Development of a Metabolomic Risk Score for Exposure to Traffic-Related Air Pollution: A Multi-Cohort Study.

To synthesize vast amounts of high-throughput biological information, omics-fields like epigenetics have applied risk scores to develop biomarkers for environmental exposures. Extending the risk score analytic tool to the metabolomic data would be highly beneficial. This research aimed to develop and evaluate metabolomic risk score (metRS) approaches reflecting the biological response to traffic-related air pollution (TRAP) exposure (fine particulate matter, black carbon, and nitrogen dioxide). A simulation study compared three metRS methodologies: elastic net regression, which uses penalized regression to select metabolites, and two variations of thresholding, where a p-value cutoff is used to select metabolites. The methods performance was compared to assess 1) ability to correctly select metabolites associated with daily TRAP and 2) ability of the risk score to predict daily TRAP exposure. Power calculations and false discovery rates (FDR) were calculated for each approach. This metRS was applied to two real cohorts, the Center for Health Discovery and Wellbeing (CHDWB, n=180) and Environment and Reproductive Health (EARTH, n=200). In simulations, elastic net regression consistently presented inflated FDR for both high and low effect sizes and across all three sample sizes (n=200; 500; 1,000). Power to detect correct metabolites exceeded 0.8 for all three sample sizes in all three methods. In the real data application assessing associations of metabolomics risk scores and TRAP, associations were largely null. Black Carbon was positively associated with the metRS in CHDWB data. While we did not identify significant associations between the risk scores and TRAP in the real data application, metabolites selected by the risk score approaches were enriched in pathways that are well-known for their association with TRAP. These results demonstrate that certain methodologies to construct metabolomics risk scores are statistically robust and valid; however, standardized metabolic profiling and large sample sizes are required.

History of infertility and anti-Müllerian hormone levels among participants in the Nurses' Health Study II.

OBJECTIVES: To better understand whether history of infertility is associated with anti-Müllerian hormone (AMH) levels later in life, outside of reproduction. METHODS: Among 1,758 premenopausal women in the Nurses' Health Study II with measured AMH, we used multivariable generalized linear models to compare log-transformed plasma AMH for women with a history of infertility compared with fertile women. We investigated AMH levels by cause of infertility and effect modification by menstrual cycle regularity. Lastly, we investigated AMH levels by history of primary and secondary infertility and age at reported infertility. RESULTS: Mean age at blood collection was 40 years. We observed no association between overall history of infertility and AMH levels (% difference AMH: -8.1% [CI, -19.4 to 4.8]). The association between overall infertility and AMH was strongest among women who first reported infertility at >30 years (-17.7% [CI, -32.1 to -0.3]). CONCLUSIONS: Overall, we observed no association between the history of infertility and AMH levels later in life. However, specific subgroups of women with a history of infertility may have lower AMH levels throughout life compared with fertile women. This association was observed among subgroups, such as those who first experienced infertility at >30 years. These findings have implications for mechanisms through which infertility may be associated with premature menopause and chronic disease risk.

Associations between exposure to extreme ambient heat and neural tube defects in Georgia, USA: A population-based case-control study.

INTRODUCTION: The association between extreme ambient heat exposures during pregnancy and neural tube defects (NTDs) in offspring remains unclear. This study sought to estimate the association between exposure to extreme ambient heat during periconception and NTDs. METHODS: This population-based case-control study in Georgia, USA (1994-2017) included 825 isolated NTD cases (473 anencephaly, 352 spina bifida) and 3,300 controls matched 1:4 on county of residence and time period of delivery. Daily ambient temperature data were linked to fetal death and birth records by county of residence. Extreme ambient heat exposure was defined as the number of consecutive days the daily apparent temperature exceeded the county-specific 95th percentile (derived over 1980-2010) during an eight-week periconception period. We calculated adjusted odds ratios (aORs) and 95% confidence intervals (CI) using conditional logistic regression models adjusted for maternal age, education, and ethnicity and month and year of last menstrual period. RESULTS: The aORs for NTDs were 1.09 (95% CI 1.01, 1.17), 1.18 (95% CI 1.03, 1.36), and 1.29 (95% CI 1.04, 1.58) for exposure to 1-2, 3-5, and 6 or more consecutive days with apparent ambient temperatures exceeding the county-specific 95th percentile during periconception, respectively, compared to no days of extreme ambient heat exposure. Weekly analysis of extreme heat exposure indicated consistently elevated odds of offspring NTDs during periconception. These results were largely driven by spina bifida cases. CONCLUSIONS: Our results highlight potential health threats posed by increasing global average temperatures for pregnant people with implications for increased risk of neural tube defects in their offspring.

