Scott A. Venners

Serum DDT, age at menarche, and abnormal menstrual cycle length

Background: Although dichlorodiphenyl trichloroethane (DDT) exposure is known to affect human endocrine function, few previous studies have investigated the effects of DDT exposure on age at menarche or menstrual cycle length. Methods: A cross sectional study was conducted to study the effects of DDT exposure on age at menarche and menstrual cycle length among 466 newly married, nulliparous female Chinese textile workers aged 20–34 years enrolled between 1996 and 1998. Serum was analysed for DDT and its major metabolites. Multivariate linear regression was used to estimate DDT exposure effects on age at menarche and multivariate logistic regression was used to estimate DDT exposure effects on odds of experiencing short or long cycles. Results: Relative to those in the lowest DDT quartile, the adjusted mean age at menarche was younger in those in the fourth quartile (−1.11 years). Modeled as a continuous variable, a 10 ng/g increase in serum DDT concentration was associated with an adjusted reduction in age at menarche of 0.20 years. Relative to those in the lowest DDT quartile, odds of any short cycle (<21 days) in the previous year were higher for those in the fourth quartile (odds ratio = 2.78; 95% CI 1.07 to 7.14). There were no associations between serum DDT concentrations and odds of experiencing a long cycle (>40 days). Conclusion: Results suggest that DDT exposure was associated with earlier age at menarche and increased risk of experiencing a shortened menstrual cycle.

A Common Mutation in the Defensin DEFB126 Causes Impaired Sperm Function and Subfertility

A frequent frameshift mutation in defensin DEFB126, a protein that adheres to the surface of human sperm, weakens its ability to penetrate cervical mucus-like gels and causes low fertility. Defensin-Deficient Sperm Get Stuck Like Robert Burns’ best laid schemes of mice and men, the joining of egg and sperm “gang aft agley” (transl., often go awry)—and it’s no wonder, considering the many molecular events that must be correctly executed for successful fertilization. The current clinical tests still fail to explain infertility in almost one-fifth of infertile couples. Now, Tollner et al. pinpoint one more critical cog in this vital process: Men who carry a genetic variant of a certain sperm surface protein are less fertile than normal. This common but life-altering deviation likely accounts for some of the currently unexplained cases of infertility. β-Defensin is a protein made in the paired coils of the epididymis, which carries sperm from testes. This defensin is secreted as the sperm travels by and is integrated into the glycocalyx, a protein-sugar coating on the sperm surface. Surface-hugging β-defensins protect sperm from immune attack and help them to penetrate the cervical mucus in the female. While cloning the human version of this defensin, the authors found a mutated variant that was surprisingly prevalent; about 20% of the European, Chinese, and Japanese men that the authors examined carried the variation on both chromosomes (del/del). Although they did not uniformly display deficiencies usually associated with infertility (such as inadequate semen volume and low sperm motility), sperm from del/del men did show lower lectin binding relative to controls; this measure was shown to be a marker for sperm-associated O-linked oligosaccharides that cannot attach to the mutated defensin. The del/del sperm were poor penetrators of hyaluronic acid, an in vitro surrogate for cervical mucus. But did the presence of the defensin variant actually cause lower fertility? In a group of 509 newly married Chinese couples, the authors showed that it did. Wives of men with the del/del genotype were only 60% as likely to get pregnant as were women who mated with men who carried wild-type or wt/del genotypes, and the time from enrollment in the study to the live birth of a child was 2 months longer in the former group. The impaired fertility among carriers of this deletion might imply that these individuals are headed for extinction, but their prevalence in the population indicates otherwise. How can this be? The authors speculate that carriers of a single copy of the mutated defensin may have an as yet undefined survival advantage over wild-type carriers, an evolutionary situation known as balancing selection. Whatever the reason for variation persistence, our new understanding of β-defensin will enable better appreciation of human fertility and help to keep our reproductive plans on track. A glycosylated polypeptide, β-defensin 126 (DEFB126), derived from the epididymis and adsorbed onto the sperm surface, has been implicated in immunoprotection and efficient movement of sperm in mucosal fluids of the female reproductive tract. Here, we report a sequence variant in DEFB126 that has a two-nucleotide deletion in the open reading frame, which generates an abnormal mRNA. The allele frequency of this variant sequence was high in both a European (0.47) and a Chinese (0.45) population cohort. Binding of the Agaricus bisporus lectin to the sperm surface glycocalyx was significantly lower in men with the homozygous variant (del/del) genotype than in those with either a del/wt or a wt/wt genotype, suggesting an altered sperm glycocalyx with fewer O-linked oligosaccharides in del/del men. Moreover, sperm from del/del carriers exhibited an 84% reduction in the rate of penetration of a hyaluronic acid gel, a surrogate for cervical mucus, compared to the other genotypes. This reduction in sperm performance in hyaluronic acid gels was not a result of decreased progressive motility (average curvilinear velocity) or morphological deficits. Nevertheless, DEFB126 genotype and lectin binding were correlated with sperm performance in the penetration assays. In a prospective cohort study of newly married couples who were trying to conceive by natural means, couples were less likely to become pregnant and took longer to achieve a live birth if the male partner was homozygous for the variant sequence. This common sequence variation in DEFB126, and its apparent effect of impaired reproductive function, will allow a better understanding, clinical evaluation, and possibly treatment of human infertility.

