Associations of parental preconception and maternal pregnancy urinary phthalate biomarker and bisphenol-a concentrations with child eating behaviors.

BACKGROUND: Eating behaviors are controlled by the neuroendocrine system. Whether endocrine disrupting chemicals have the potential to affect eating behaviors has not been widely studied in humans. We investigated whether maternal and paternal preconception and maternal pregnancy urinary phthalate biomarker and bisphenol-A (BPA) concentrations were associated with children's eating behaviors. METHODS: We used data from mother-father-child triads in the Preconception Environmental exposure And Childhood health Effects (PEACE) Study, an ongoing prospective cohort study of children aged 6-13 years whose parent(s) previously enrolled in a fertility clinic-based prospective preconception study. We quantified urinary concentrations of 11 phthalate metabolites and BPA in parents' urine samples collected preconceptionally and during pregnancy. Parents rated children's eating behavior using the Child Eating Behavior Questionnaire (CEBQ). Using multivariable linear regression, accounting for correlation among twins, we estimated covariate-adjusted associations of urinary phthalate biomarkers and BPA concentrations with CEBQ subscale scores. RESULTS: This analysis included 195 children (30 sets of twins), 160 mothers and 97 fathers; children were predominantly non-Hispanic white (84%) and 53% were male. Paternal and maternal preconception monobenzyl phthalate (MBzP) concentrations and maternal preconception mono-n-butyl phthalate (MnBP) were positively associated with emotional overeating, food responsiveness, and desire to drink scores in children (ß's= 0.11 [95% CI: 0.01, 0.20]-0.21 [95% CI: 0.10, 0.31] per loge unit increase in phthalate biomarker concentration). Paternal preconception BPA concentrations were inversely associated with scores on food approaching scales. Maternal pregnancy MnBP, mono-isobutyl phthalate (MiBP) and MBzP concentrations were associated with increased emotional undereating scores. Maternal pregnancy monocarboxy-isononyl phthalate concentrations were related to decreased food avoiding subscale scores. CONCLUSIONS: In this cohort, higher maternal and paternal preconception urinary concentrations of some phthalate biomarkers were associated with increased food approaching behavior scores and decreased food avoiding behavior scores, which could lead to increased adiposity in children.

Paternal and maternal preconception and maternal pregnancy urinary phthalate metabolite and BPA concentrations in relation to child behavior.

BACKGROUND: Epidemiologic studies on health effects of parental preconception exposures are limited despite emerging evidence from toxicological studies suggesting that such exposures, including to environmental chemicals, may affect offspring health. OBJECTIVE: We investigated whether maternal and paternal preconception and maternal pregnancy urinary phthalate metabolite and bisphenol A (BPA) concentrations were associated with child behavior. METHODS: We analyzed data from the Preconception Environmental exposure And Childhood health Effects (PEACE) Study, an ongoing prospective cohort study of children aged 6-11 years whose parent(s) previously enrolled in the prospective preconception Environment and Reproductive Health (EARTH) study. Using linear mixed models, we estimated covariate-adjusted associations of 11 urinary phthalate metabolite and BPA concentrations collected prior to conception and during pregnancy with Behavioral Assessment System for Children-3 (BASC-3) T-scores (higher scores indicate more problem behaviors). RESULTS: This analysis included 134 mothers, 87 fathers and 157 children (24 sets of twins); parents were predominantly non-Hispanic white (mothers and fathers86%). Higher maternal preconception or pregnancy monobenzyl phthalate (MBzP) concentrations were related to higher mean externalizing problems T-scores in their children (ß = 1.3 per 1-loge unit increase; 95 % CI: -0.2, 2.4 and ß = 2.1, 95 % CI: 0.7, 3.6, respectively). Higher maternal preconception monocarboxyoctyl phthalate (MCOP) was suggested to be related to lower mean externalizing problems T-scores (ß = -0.9; 95 % CI: -1.8, 0.0). Higher paternal preconception MCOP was suggestively associated with lower internalizing problems (ß = -0.9; 95 %CI:-1.9, 0.1) and lower Behavioral Symptoms Index (BSI) T-scores (ß = -1.3; 95 % CI: -2.1, -0.4). CONCLUSION: In this cohort, higher maternal preconception and pregnancy MBzP were associated with worse parent-reported child behavior, while higher maternal and paternal preconception MCOP concentrations were related to lower BASC-3 scores.