Epigenetic age acceleration in follicular fluid and markers of ovarian response among women undergoing IVF.

STUDY QUESTION: Are markers of epigenetic age acceleration in follicular fluid associated with outcomes of ovarian stimulation? SUMMARY ANSWER: Increased epigenetic age acceleration of follicular fluid using the Horvath clock, but not other epigenetic clocks (GrimAge and Granulosa Cell), was associated with lower peak estradiol levels and decreased number of total and mature oocytes. WHAT IS KNOWN ALREADY: In granulosa cells, there are inconsistent findings between epigenetic age acceleration and ovarian response outcomes. STUDY DESIGN, SIZE, DURATION: Our study included 61 women undergoing IVF at an academic fertility clinic in the New England area who were part of the Environment and Reproductive Health Study (2006-2016). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants provided a follicular fluid sample during oocyte retrieval. DNA methylation of follicular fluid was assessed using a genome-wide methylation screening tool. Three established epigenetic clocks (Horvath, GrimAge, and Granulosa Cell) were used to predict DNA-methylation-based epigenetic age. To calculate the age acceleration, we regressed epigenetic age on chronological age and extracted the residuals. The association between epigenetic age acceleration and ovarian response outcomes (peak estradiol levels, follicle stimulation hormone, number of total, and mature oocytes) was assessed using linear and Poisson regression adjusted for chronological age, three surrogate variables (to account for cellular heterogeneity), race, smoking status, initial infertility diagnosis, and stimulation protocol. MAIN RESULTS AND ROLE OF CHANCE: Compared to the median chronological age of our participants (34 years), the Horvath clock predicted, on an average, a younger epigenetic age (median: 24.2 years) while the GrimAge (median: 38.6 years) and Granulosa Cell (median: 39.0 years) clocks predicted, on an average, an older epigenetic age. Age acceleration based on the Horvath clock was associated with lower peak estradiol levels (-819.4 unit decrease in peak estradiol levels per standard deviation increase; 95% CI: -1265.7, -373.1) and fewer total (% change in total oocytes retrieved per standard deviation increase: -21.8%; 95% CI: -37.1%, -2.8%) and mature oocytes retrieved (% change in mature oocytes retrieved per standard deviation increase: -23.8%; 95% CI: -39.9%, -3.4%). The age acceleration based on the two other epigenetic clocks was not associated with markers of ovarian response. LIMITATIONS, REASONS FOR CAUTION: Our sample size was small and we did not specifically isolate granulosa cells from follicular fluid samples so our samples could have included mixed cell types. WIDER IMPLICATIONS OF THE FINDINGS: Our results highlight that certain epigenetic clocks may be predictive of ovarian stimulation outcomes when applied to follicular fluid; however, the inconsistent findings for specific clocks across studies indicate a need for further research to better understand the clinical utility of epigenetic clocks to improve IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by grants ES009718, ES022955, ES000002, and ES026648 from the National Institute of Environmental Health Sciences (NIEHS) and a pilot grant from the NIEHS-funded HERCULES Center at Emory University (P30 ES019776). RBH was supported by the Emory University NIH Training Grant (T32-ES012870). TRIAL REGISTRATION NUMBER: N/A.

BMI status and weight trajectories across females' reproductive years and risk of adverse pregnancy outcomes: a prospective cohort study.

BACKGROUND: Prepregnancy body mass index (BMI) is a well-established risk factor of adverse pregnancy outcomes (APOs). The associations of long-term and short-term weight trajectories with APOs are less clear. OBJECTIVES: This study aimed to determine the associations of weight trajectories during females' reproductive years, before and between pregnancies, with risk of APOs. METHODS: We followed 16,241 females (25,386 singleton pregnancies) participating in a prospective cohort, the Nurses' Health Study II. Weight at age 18 y, current weight, and height were assessed at baseline (1989), and weight was updated biennially. Pregnancy history was self-reported in 2009. The primary outcome was a composite of hypertensive disorders of pregnancy (HDP), gestational diabetes (GDM), preterm birth, and stillbirth. Secondary outcomes were individual APOs. The associations of weight change with APOs were estimated using log-binomial regression, adjusting for demographic, lifestyle, reproductive factors, and baseline BMI (in kg/m2). RESULTS: The mean (standard deviation [SD]) age at first in-study pregnancy was 33.7 (4.1) y. The mean (SD) time from age 18 y to pregnancy, baseline to pregnancy, and between pregnancies was 16.3 (4.0), 6.1 (3.0), and 2.9 (1.6) y, with a corresponding weight change of 6.4 (9.1), 3.1 (5.8), and 2.3 (4.8) kg, respectively. Of the pregnancies, 4628 (18.2%) were complicated by ≥1 APOs. Absolute weight change since age 18 y was most strongly associated with APOs. Compared with females whose weight remained stable (0-2 kg) since age 18, females who gained >2 kg had higher risk of APO (2.1-9.9 kg, relative risk [RR]: 1.12; 95% confidence interval [CI]: 1.02, 1.23; 10.0-14.9 kg, RR: 1.43; 95% CI: 1.29, 1.60; ≥15 kg, RR: 1.87; 95% CI: 1.69, 2.08), primarily driven by HDP and GDM. The associations of per 1 kg weight gain before and between pregnancies with HDP were nearly identical. CONCLUSIONS: Weight trajectories prior to and between pregnancies were associated with the risk of APOs, particularly HDP. Longer periods of weight gain, corresponding to greater absolute weight gain, were most strongly associated with higher risk of APOs.

