin

Associations between drinking water and urinary arsenic levels and skin lesions in Bangladesh.

The present study examined the associations between drinking water and urinary arsenic levels and skin lesions among 167 residents of three contiguous villages in Bangladesh. Thirty-six (21.6%) had skin lesions (melanosis, hyperkeratosis, or both), of which 13 (36.1%) occurred in subjects who were currently drinking water containing concentrations of arsenic <50 &mgr;g/L. The risk for skin lesions in relation to the exposure estimates based on urinary arsenic was elevated more than 3-fold, with the odds ratios for the highest versus the lowest quartiles being 3.6 (95% confidence interval, 1.2 to 12.1) for urinary total arsenic and 3.2 (95% confidence interval, 1.1 to 10.0) for urinary creatinine-adjusted total arsenic. The risks for skin lesions in relation to the exposure estimates based on arsenic in drinking water were less strongly elevated, with the odds ratios for the highest versus the lowest quartiles of exposure being 1.7 (95% confidence interval, 0.6 to 5.1) for drinking-water arsenic and 2.3 for cumulative arsenic index. The study suggests that arsenic exposure is associated with skin lesions in the Bangladesh population and that urinary arsenic may be a stronger predictor of skin lesions than arsenic in drinking water in this population.

Acute maternal stress in pregnancy and schizophrenia in offspring: A cohort prospective study

Schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine and major disasters. Recent evidence suggests that human vulnerability may be greatest in the first trimester of gestation and rodent experiments suggest sex specificity. We aimed to describe the consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli war of 1967. A priori, we focused on gestational month and offsprings sex.MethodIn a pilot study linking birth records to Israels Psychiatric Registry, we analyzed data from a cohort of 88,829 born in Jerusalem in 1964–76. Proportional hazards models were used to estimate the relative risk (RR) of schizophrenia, according to month of birth, gender and other variables, while controlling for fathers age and other potential confounders. Other causes of hospitalized psychiatric morbidity (grouped together) were analyzed for comparison.ResultsThere was a raised incidence of schizophrenia for those who were in the second month of fetal life in June 1967 (RR = 2.3, 1.1–4.7), seen more in females (4.3, 1.7–10.7) than in males (1.2, 0.4–3.8). Results were not explained by secular or seasonal variations, altered birth weight or gestational age. For other conditions, RRs were increased in offspring who had been in the third month of fetal life in June 1967 (2.5, 1.2–5.2), also seen more in females (3.6, 1.3–9.7) than males (1.8, 0.6–5.2).ConclusionThese findings add to a growing literature, in experimental animals and humans, attributing long term consequences for offspring of maternal gestational stress. They suggest both a sex-specificity and a relatively short gestational time-window for gestational effects on vulnerability to schizophrenia.

Cancer Risk After Exposure to Treatments for Ovulation Induction

Uncertainty continues as to whether treatments for ovulation induction are associated with increased risk of cancer. The authors conducted a long-term population-based historical cohort study of parous women. A total of 15,030 women in the Jerusalem Perinatal Study who gave birth in 1974-1976 participated in a postpartum survey. Cancer incidence through 2004 was analyzed using Coxs proportional hazards models, controlling for age and other covariates. Women who used drugs to induce ovulation (n = 567) had increased risks of cancer at any site (multivariate hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.06, 1.74). An increased risk of uterine cancer was found among women treated with ovulation-inducing agents (HR = 3.39, 95% CI: 1.28, 8.97), specifically clomiphene (HR = 4.56, 95% CI: 1.56, 13.34). No association was noted between use of ovulation-inducing agents and ovarian cancer (age-adjusted HR = 0.61, 95% CI: 0.08, 4.42). Ovulation induction was associated with a borderline-significant increased risk of breast cancer (multivariate HR = 1.42, 95% CI: 0.99, 2.05). Increased risks were also observed for malignant melanoma and non-Hodgkin lymphoma. These associations appeared stronger among women who waited more than 1 year to conceive. Additional follow-up studies assessing these associations by drug type, dosage, and duration are needed.

Repetitive element DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry

Global decreases in DNA methylation, particularly in repetitive elements, have been associated with genomic instability and human cancer. Emerging, though limited, data suggest that in white blood cell (WBC) DNA levels of methylation, overall or in repetitive elements, may be associated with cancer risk. We measured methylation levels of three repetitive elements [Satellite 2 (Sat2)], long interspersed nuclear element-1 (LINE-1) and Alu) by MethyLight, and LINE-1 by pyrosequencing in a total of 282 breast cancer cases and 347 unaffected sisters from the New York site of the Breast Cancer Family Registry (BCFR) using DNA from both granulocytes and total WBC. We found that methylation levels in all markers were correlated between sisters (Spearman correlation coefficients ranged from 0.17 to 0.55). Sat2 methylation was statistically significantly associated with increased breast cancer risk [odds ratio (OR) = 2.09, 95% confidence interval (CI) = 1.09-4.03; for each unit decrease in the natural log of the methylation level, OR = 2.12, 95% CI = 0.88-5.11 for the lowest quartile compared with the highest quartile]. These associations were only observed in total WBC but not granulocyte DNA. There was no association between breast cancer and LINE-1 and Alu methylation. If replicated in larger prospective studies, these findings support that selected markers of epigenetic changes measured in WBC, such as Sat2, may be potential biomarkers of breast cancer risk.