Paternal and maternal preconception and maternal pregnancy urinary concentrations of parabens in relation to child behavior.

BACKGROUND: Epidemiologic studies of the effects of parental preconception paraben exposures on child behavior are limited despite emerging evidence suggesting that such exposures may affect offspring neurodevelopment. OBJECTIVE: We investigated whether maternal and paternal preconception and maternal pregnancy urinary concentrations of parabens were associated with child behavior. METHODS: We analyzed data from the Preconception Environmental exposure And Childhood health Effects Study, an ongoing prospective cohort of children aged 6-13 years and their parents. We estimated covariate-adjusted associations of loge -transformed urinary methyl, propyl, and butyl paraben concentrations (individually using linear regression models and as a mixture using quantile g-computation) collected prior to conception and during pregnancy with Behavioral Assessment System for Children-3 and Behavior Rating Inventory of Executive Function T-scores (higher scores indicate more problem behaviors). RESULTS: This analysis included 140 mothers, 81 fathers, and 171 children (25 sets of twins); parents were predominantly non-Hispanic white (88% for both mothers and fathers). In single paraben models, higher paternal preconception urinary propyl and methyl paraben concentrations were associated with higher Internalizing Problem T-scores (propyl paraben ß $\beta \;$ = 1.7; 95% confidence interval: 0.6, 2.8, methyl paraben ß $\beta \;$ = 2.2; 95% confidence interval: 0.5, 3.9) and higher Behavioral Symptom Index T-scores (propyl paraben ß $\beta \;$ = 1.4; 95% confidence interval: 0.3, 2.5, methyl paraben ß $\beta \;$ = 1.6; 95% confidence interval: -0.1, 3.3). Each quantile increase in the paternal mixture of three parabens was associated with a 3.4 (95% confidence interval: 0.67, 6.1) and 2.5 (95% confidence interval: 0.01, 5.0) increased internalizing problem and Behavioral Symptom Index T-scores respectively. Higher paternal preconception ( ß $\beta \;$ = 1.0; 95% confidence interval: 0.04, 1.9) and maternal preconception ( ß $\beta \;$ = 1.1 95% confidence interval: -0.1, 2.2) concentrations of propyl paraben were associated with higher Behavior Rating Inventory of Executive Function Metacognition Index T-scores in children, but the paraben mixtures was not. CONCLUSION: In this cohort, paternal preconception urinary concentrations of propyl and methyl paraben were associated with worse parent-reported child behaviors.

Substantial Weight Gain in Adulthood Is Associated with Lower Probability of Live Birth Following Assisted Reproduction.

BACKGROUND: Overweight and obesity among women have been associated with lower success of assisted reproduction technologies (ARTs). However, the relation of adolescent body weight and adult weight change to ART outcomes is not well understood. OBJECTIVE: Our objective was to evaluate the associations of female BMI (in kg/m2) at 18 y and weight change from 18 y to current age with ART outcomes. METHODS: We included 486 women in a prospective cohort at the Massachusetts General Hospital Fertility Center (2004-2018) who underwent 863 ART cycles. At study entry, height and weight were measured by research personnel. Women recalled their weight at 18 y. Restricted cubic splines were used to evaluate the associations between BMI at 18 y and weight change since 18 y and ART outcomes adjusting for age, race, education, smoking, and height and accounting for the correlated cycles within women. RESULTS: Women had a median (range) BMI of 20.6 (14.8 to 36.4) at 18 y and 23.3 (16.1 to 45.8) at study entry. The median (range) weight change since 18 y was 7.4 kg (-12.1 to 60.1 kg). There was no association between BMI at 18 y and clinical ART outcomes. Long-term weight change had a nonlinear association with live birth such that higher weight gain since 18 y (particularly ≥15 kg) and weight loss were both associated with lower odds of live birth. The negative association between weight change and live birth was stronger in women ≥22.5 kg/m2 at 18 y such that each 10-kg increase was associated with a 30% (6%, 48%) lower odds of live birth. CONCLUSIONS: Weight gain in adulthood is negatively associated with ART success, particularly among women who were heavier at 18 y. These results add to the growing literature supporting the benefits of preventing weight gain in adulthood on female fertility.