The associations between pre-conception urinary phthalate concentrations, the serum metabolome, and live birth among women undergoing assisted reproduction.

BACKGROUND: Phthalates are ubiquitous endocrine disruptors. Past studies have shown an association between higher preconception urinary concentrations of phthalate metabolites and lower fertility in women; however, the biological mechanisms remain unclear. Our exploratory study aimed to understand the metabolites and pathways associated with maternal preconception phthalate exposure and examine if any may underline the association between phthalate exposure and live birth using untargeted metabolomics. METHODS: Participants (n = 183) were part of the Environment and Reproductive Health (EARTH) study, a prospective cohort that followed women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital Fertility Center (2005-2016). On the same day, women provided a serum sample during controlled ovarian stimulation, which was analyzed for metabolomics using liquid chromatography coupled with high-resolution mass spectrometry and two chromatography columns, and a urine sample, which was analyzed for 11 phthalate metabolites using targeted approaches. We used multivariable generalized linear models to identified metabolic features associated with urinary phthalate metabolite concentrations and live birth, followed by enriched pathway analysis. We then used a meet-in-the-middle approach to identify overlapping pathways and features. RESULTS: Metabolic pathway enrichment analysis revealed 43 pathways in the C18 negative and 32 pathways in the HILIC positive columns that were significantly associated (p < 0.05) with at least one of the 11 urinary phthalate metabolites or molar sum of di-2-ethylhexyl phthalate metabolites. Lipid, amino acid, and carbohydrate metabolism were the most common pathways associated with phthalate exposure. Five pathways, tryptophan metabolism, tyrosine metabolism, biopterin metabolism, carnitine shuttle, and vitamin B6 metabolism, were also identified as being associated with at least one phthalate metabolite and live birth following IVF. CONCLUSION: Our study provides further insight into the metabolites and metabolomics pathways, including amino acid, lipid, and vitamin metabolism that may underlie the observed associations between phthalate exposures and lower fertility in women.

Neighborhood deprivation in relation to ovarian reserve and outcomes of ovarian stimulation among oocyte donors.

OBJECTIVE: To study the relationship between neighborhood deprivation index (NDI) and markers of ovarian reserve and outcomes of controlled ovarian stimulation among young, healthy oocyte donors. DESIGN: Retrospective cohort study. PATIENTS: A total of 547 oocyte donors who underwent 905 oocyte retrieval cycles (2008-2020) at a private fertility center in Sandy Springs, Georgia, United States. INTERVENTIONS: Neighborhood deprivation index was calculated using principal component analysis applied to census-level measures of poverty, employment, household composition, and public assistance, which was then standardized and linked to donor information on the basis of donor residence. MAIN OUTCOME MEASURES: Markers of ovarian reserve, including antral follicle count (AFC) and antimüllerian hormone (AMH) levels, and outcomes of controlled ovarian stimulation including number of total and mature oocytes retrieved and ovarian sensitivity index (OSI) (defined as the number of oocytes retrieved/total gonadotropin dose × 1,000). Multivariable generalized estimating equations with Poisson and normal distribution were used to model the relationship between NDI and outcome measures adjusting for age, body mass index, and year of retrieval. RESULTS: The mean (SD) age of donors was 25.0 (2.8) years and 29% of the donors were racial or ethnic minorities. There were no associations between donor NDI and ovarian reserve markers. For every interquartile range increase in NDI, there was a reduction of -1.5% (95% confidence interval: -5.3% to 2.4%) in total oocytes retrieved although the effect estimate was imprecise. Associations of NDI with a number of mature oocytes retrieved and OSI were in a similar direction. We observed evidence for effect modification of the NDI and OSI association by donor race. There was a suggestive positive association between NDI and OSI in Black donors but no association in White donors. CONCLUSION: In this cohort of young, healthy, racially diverse oocyte donors, we found little evidence of associations between NDI and markers of ovarian reserve or outcomes of ovarian stimulation.