Preeclampsia and subsequent risk of cancer: update from the Jerusalem Perinatal Study

OBJECTIVE The purpose of this study was to examine the association between preeclampsia and cancer incidence. STUDY DESIGN The Jerusalem Perinatal Study is a population-based cohort of all births to 41,206 residents of Western Jerusalem from 1964-76. Cancer incidence to 2004 was assessed by linkage of the cohort with the Israel Cancer Registry. Coxs proportional hazards models were constructed to estimate the hazard ratio for cancer among women who had had preeclampsia. RESULTS Preeclampsia was associated with a 1.23-fold increased risk of cancer at all sites, a 37% increased risk of breast cancer, and more than a doubling of ovarian cancer risk. Analysis by morphologic condition yielded significantly increased risks for malignancies that were classed as cystic mucinous and serous (relative risk, 1.96; 95% CI, 1.00-3.83) and for ductal, lobular, and medullary carcinomas (relative risk, 1.40; 95% CI, 1.07-1.83). No differential association was observed by sex of offspring. CONCLUSION Our study suggests that the previously described protective effect of preeclampsia on cancer is not universal.

Telomere length, family history, and paternal age in schizophrenia

Leukocyte telomere length (LTL) is longer in association with advanced paternal age, but this association has not been examined along with family history (FH) in schizophrenia. LTL was measured by PCR and compared across cases and controls as part of a study to examine the characteristics of paternal age related schizophrenia. The 53 schizophrenia cases had similar mean LTL as 20 controls, although cases were significantly older than controls and overwhelmingly smoked cigarettes. Multivariate analyses showed that a FH of schizophrenia was associated with longer LTL in both male and female cases. Later paternal age was also related to longer LTL in male cases, but with shorter LTL in female cases. Male cases with older fathers and a FH had the longest LTL. The genetic architecture associated with a familial risk for schizophrenia may include pathways that lengthen LTL. Paternal aging conferred an additional increase in LTL lengthening in male cases, but reduced LTL in female cases. The gender difference in LTL for paternal aging is consistent with the severe illness features reported for female cases with older fathers and could implicate epigenetic alterations in the paternal X chromosomal region with advanced paternal age in association with the risk for schizophrenia.

Tetrachloroethylene exposure and risk of schizophrenia: Offspring of dry cleaners in a population birth cohort, preliminary findings

Tetrachloroethylene is a solvent used in dry cleaning with reported neurotoxic effects. Using proportional hazard methods, we examined the relationship between parental occupation as a dry cleaner and risk for schizophrenia in a prospective population-based cohort of 88,829 offspring born in Jerusalem from 1964 through 1976, followed from birth to age 21-33 years. Of 144 offspring whose parents were dry cleaners, 4 developed schizophrenia. We observed an increased incidence of schizophrenia in offspring of parents who were dry cleaners (RR=3.4, 95% CI, 1.3-9.2, p=0.01). Tetrachloroethylene exposure warrants further investigation as a risk factor for schizophrenia.

Prenatal stress and affective disorders in a population birth cohort.

Kleinhaus K, Harlap S, Perrin M, Manor O, Margalit‐Calderon R, Opler M, Friedlander Y, Malaspina D. Prenatal stress and affective disorders in a population birth cohort. 
Bipolar Disord 2012: 00: 000–000.

Gestational diabetes as a risk factor for pancreatic cancer: a prospective cohort study

BackgroundDiabetes is known to be associated with cancer of the pancreas, though there is some debate as to whether it is a cause or a consequence of the disease. We investigated the incidence of pancreatic cancer in a cohort of 37926 Israeli women followed for 28–40 years for whom information on diabetes had been collected at the time they gave birth, in 1964–1976, in Jerusalem. There were 54 cases of pancreatic cancer ascertained from the Israel Cancer Registry during follow-up.MethodsWe used Cox proportional hazards models to adjust for age at baseline and explore effects of other risk factors, including ethnic groups, preeclampsia, birth order and birth weight of offspring.ResultsWe observed no cases of pancreatic cancer in the women with insulin dependent diabetes; however, there were five cases in the women with gestational diabetes. The interval between the record of diabetes in pregnancy and the diagnosis of pancreatic cancer ranged from 14–35 years. Women with a history of gestational diabetes showed a relative risk of pancreatic cancer of 7.1 (95% confidence interval, 2.8–18.0).ConclusionWe conclude that gestational diabetes is strongly related to the risk of cancer of the pancreas in women in this population, and that gestational diabetes can precede cancer diagnosis by many years.

Global DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry

Lower global DNA methylation is associated with genomic instability and it is one of the epigenetic mechanisms relevant to carcinogenesis. Emerging evidence for several cancers suggests that lower overall levels of global DNA methylation in blood are associated with different cancer types, although less is known about breast cancer. We examined global DNA methylation levels using a sibling design in 273 sisters affected with breast cancer and 335 unaffected sisters from the New York site of the Breast Cancer Family Registry. We measured global DNA methylation in total white blood cell (WBC) and granulocyte DNA by two different methods, the [3H]-methyl acceptance assay and the luminometric methylation assay (LUMA). Global methylation levels were only modestly correlated between sisters discordant for breast cancer (Spearman correlation coefficients ranged from -0.08 to 0.24 depending on assay and DNA source). Using conditional logistic regression models, women in the quartile with the lowest DNA methylation levels (as measured by the [3H]-methyl acceptance assay) had a 1.8-fold (95% CI = 1.0–3.3) higher relative association with breast cancer than women in the quartile with the highest DNA methylation levels. When we examined the association on a continuous scale, we also observed a positive association (odds ratio, OR = 1.3, 95% CI = 1.0–1.7, for a one unit change in the natural logarithm of the DPM/μg of DNA). We observed no association between measures by the LUMA assay and breast cancer risk. If replicated in prospective studies, this study suggests that global DNA methylation levels measured in WBC may be a potential biomarker of breast cancer risk even within families at higher risk of cancer.