Association of personal exposure to power-frequency magnetic fields with pregnancy outcomes among women seeking fertility treatment in a longitudinal cohort study.

OBJECTIVE: To assess for the first time the potential relationships of personal exposure to magnetic fields (MF) with pregnancy outcomes among a cohort of women from a fertility clinic, addressing, through study design, some of the primary limitations of previous studies on this topic. DESIGN: Longitudinal preconception prospective cohort. SETTING: Fertility center. PATIENT(S): Our analysis included 119 women recruited from 2012 to 2018, who underwent in vitro fertilization (IVF) (n = 163 cycles) and/or intrauterine insemination (IUI) (n = 123 cycles). INTERVENTION(S): Women wore personal exposure monitors continuously for up to three consecutive 24-hour time periods separated by several weeks. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy, live birth, and pregnancy loss. RESULT(S): The median and maximum of the overall daily mean (daily peak) MF exposure levels were 1.10 mG (2.14 mG) and 15.54 mG (58.73 mG), respectively. MF exposure metrics were highest among women who changed environments four or more times per day. Overall, no statistically significant associations between MF exposure metrics and fertility treatment or pregnancy outcomes were observed in crude or adjusted models. Effect estimates, both positive and negative, varied by outcome and the exposure metric, including the way in which exposure was modeled. CONCLUSION(S): Personal MF exposures were not associated with fertility treatment outcomes or pregnancy outcomes. Despite its limited size, strengths of the study include a longitudinal repeated-measures design, the collection of personal MF exposure data across multiple days, and carefully documented outcome and covariate information among a potentially susceptible study population.

Urinary triclosan concentrations and semen quality among men from a fertility clinic.

BACKGROUND: Triclosan, a widely-used antimicrobial in personal care products, has shown endocrine disrupting activity in experimental studies. However, there is limited evidence from epidemiologic studies on health effects. OBJECTIVE: To examine the association between urinary triclosan concentrations and semen quality. METHODS: A total of 262 men enrolled in the Environmental and Reproductive Health (EARTH) Study provided 581 paired urine and semen samples (2009-2017). Urinary triclosan concentrations were quantified and semen analysis was evaluated according to WHO guidelines. We used linear mixed regression models to estimate the associations between specific gravity-adjusted urinary triclosan concentrations with semen parameters, with a random intercept to account for multiple samples per man and adjusting for age, body mass index (BMI), smoking, physical activity, sexual abstinence time, and season and year of samples' collection. RESULTS: Men had a mean (standard deviation) age of 36.6 (5.24) years and BMI of 27.9 (5.94) kg/m2. Seventy four percent of the samples had detectable (>2.3 µg/L) concentrations. We did not observe significant dose response trends between SG-adjusted urinary triclosan concentrations and semen parameters. However, in the adjusted analysis, compared to men with non-detectable triclosan concentrations in the lowest quartile, those in the second, third, and fourth quartiles had -1.32% (95%CI: -2.04, -0.59), -0.91% (95%CI: -1.63, -0.18), and -0.46% (95%CI: -1.25, 0.33) lower percent morphologically normal sperm, respectively. Similarly, a lower percentage of morphologically normal sperm was found among men with detectable triclosan concentrations, compared to men with non-detectable triclosan [-0.96% (95% CI: -1.57, -0.35)]. In sensitivity analyses, there was stronger negative associations on the percent morphologically normal sperm in the earlier time period due to the significant negative trend in detectable triclosan concentrations over time. CONCLUSION: Despite the lack of observed dose response relationship, we found consistent patterns of lower percent morphologically normal sperm for men with urinary triclosan in the 2nd or 3rd quartile compared to undetectable concentrations.This association was stronger for samples obtained prior to 2013 when triclosan was more often detectable in urine.