Former smoking associated with epigenetic modifications in human granulosa cells among women undergoing assisted reproduction.

Smoking exposure during adulthood can disrupt oocyte development in women, contributing to infertility and possibly adverse birth outcomes. Some of these effects may be reflected in epigenome profiles in granulosa cells (GCs) in human follicular fluid. We compared the epigenetic modifications throughout the genome in GCs from women who were former (N = 15) versus never smokers (N = 44) undergoing assisted reproductive technologies (ART). This study included 59 women undergoing ART. Smoking history including time since quitting was determined by questionnaire. GCs were collected during oocyte retrieval and DNA methylation (DNAm) levels were profiled using the Infinium MethylationEPIC BeadChip. We performed an epigenome-wide association study with robust linear models, regressing DNAm level at individual loci on smoking status, adjusting for age, ovarian stimulation protocol, and three surrogate variables. We performed differentially methylated regions (DMRs) analysis and over-representation analysis of the identified CpGs and corresponding gene set. 81 CpGs were differentially methylated among former smokers compared to never smokers (FDR < 0.05). We identified 2 significant DMRs (KCNQ1 and RHBDD2). The former smoking-associated genes were enriched in oxytocin signaling, adrenergic signaling in cardiomyocytes, platelet activation, axon guidance, and chemokine signaling pathway. These epigenetic variations have been associated with inflammatory responses, reproductive outcomes, cancer development, neurodevelopmental disorder, and cardiometabolic health. Secondarily, we examined the relationships between time since quitting and DNAm at significant CpGs. We observed three CpGs in negative associations with the length of quitting smoking (p < 0.05), which were cg04254052 (KCNIP1), cg22875371 (OGDHL), and cg27289628 (LOC148145), while one in positive association, which was cg13487862 (PLXNB1). As a pilot study, we demonstrated epigenetic modifications associated with former smoking in GCs. The study is informative to potential biological pathways underlying the documented association between smoking and female infertility and biomarker discovery for smoking-associated reproductive outcomes.

Neighborhood deprivation and racial differences in in vitro fertilization outcomes.

BACKGROUND: There are significant racial disparities in in vitro fertilization outcomes, which are poorly explained by individual-level characteristics. Environmental factors such as neighborhood-level socioeconomic factors may contribute to these disparities. However, few studies have directly addressed this research question in a large, racially diverse cohort. OBJECTIVE: This study aimed to investigate whether neighborhood deprivation is associated with differences in in vitro fertilization outcomes. STUDY DESIGN: Our retrospective cohort study included 1110 patients who underwent 2254 autologous in vitro fertilization cycles between 2014 and 2019 at an academic fertility center in the Southeastern United States. Neighborhood deprivation was estimated using the Neighborhood Deprivation Index, a composite variable measuring community levels of material capital based on poverty, occupation, housing, and education domains. Using multivariable log-binomial generalized estimating equations with cluster weighting, risk ratios and 95% confidence intervals were estimated for cycle cancellation, miscarriage (defined as spontaneous pregnancy loss before 20 weeks after a confirmed intrauterine gestation), and live birth according to patient Neighborhood Deprivation Index. RESULTS: There were positive associations between increasing Neighborhood Deprivation Index (indicating worsening neighborhood deprivation) and body mass index, as well as increasing prevalence of tubal and uterine factor infertility diagnoses. The crude probability of live birth per cycle was lower among Black (24%) than among White patients (32%), and the crude probability of miscarriage per clinical pregnancy was higher among Black (22%) than among White patients (12%). After adjustment, the Neighborhood Deprivation Index was not significantly associated with risk of cycle cancellation or live birth. Results were consistent when analyses were stratified by race. CONCLUSION: Our research demonstrates racial disparities between Black and White women in the incidence of miscarriage and live birth following in vitro fertilization. Although the level of neighborhood deprivation was closely related to race, it did not have strong associations with in vitro fertilization outcomes in our population as a whole or within strata of race.

In-utero exposure to polybrominated biphenyl (PBB) and menstrual cycle function in adulthood.