Early-life bisphenol a exposure and child body mass index: a prospective cohort study.

Background: Early-life exposure to bisphenol A (BPA) may increase childhood obesity risk, but few prospective epidemiological studies have investigated this relationship. Objective: We sought to determine whether early-life exposure to BPA was associated with increased body mass index (BMI) at 2–5 years of age in 297 mother–child pairs from Cincinnati, Ohio (HOME Study). Methods: Urinary BPA concentrations were measured in samples collected from pregnant women during the second and third trimesters and their children at 1 and 2 years of age. BMI z-scores were calculated from weight/height measures conducted annually from 2 through 5 years of age. We used linear mixed models to estimate BMI differences or trajectories with increasing creatinine-normalized BPA concentrations. Results: After confounder adjustment, each 10-fold increase in prenatal (β = –0.1; 95% CI: –0.5, 0.3) or early-childhood (β = –0.2; 95% CI: –0.6, 0.1) BPA concentrations was associated with a modest and nonsignificant reduction in child BMI. These inverse associations were suggestively stronger in girls than in boys [prenatal effect measure modification (EMM) p-value = 0.30, early-childhood EMM p-value = 0.05], but sex-specific associations were imprecise. Children in the highest early-childhood BPA tercile had lower BMI at 2 years (difference = –0.3; 95% CI: –0.6, 0.0) and larger increases in their BMI slope from 2 through 5 years (BMI increase per year = 0.12; 95% CI: 0.07, 0.18) than children in the lowest tercile (BMI increase per year = 0.07; 95% CI: 0.01, 0.13). All associations were attenuated without creatinine normalization. Conclusions: Prenatal and early-childhood BPA exposures were not associated with increased BMI at 2–5 years of age, but higher early-childhood BPA exposures were associated with accelerated growth during this period. Citation: Braun JM, Lanphear BP, Calafat AM, Deria S, Khoury J, Howe CJ, Venners SA. 2014. Early-life bisphenol A exposure and child body mass index: a prospective cohort study. Environ Health Perspect 122:1239–1245; http://dx.doi.org/10.1289/ehp.1408258

Antineoplastic Drug Contamination of Surfaces Throughout the Hospital Medication System in Canadian Hospitals

We previously reported that there is a potential for antineoplastic drug contamination throughout the hospital medication system (process flow of drug within a facility from delivery to waste disposal) due to the various surfaces contacted by health care workers. This article describes the contamination of these frequently contacted surfaces as well as identifies factors that may be associated with surface contamination. Surfaces which health care workers frequently contact were wiped and the concentration of cyclophosphamide (CP) was determined using high-performance liquid chromatography-tandem mass spectrometry. Descriptive and inferential statistical analyses were performed. A backward stepwise multiple linear regression was conducted to identify determinants associated with surface contamination. Overall, 229 surfaces were sampled, most on two occasions, for a total of 438 surface wipes. The mean CP concentration was 0.201 ng/cm2, the geometric mean 0.019 ng/cm2, and the geometric standard deviation 2.54, with a range of less than detection (LOD) to 26.1 ng/cm2. (Method LOD was 0.356 ng/wipe; factoring in the surface area of the wiped surface, results in a sample LOD ranging from 0.00 to 0.049 ng/cm2). Our study found that frequently contacted surfaces at every stage of the hospital medication system had measureable levels of antineoplastic drug contamination. Two factors were statistically significant with respect to their association with surface contamination: (1) the stage of the hospital medication system, and (2) the number of job categories responsible for drug transport. The drug preparation stage had the highest average contamination. Those hospitals that had two or more drug transport job categories had higher levels of surface contamination. Neither the reported handling of CP prior to wipe sampling nor the cleaning of surfaces appeared to be associated with contamination.