Secular trends in semen parameters among men attending a fertility center between 2000 and 2017: Identifying potential predictors.

BACKGROUND: Multiple meta-analyses have shown sperm count declines in Western countries spanning eight decades. Secular trends in other parameters remain unclear, as are potential predictors of these trends. OBJECTIVE: To analyze secular trends in semen quality and to evaluate whether factors previously found to be related to semen quality were responsible for these patterns. METHODS: This is a prospective study including 936 men of couples seeking infertility treatment who provided 1618 semen samples at a single center (2000-2017). Self-reported demographic, nutritional and reproductive characteristics were collected using standardized questionnaires. Urinary concentrations of bisphenol A, parabens and phthalates were quantified by isotope-dilution tandem mass spectrometry. Semen samples were analyzed for volume, sperm concentration, count, motility and morphology following WHO guidelines. We estimated the differences in semen parameters over time by fitting generalized linear mixed models with random intercepts to account for repeated samples while adjusting for abstinence time. We also adjusted for demographic, nutritional and environmental factors to investigate these as potential predictors of time trends. RESULTS: Sperm concentration and count declined by 2.62% per year (95% CI -3.84, -1.38) and 3.12% per year (95% CI: -4.42, -1.80), corresponding to an overall decline of 37% and 42%, respectively, between 2000 and 2017. Decreasing trends were also observed for total motility (per year: -0.44 percentage units, 95% CI -0.71, -0.17) and morphologically normal sperm (per year: -0.069 percentage units, 95% CI -0.116, -0.023). These decreases reflected relative percentage declines of 15% and 16% over the 17 year study period, respectively. When reproductive factors were included in the model, the downward trends in sperm concentration and sperm count were attenuated by 29% and 26%, respectively, while the trends in motility and morphology were attenuated by 54% and 53%, respectively. Also, the downward trends in both sperm concentration and sperm morphology over time were attenuated by 19% when including the DEHP and non-DEHP metabolites, respectively. CONCLUSIONS: Sperm concentration, total count, motility and morphology significantly declined between 2000 and 2017 among subfertile men. These negative trends were attenuated when considering simultaneous changes in reproductive characteristics and urinary phthalates during the course of the study.

The Environment and Reproductive Health (EARTH) Study: A Prospective Preconception Cohort.

BACKGROUND: The Environment and Reproductive Health (EARTH) Study is an ongoing prospective preconception cohort designed to investigate the impact of environmental, nutritional, and lifestyle factors among both women and men on fertility and pregnancy outcomes. METHODS: The EARTH Study recruits women 18 to 45 years and men 18 to 55 years seeking fertility evaluation and treatment at the Massachusetts General Hospital (MGH) Fertility Center, Boston, USA. Women and men are eligible to join either independently or as a couple. Participants are followed from study entry throughout each fertility treatment cycle, once per trimester of pregnancy (for those achieving pregnancy), and up to labor and delivery, or until they discontinue treatment or withdraw from the study. The study collects biological samples, self-reported questionnaire data (including a food frequency questionnaire) and clinically abstracted information. RESULTS: As of June 2017, the study cohort included 799 women and 487 men (447 couples; 40 men joined without female partners). Women were on average 34.7 years old at time of enrolment and predominantly Caucasian (81%), educated (49% have a graduate degree), and nulliparous (83%). Men were on average 36.6 years at baseline and mostly Caucasian (86%) and never-smokers (67%). CONCLUSIONS: The EARTH Study is one of the few cohorts designed to examine multiple potentially critical windows of vulnerability, including the paternal and maternal preconception windows and the periconception and prenatal windows in pregnancy. It is also one of the few human studies that has assessed potential interactions between environmental exposures and dietary factors.