BACKGROUND: There is evidence that in-utero exposure to PBBs, and similar chemicals, are associated with several adverse reproductive health outcomes including altered pubertal timing. However, less is known about the effects of in-utero exposure to PBBs on menstrual cycle function and reproductive hormone levels in adulthood. METHODS: For this menstrual cycle study, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications (2004-2014). A total of 41 women who were born after the PBB contamination incident (1973-1974) and were prenatally exposed to PBBs, were included in this analysis. We estimated in-utero PBB exposure using maternal serum PBB measurements taken after exposure and extrapolated to time of pregnancy using a PBB elimination model. Women were followed for up to 6 months during which they provided daily urine samples and completed daily diaries. The urine samples were assayed for estrone 3-glucuronide (E13G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). RESULTS: Women in our study were, on average, 27.5 (SD:5.3) years old and contributed 4.9 (SD:1.9) menstrual cycles of follow-up. Compared to women with low in-utero PBB exposure (≤1 ppb), women with medium (>1.0-3.0 ppb) and high (>3.0 ppb) exposure had higher maximum 3-day mean Pd3G levels during the luteal phase. Specifically, the age- and creatinine-adjusted maximum 3-day mean luteal phase Pd3G levels (95% CI) in increasing categories of in-utero PBB exposure were 9.2 (4.6,13.9), 14.8 (11.6,18.0), and 16.1 (12.9,19.3) µg/mg creatinine. There were no meaningful differences in average cycle length, follicular or luteal phase cycle length, bleed length, or creatinine-adjusted E13G or FSH levels by category of in-utero PBB exposure. CONCLUSION: Higher exposure to PBB in-utero was associated with increased progesterone levels across the luteal phase, however, most other menstrual cycle characteristics were largely unassociated with in-utero PBB exposure. Given our modest sample size, our results require cautious interpretation.

Food, nutrition, and fertility: from soil to fork.

Food and nutrition-related factors, including foods and nutrients consumed, dietary patterns, use of dietary supplements, adiposity, and exposure to food-related environmental contaminants, have the potential to impact semen quality and male and female fertility; obstetric, fetal, and birth outcomes; and the health of future generations, but gaps in evidence remain. On 9 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and the school's Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships between food, nutrition, and fertility. Topics addressed included male fertility, female fertility and gestation, and intergenerational effects. This meeting report summarizes the presentations and deliberations from the meeting. Regarding male fertility, a positive association exists with a healthy dietary pattern, with high-quality evidence for semen quality and lower quality evidence for clinical outcomes. Folic acid and zinc supplementation have been found to not impact male fertility. In females, body weight status and other nutrition-related factors are linked to nearly half of all ovulation disorders, a leading cause of female infertility. Females with obesity have worse fertility treatment, pregnancy-related, and birth outcomes. Environmental contaminants found in food, water, or its packaging, including lead, perfluorinated alkyl substances, phthalates, and phenols, adversely impact female reproductive outcomes. Epigenetic research has found that maternal and paternal dietary-related factors can impact outcomes for future generations. Priority evidence gaps identified by meeting participants relate to the effects of nutrition and dietary patterns on fertility, gaps in communication regarding fertility optimization through changes in nutritional and environmental exposures, and interventions impacting germ cell mechanisms through dietary effects. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and fertility.

Ambient traffic related air pollution in relation to ovarian reserve and oocyte quality in young, healthy oocyte donors.

Studies in mice and older, subfertile women have found that air pollution exposure may compromise female reproduction. Our objective was to evaluate the effects of air pollution on ovarian reserve and outcomes of ovarian stimulation among young, healthy females. We included 472 oocyte donors who underwent 781 ovarian stimulation cycles at a fertility clinic in Atlanta, Georgia, USA (2008-2019). Antral follicle count (AFC) was assessed with transvaginal ultrasonography and total and mature oocyte count was assessed following oocyte retrieval. Ovarian sensitivity index (OSI) was calculated as the total number of oocytes divided by total gonadotrophin dose × 1000. Daily ambient exposure to nitric oxide (NOx), carbon monoxide (CO), and particulate matter ≤ 2.5 (PM2.5) was estimated using a fused regional + line-source model for near-surface releases at a 250 m resolution based on residential address. Generalized estimating equations were used to evaluate the associations of an interquartile range (IQR) increase in pollutant exposure with outcomes adjusted for donor characteristics, census-level poverty, and meteorological factors. The median (IQR) age among oocyte donors was 25.0 (5.0) years, and 31% of the donors were racial/ethnic minorities. The median (IQR) exposure to NOx, CO, and PM2.5 in the 3 months prior to stimulation was 37.7 (32.0) ppb, 612 (317) ppb, and 9.8 (2.9) µg/m3, respectively. Ambient air pollution exposure in the 3 months before AFC was not associated with AFC. An IQR increase in PM2.5 in the 3 months before AFC and during stimulation was associated with -7.5% (95% CI -14.1, -0.4) and -6.4% (95% CI -11.0, -1.6) fewer mature oocytes, and a -1.9 (95% CI -3.2, -0.5) and -1.0 (95% CI -1.8, -0.2) lower OSI, respectively. Our results suggest that lowering the current 24-h PM2.5 standard in the US to 25 µg/m3 may still not adequately protect against the reprotoxic effects of short-term PM2.5 exposure.