Organophosphorous pesticide exposures and sperm quality

Many Americans are exposed to low levels of organophosphorous (OP) pesticides. It is unclear whether these exposures impact sperm production. We investigated whether there was an association between urinary OP insecticide metabolites and sperm concentration and motility in newly married men from a rural area of eastern Peoples Republic of China. Ninety-four cases and 95 controls were included based on their median residual value of sperm concentration and motility after adjusting for relevant covariates. Their urine was analyzed for six dialkylphosphate (DAP) compounds. After adjustment for demographic and exposure variables, the odds of being a case were greater (odds ratio=1.30, 95% confidence interval 1.02-1.65) in men with higher urinary concentrations of dimethylphosphate (DMP) compared to men with lower levels. No significant differences between cases and controls were found among the other DAP concentrations. DMP exposure and sperm concentration and motility should be explored further in environmental exposure studies.

Patterns and interrelationships of body-fat measures among rural Chinese children aged 6 to 18 years.

OBJECTIVES. Our goal was to compare BMI and waist circumference with dual-energy radiograph absorptiometry–based measures of adiposity and to describe the pattern and interrelations of these surrogate and direct adiposity measures in prepubertal and pubertal rural Chinese children. METHODS. This was a cross-sectional study of 2493 children aged 6 to 18 years from a population-based cohort of twin pairs. Dual-energy radiograph absorptiometry–based measurements included total body fat, percentage of body fat, trunk fat, and percentage of trunk fat. Age- and gender-specific patterns and interrelationships among BMI, waist circumference, and dual-energy radiograph absorptiometry–based measurements were described by using smoothing plots and age- and gender-specific correlation analyses. RESULTS. In girls, BMI, waist circumference, total body fat, percentage of body fat, trunk fat, and percentage of trunk fat all increased linearly with age. In boys, BMI and waist circumference increased linearly with age, but total body fat, percentage of body fat, and trunk fat did not increase significantly with age. In both genders, percentage of trunk fat reached a nadir around 12 years of age and then increased with age. Before puberty (6–11 years), BMI and waist circumference were correlated well with total body fat, percentage of body fat, and trunk fat in both genders. During puberty (12–18 years), the correlations between BMI and each of the dual-energy radiograph absorptiometry–based measurements were higher in girls than in boys. Similar trends were found in the correlations between waist circumference and each of the dual-energy radiograph absorptiometry–based measurements. CONCLUSIONS. In this relatively lean rural Chinese population, BMI and waist circumference were highly correlated with each other and were good surrogates of total body fat, trunk fat, and percentage of body fat in prepubertal children of both genders and in pubertal girls. However, both BMI and waist circumference overestimated total and trunk fat, especially percentage of body fat in pubertal boys.

Indoor air pollution and respiratory health in urban and rural China.

Abstract During the summer of 1999, information about respiratory health outcomes and relevant covariates was collected from 3,709 Chinese adults in Beijing, Anqing City, and rural communities in Anqing Prefecture. Indoor PM10 and SO2 were measured in a randorn sample of selected households. Using logistic regression and controlling for important covariates (excluding PM10 and SO2) and familial intraclass correlation, highly significant differences were found between study areas in the prevalences of chronic cough, chronic phlegm, wheeze, and shortness of breath, but not physician-diagnosed asthma. Generally, the lowest prevalence of respiratory symptoms was observed in Anqing City, a higher prevalence in rural Anqing, and the highest prevalence in Beijing. Median indoor concentrations of PM10 were similar in Anqing City (239 μg/m3) and rural Anqing (248 μg/m3), but much higher in Beijing (557 μg/m3).Median indoor concentrations of SO 2 were similar in all three areas (Beijing: 14 μg/m3,Anqing City: 25 μg/m3,rural Anqing: 20 μg/m3).

Body Mass Index and Serum 1,1,1-Trichloro-2,2-Bis(p-Chlorophenyl)Ethane in Nulliparous Chinese Women

Background: Basic health indicators, such as body mass index (BMI), have been associated with serum 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane/1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDT/DDE) levels; however, both positive and inverse associations of BMI with serum DDT/DDE have been reported. Given the association of BMI with a number of outcomes, it may confound studies of DDT/DDE-associated health effects. We investigated the relationship of BMI with serum DDT/DDE accounting for other determinants of exposure among women with relatively recent environmental exposures to DDT. Methods: Serum DDT/DDE was analyzed in 466 nonsmoking, nulliparous women recruited from Anhui province in China between 1996 and 1998 as part of a reproductive health study of textile workers. The women in the sample were born between 1963 and 1977, 8 to 21 years before Chinas 1984 DDT ban. We used multivariate linear regression to investigate associations of BMI, age, and birth year with serum DDT/DDE. Results: Mean (SD) serum total DDT concentration was 32 ng/g (17.8 ng/g). Birth year showed an inverse relationship with serum DDT independent of age. Despite limited variability in BMI, there was a consistent inverse relationship between BMI and serum DDT. Specifically, each kg/m2 increase in BMI was associated with a −1.34 ng/g (95% confidence interval, −2.12 to −0.56 ng/g) decrease in serum total DDT. Conclusions: There were high total DDT levels in this sample of nulliparous Chinese women relative to Western populations, birth year was more strongly associated with serum DDT than age, and BMI was inversely related to serum DDT in this study.