Residential distance to major roadways and semen quality, sperm DNA integrity, chromosomal disomy, and serum reproductive hormones among men attending a fertility clinic.

OBJECTIVE: We examined associations of residential distance to major roadways, as a proxy for traffic-related air pollution exposures, with sperm characteristics and male reproductive hormones. DESIGN: The cohort included 797 men recruited from Massachusetts General Hospital Fertility Center between 2000 and 2015 to participate in fertility research studies. MATERIALS AND METHODS: Men reported their residential addresses at enrollment and provided 1-6 semen samples and a blood sample during follow-up. We estimated the Euclidean distance to major roadways (e.g. interstates and highways: limited access highways, multi-lane highways (not limited access), other numbered routes, and major roads) using information from the Massachusetts Department of Geographic Information Systems. Semen parameters (1238 semen samples), sperm DNA integrity (389 semen samples), chromosomal disomy (101 semen samples), and serum reproductive hormones (405 serum samples) were assessed following standard procedures. RESULTS: Men in this cohort were primarily Caucasian (86%), not current smokers (92%), with a college or higher education (88%), and had an average age of 36 years and BMI of 27.7 kg/m2. The median (interquartile range) residential distance to a major roadway was 111 (37, 248) meters. Residential proximity to major roadways was not associated with semen parameters, sperm DNA integrity, chromosomal disomy, or serum reproductive hormone concentrations. The adjusted percent change (95% CI) in semen quality parameters associated with a 500 m increase in residential distance to a major roadway was -1.0% (-6.3, 4.5) for semen volume, 4.3% (-5.8, 15.7) for sperm concentration, 3.1% (-7.2, 14.5) for sperm count, 1.1% (-1.2, 3.4) for % total motile sperm, and 0.1% (-0.3, 0.5) for % morphologically normal sperm. Results were consistent when we modeled the semen parameters dichotomized according to WHO 2010 reference values. CONCLUSION: Residential distance to major roadways, as a proxy for traffic-related air pollution exposure, was not related to sperm characteristics or serum reproductive hormones among men attending a fertility clinic in Massachusetts.

Urinary concentrations of 3-(diethylcarbamoyl)benzoic acid (DCBA), a major metabolite of N,N-diethyl-m-toluamide (DEET) and semen parameters among men attending a fertility center.