Diet and recreational drug use in relation to male reproductive health.

Diet and lifestyle interventions present promising avenues for the improvement of male fertility. Our objective was to review and synthesize the existing observational and experimental studies among humans on the associations of diet and recreational drug use with semen quality and fertility outcomes. The available data on this topic are limited and, at times, conflicting. Nevertheless, on the basis of this review, dietary patterns that are composed of higher intakes of fruits, vegetables, whole grains, nuts, low-fat dairy, and seafood, as well as lower intakes of red and processed meats, sweets, and sugar-sweetened beverages were identified as having the strongest evidence for associations with better sperm quality. However, whether these dietary patterns translate into positive associations with clinical fertility endpoints such as assisted reproductive technology success rates or time-to-pregnancy among couples trying to conceive without medical assistance remains unclear. Male caffeine and alcohol intake, within low-to-moderate ranges of intake, do not appear to be detrimental to semen quality. Yet high-quality research on this topic, focused on clinical fertility endpoints, should continue given the conflicting evidence, particularly in populations undergoing infertility treatment with assisted reproductive technology. Recreational drug use, including marijuana, electronic cigarettes, and other illicit drugs, does not appear to be beneficial for male reproductive health and should be avoided or ceased. In conclusion, men should be encouraged to consume a healthy diet rich in fruits, vegetables, whole grains, nuts, low-fat dairy, and seafood, as well as lacking in red and processed meats, sweets, and sugar-sweetened beverages, and to avoid recreational drug use for improved male reproductive health.

Deafening Silence of Male Infertility.

Think about 6 loved ones of reproductive age in your life. Now imagine that 1 of these 6 individuals is suffering from infertility. Perhaps they feel alone and isolated, unable to discuss their heartbreak with their closest friends, family, and support network. Suffering in silence. In this editorial, we discuss the infertility journey through the lens of the patients, the providers, and the scientists who struggle with infertility each and every day. Our goal is to open a dialogue surrounding infertility, with an emphasis on dismantling the longstanding societal barriers to acknowledging male infertility as a disease. Through education, communication, compassion, and advocacy, together we can all begin to break the deafening silence of male infertility.

Endocrine-disrupting chemicals and male reproductive health.

Modifiable factors, such as environmental exposures, can impact human fertility. The objective of this review is to summarize the potential effects of exposure to important endocrine-disrupting chemicals on male reproductive health. Most experimental and animal data demonstrate strong evidence for the negative effects of exposure to phenols, phthalates, pesticides, and perfluoroalkyl and polyfluoroalkyl substances on male reproductive health. Although evidence of negative associations in humans was overall strong for phthalates and pesticides, limited and inconclusive relationships were found for the other examined chemical biomarkers. Reasons for the discrepancies in results include but are not limited to, differences in study populations, exposure concentrations, number of samples collected, sample sizes, study design, and residual confounding. Additional studies are needed, particularly for newer phenols and perfluoroalkyl and polyfluoroalkyl substances, given the scarce literature on the topic and increasing exposures over time.

Exposure to Particulate Matter Air Pollution and Age of Menarche in a Nationwide Cohort of U.S. Girls.

BACKGROUND: It remains unclear whether in utero and childhood exposure to air pollution affects pubertal development, particularly age of menarche in girls. OBJECTIVE: The aim of this study was to determine whether residential ambient particulate matter (PM) exposure in utero and during childhood is associated with age of menarche. METHODS: We studied 5,201 girls in the Growing Up Today Study 2 (2004-present) who were 10-17 y of age at enrollment (47.7% premenarchal; 52.3% postmenarchal). Exposure to three size fractions of PM [fine PM with aerodynamic diameter ≤2.5µm (PM2.5), PM with aerodynamic diameters between 2.5µm and 10µm (PM2.5-10), and PM with aerodynamic diameter 10µm (PM10)] was assigned based on maternal residential address, updated every 2 y, using nationwide spatiotemporal models. We estimated average PM exposure in utero, and time-varying windows: annual average exposure in the prior 1 and 2 y and cumulative average from birth. Age of menarche was self-reported on three surveys administered in 2004, 2006, and 2008. We calculated hazard ratios (HR) for menarche for an interquartile range (IQR) increase in PM exposure using Cox proportional hazard models adjusting for potential confounders. RESULTS: Girls attained menarche at 12.3 y of age on average. In the adjusted model, higher residential exposure to ambient PM2.5 during all time windows was associated with earlier age of menarche. The HRs of menarche for each IQR (4 µg/m3) increase in exposure to PM2.5 during the in utero period, 1 y prior to menarche, and throughout childhood were 1.03 [95% confidence interval (CI): 1.00, 1.06], 1.06 (95% CI: 1.02, 1.10) and 1.06 (95% CI: 1.02, 1.10), respectively. Effect estimates for PM10 exposure were similar, albeit attenuated, for all time windows. PM2.5-10 exposure was not associated with age of menarche. DISCUSSION: Among a large, nationwide, prospective cohort of U.S. girls, higher exposure to PM2.5 and PM10 in utero and throughout childhood was associated with an earlier age of menarche. Our results suggest that PM2.5 and PM10 may have endocrine-disrupting properties that could lead to altered timing of menarche. https://doi.org/10.1289/EHP12110.