Cross-Sectional Associations of Serum Perfluoroalkyl Acids and Thyroid Hormones in U.S. Adults: Variation According to TPOAb and Iodine Status (NHANES 2007–2008)

Background: Perfluoroalkyl acids (PFASs) are suspected thyroid toxicants, but results from epidemiological studies are inconsistent. Objectives: We examined associations between serum PFASs and thyroid hormones (THs) in a representative, cross-sectional sample of U.S. adults. We hypothesized that people with high thyroid peroxidase antibodies and low iodine would be more susceptible to PFAS-induced thyroid disruption. Methods: Our sample included 1,525 adults (≥ 18 years) from the 2007–2008 NHANES study with available serum PFASs and THs. We examined associations between four serum PFASs [perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA), perfluorooctanoate (PFOA), and perfluorooctane sulfonate (PFOS)], and serum THs [free triiodothyronine (fT3), free thyroxine (fT4), fT3/fT4, thyroid-stimulating hormone (TSH), total T3 (TT3), and total T4 (TT4)] using multivariable linear regression. We stratified subjects into four groups by two indicators of thyroid “stress”: thyroid peroxidase antibody (TPOAb ≥ 9 IU/mL) and iodine status (< 100 μg/L urine). Results: Of 1,525 participants, 400 (26%) had low iodine only (T0I1), 87 (6%) had high TPOAb only (T1I0), and 26 (2%) had both high TPOAb and low iodine (T1I1). In general, associations were similar among participants in the groups with neither (T0I0) or only one thyroid stressor (T0I1 or T1I0), suggesting that PFAS–TH associations were not modified by high TPOAb or low iodine alone. However, PFHxS and PFOS were negatively associated (p < 0.05) with fT4, and all four PFASs were positively associated (p < 0.05) with fT3, fT3/fT4, TSH, and TT3 in the group with joint exposure to high TPOAb and low iodine (T1I1). Conclusions: We found evidence of PFAS-associated thyroid disruption in a subset of U.S. adults with high TPOAb (a marker of autoimmune hypothyroidism) and low iodine status, who may represent a vulnerable subgroup. However, the small sample size, cross-sectional design, and possibility of reverse causation are limitations of this work. Citation: Webster GM, Rauch SA, Ste Marie N, Mattman A, Lanphear BP, Venners SA. 2016. Cross-sectional associations of serum perfluoroalkyl acids and thyroid hormones in U.S. adults: variation according to TPOAb and iodine status (NHANES 2007–2008). Environ Health Perspect 124:935–942; http://dx.doi.org/10.1289/ehp.1409589

Effect of Simvastatin on Plasma Homocysteine Levels and Its Modification by MTHFR C677T Polymorphism in Chinese Patients with Primary Hyperlipidemia

OBJECTIVE We investigate the effect of simvastatin on plasma homocysteine (Hcy) levels and whether genetic factor affects the effect of simvastatin. METHODS A total of 338 patients with hyperlipidemia were enrolled. Simvastatin was orally administered at a dose of 20 mg/day for 8 weeks. Plasma Hcy levels were measured by high-performance liquid chromatography at baseline and after 8 weeks of treatment. Genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism was performed by TaqMan probe technique. RESULTS Serum total Hcy levels were positively correlated with serum creatinine (r = 0.332, P < 0.001). Among total subjects, simvastatin treatment resulted in a significant reduction in serum Hcy levels after 8 weeks (-0.37 ± 2.21 μmol/L, P = 0.003), and this effect was dependent on the initial levels of serum Hcy. The individuals with 677TT genotype had a significantly higher baseline Hcy level and a greater change in Hcy levels. After stratification by body mass index (BMI), we observed a significant increase in Hcy levels among the TT genotype group in adjusted model (beta±SE: 2.64 ± 0.84 μmol/L; P = 0.002) among patients with BMI ≥ 25 (kg/m(2) ). CONCLUSIONS Simvastatin can cause a marked decrease in plasma Hcy levels. MTHFR C677T genetic variant contributes to simvastatins effects among Chinese subjects with primary hyperlipidemia.