STUDY QUESTION: Are specific gravity (SG)-adjusted urinary concentrations of 3-(diethylcarbamoyl)benzoic acid (DCBA) associated with semen parameters among men attending an academic fertility center? SUMMARY ANSWER: Our study did not demonstrate any association between SG-adjusted urinary DCBA concentrations and semen parameters among men attending an academic fertility center. WHAT IS KNOWN ALREADY: N,N-Diethyl-m-toluamide (DEET) is the most common active ingredient in consumer insect repellents. The recent rise in public health concerns regarding mosquito-borne diseases such as Zika, have led to an increased use of DEET insect repellents, especially among couples planning pregnancy. Animal studies have observed reproductive toxicity from DEET exposure. However, the reproductive health effects of DEET and its metabolites on human reproduction are unknown. STUDY DESIGN, SIZE, DURATION: Between 2007 and 2015, 90 men participating in a prospective cohort study at the Massachusetts General Hospital Fertility Center provided 171 urine samples and 250 semen samples for analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: The urinary concentrations of DEET, N,N-diethyl-3-hydroxymethylbenzamide (DHMB) and DCBA were quantified by isotope-dilution tandem mass spectrometry and adjusted by SG. We used linear mixed models to evaluate the association between tertiles of SG-adjusted urinary DCBA concentrations and semen parameters (semen volume, sperm concentration, total sperm count, progressive motility, total progressive motility count, normal morphology and total normal morphology count), adjusting for covariates. DEET and DHMB were not considered for analysis because of the low percentage of detectable concentrations (<7%). Effect modification by BMI and smoking status was explored. MAIN RESULTS AND THE ROLE OF CHANCE: Participants had a median age of 36 years and BMI of 27 kg/m2, and 68% had never smoked. The SG-adjusted geometric mean DCBA urinary concentration was 2.20 µg/l, with 85% detection frequency. The majority of semen parameters fell within the normal range with the exception of progressive motility, where 64% of the men had values below the WHO 2010 lower reference limits. SG-adjusted urinary DCBA concentrations were not associated with semen parameters in unadjusted or adjusted models. Men in the highest tertile of SG-adjusted urinary DCBA concentrations had comparable semen parameters to men in the lowest tertile (2.59 vs. 2.88 ml for semen volume, 47.9 vs. 45.8 million/ml for sperm concentration, 116 vs. 118 million for total sperm count, 25 vs. 24% for progressive sperm motility, and 6.1 vs. 5.8% for morphologically normal sperm). In addition, BMI and smoking status did not modify the associations. LIMITATIONS REASONS FOR CAUTION: We had a relatively small sample size with similar socioeconomic backgrounds and with overall relatively low urinary concentrations of DEET biomarkers. However, our sample size was enough to detect moderate differences with at least 80% statistical power, between the first and third tertiles of urinary DCBA concentrations. Limitations also include possible misclassification of DCBA exposure and difficulties in extrapolating the findings to the general population. WIDER IMPLICATIONS OF THE FINDINGS: Our study found no associations between urinary concentrations of DCBA, a major metabolite of the insect repellent DEET, and semen parameters in men presenting for infertility treatment. While these results are reassuring, further studies including larger sample sizes and higher exposures are warranted. STUDY FUNDING/COMPETING INTEREST(S): The project was financed by the National Institute of Health grants R01ES022955 and R01ES009718 and by grant P30ES000002 from the National Institute of Environmental Health Sciences (NIEHS). None of the authors has any conflicts of interest to declare. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. TRIAL REGISTRATION NUMBER: N/A.

A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and semen quality in men with inflammatory bowel disease.

BACKGROUND: Phthalates are widely used chemicals with ubiquitous exposure. Dibutyl-phthalate (DBP), a male reproductive toxicant in animals, is understudied in humans. Some mesalamine medications used to treat inflammatory bowel disease (IBD) have DBP in their coating, whereas other mesalamine formulations do not. OBJECTIVES: Taking advantage of differences in mesalamine formulations, we investigated whether high-DBP exposure from mesalamine medications was associated with decreased semen parameters. METHODS: 73 men with IBD taking mesalamine participated in a crossover-crossback prospective study. Men taking non-DBP containing mesalamine at baseline i.e., background exposure, crossed-over for four months to high-DBP mesalamine and then crossed-back for four months to their non-DBP mesalamine (B1HB2-arm;Background1-High-Background2) and vice versa for men taking high-DBP mesalamine at baseline (H1BH2-arm;High1-Background-High2). Men provided up to six semen samples (2: baseline, 2: crossover and 2: crossback). RESULTS: We estimated crossover, crossback and carryover effects using linear mixed models adjusted for abstinence time, age, season and duration on high-DBP mesalamine at baseline. Semen parameters in B1HB2-arm (26 men, 133 samples) decreased after high-DBP mesalamine exposure (crossover versus baseline), especially motility parameters, and continued to decrease further even after crossback to non-DBP mesalamine (crossback versus crossover). The cumulative carryover effect of high-DBP (crossback versus baseline) was a decrease of % total sperm motility by 7.61(CI:-13.1, -2.15), % progressive sperm motility by 4.23(CI:-8.05, -0.4) and motile sperm count by 26.0% (CI:-46.2%, 1.7%). However, H1BH2-arm (47 men, 199 samples) had no significant change during crossover or crossback. CONCLUSIONS: Men newly exposed to high-DBP mesalamine for four months had a cumulative reduction in several semen parameters, primarily sperm motility, that was more pronounced and statistically significant even after exposure ended for four months.