Serum and follicular fluid metabolome and markers of ovarian stimulation.

STUDY QUESTION: What metabolic pathways and metabolites in the serum and follicular fluid are associated with peak estradiol levels and the number of mature oocytes? SUMMARY ANSWER: In the serum metabolome, mostly fatty acid and amino acid pathways were associated with estradiol levels and mature oocytes while in the follicular fluid metabolome, mostly lipid, vitamin, and hormone pathways were associated with peak estradiol levels and mature oocytes. WHAT IS KNOWN ALREADY: Metabolomics has identified several metabolic pathways and metabolites associated with infertility but limited data are available for ovarian stimulation outcomes. STUDY DESIGN, SIZE, DURATION: A prospective cohort study of women undergoing IVF from 2009 to 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 125 women undergoing a fresh IVF cycle at a fertility clinic in the Northeast United States who provided a serum and follicular fluid sample. Untargeted metabolomics profiling was conducted using liquid chromatography with high-resolution mass spectrometry in two chromatography columns (C18 and hydrophilic interaction chromatography (HILIC)). The main ovarian stimulation outcomes were peak serum estradiol levels and number of mature oocytes. We utilized adjusted generalized linear regression models to identify significant metabolic features. Models were adjusted for age,BMI, initial infertility diagnosis, and ovarian stimulation protocol. We then conducted pathway analysis using mummichog and metabolite annotation using level-1 evidence. MAIN RESULTS AND ROLE OF CHANCE: In the serum metabolome, 480 and 850 features were associated with peak estradiol levels in the C18 and HILIC columns, respectively. Additionally, 437 and 538 features were associated with mature oocytes in the C18 and HILIC columns, respectively. In the follicular fluid metabolome, 752 and 929 features were associated with peak estradiol levels in the C18 and HILIC columns, respectively, Additionally, 993 and 986 features were associated with mature oocytes in the C18 and HILIC columns, respectively. The most common pathways associated with peak estradiol included fatty acids (serum and follicular fluid), hormone (follicular fluid), and lipid pathways (follicular fluid). The most common pathways associated with the number of mature oocytes retrieved included amino acids (serum), fatty acids (serum and follicular fluid), hormone (follicular fluid), and vitamin pathways(follicular fluid). The vitamin D3 pathway had the strongest association with both ovarian stimulation outcomes in the follicularfluid. Four and nine metabolites were identified using level-1 evidence (validated identification) in the serum and follicular fluid metabolomes, respectively. LIMITATIONS, REASONS FOR CAUTION: Our sample was majority White and highly educated and may not be generalizable to thewider population. Additionally, residual confounding is possible and the flushing medium used in the follicular fluid could have diluted our results. WIDER IMPLICATIONS OF THE FINDINGS: The pathways and metabolites identified by our study provide novel insights into the biologicalmechanisms in the serum and follicular fluid that may underlie follicular and oocyte development, which could potentially be used to improve ovarian stimulation outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the following grants from the National Institute of Environmental Health Sciences (P30-ES019776, R01-ES009718, R01-ES022955, P30-ES000002, R00-ES026648, and T32-ES012870), and National Institute of Diabetes and Digestive and Kidney Diseases (P30DK046200). The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Association of Gestational Diabetes With Subsequent Long-Term Risk of Mortality.

Importance: Gestational diabetes has been associated with numerous chronic diseases. However, few studies have examined the association of gestational diabetes with long-term mortality risk. Objective: To investigate the associations between gestational diabetes and long-term risks of total and cause-specific mortality. Design, Setting, and Participants: This cohort study analyzed participants of the Nurses' Health Study II who were followed for 30 years (1989-2019). Participants included US female nurses aged 25 to 42 years who reported at least 1 pregnancy (≥6 months) at 18 years or older across their reproductive life span. Data were analyzed from May 1, 2022, to May 25, 2023. Exposure: Gestational diabetes across the reproductive life span. Main Outcomes and Measures: Hazard ratios (HRs with 95% CIs) for total and cause-specific mortality were estimated by Cox proportional hazards regression models. Results: A total of 91 426 parous participants were included, with a mean (SD) age of 34.9 (4.7) years and a body mass index of 24.1 (4.7) at baseline. During a follow-up period of 2 609 753 person-years, 3937 deaths were documented, including 255 deaths from cardiovascular disease and 1397 from cancer. Participants with a history of gestational diabetes had a higher crude mortality rate than those without a history of gestational diabetes (1.74 vs 1.49 per 1000 person-years; absolute difference = 0.25 per 1000 person-years). The corresponding HR for total mortality was 1.28 (95% CI, 1.13-1.44), which did not materially change after additional adjustment for potential confounders and lifestyle factors during the reproductive life span (HR, 1.25; 95% CI, 1.11-1.41). The association persisted regardless of the subsequent development of type 2 diabetes and was more robust among participants who adopted less healthy lifestyles; experienced gestational diabetes in 2 or more pregnancies (HR, 1.48; 95% CI, 0.99-2.19); had gestational diabetes both in the initial and subsequent pregnancies (HR, 1.71; 95% CI, 1.11-2.63); and concurrently reported hypertensive disorders in pregnancy (HR, 1.80; 95% CI, 1.21-2.67), preterm birth (HR, 2.46; 95% CI, 1.66-3.64), or low birth weight (HR, 2.11; 95% CI, 1.21-3.68). Cause-specific mortality analyses revealed that gestational diabetes was directly associated with the risk of mortality due to cardiovascular disease (HR, 1.59; 95% CI, 1.03-2.47). Additionally, gestational diabetes was inversely associated with cancer mortality (HR, 0.76; 95% CI, 0.59-0.98); however, it was only evident among participants who later developed type 2 diabetes. Conclusions and Relevance: Results of this cohort study suggest that participants who reported a history of gestational diabetes exhibited a small but elevated risk of subsequent mortality over 30 years. The findings emphasize the importance of considering gestational diabetes as a critical factor in later-life mortality risk.

Mediterranean diet and female reproductive health over lifespan: a systematic review and meta-analysis.

OBJECTIVE: We conducted a systematic review and meta-analysis of the effects of Mediterranean diet on female reproductive health outcomes over the life-course. DATA SOURCES: We searched PubMed, Embase, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov to identify eligible studies published till February 2022. Eligible references from identified studies and review articles were also considered. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials, prospective cohort studies, or nested case-control studies examining Mediterranean diet and major female reproductive outcomes over the lifespan, including clinical outcomes from childhood to adulthood (menarche, polycystic ovary syndrome, endometriosis, and outcomes related to fertility, pregnancy, and menopause), were included for review. METHODS: Two independent reviewers screened and performed data extraction and risk-of-bias assessment. We performed random-effects meta-analysis to obtain summary relative risks and 95% confidence intervals for major female reproductive outcomes. Subgroup analyses were performed for several pregnancy outcomes according to timing of the interventions for randomized controlled trials and timing of the dietary assessment for observational studies. RESULTS: Thirty-two studies (9 randomized controlled trials, 22 prospective cohort studies, and 1 nested case-control study) involving 103,204 predominantly White women (>95%) were included. The pooled relative risk (95% confidence interval) comparing randomization to Mediterranean diet vs a control diet based on 7 randomized controlled trials was 0.74 (0.55-0.99) for gestational diabetes mellitus, 0.45 (0.26-0.76) for preterm birth, 0.71 (0.51-1.00) for gestational hypertension, and 0.82 (0.54-1.22) for preeclampsia; the effect sizes for preterm birth were greater in randomized controlled trials that initiated the interventions in first trimester vs after first trimester (P heterogeneity=.02). We observed inverse associations for all the above-mentioned pregnancy outcomes based on 9 cohort studies. There was suggestive evidence of favorable associations between Mediterranean diet adherence with fertility and gestational weight management. Limited studies suggested associations between higher Mediterranean diet adherence and later time to menarche and fewer vasomotor menopausal symptoms, null associations for polycystic ovary syndrome-like phenotype and pregnancy loss, and positive associations for luteal phase deficiency. CONCLUSION: Adherence to Mediterranean diet may lower risks of adverse pregnancy outcomes among predominantly White populations. For fertility-related outcomes, available evidence supporting potential beneficial effects is suggestive yet limited. For other reproductive outcomes across the lifespan, data remains sparse.