Both environmental exposures and genetics are known to play important roles in shaping human aging. Here we aimed to quantify the relative contributions of environment (referred to as the exposome) and genetics to aging and premature mortality. To systematically identify environmental exposures associated with aging in the UK Biobank, we first conducted an exposome-wide analysis of all-cause mortality (n = 492,567) and then assessed the associations of these exposures with a proteomic age clock (n = 45,441), identifying 25 independent exposures associated with mortality and proteomic aging. These exposures were also associated with incident age-related multimorbidity, aging biomarkers and major disease risk factors. Compared with information on age and sex, polygenic risk scores for 22 major diseases explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points. Polygenic risk explained a greater proportion of variation (10.3–26.2%) compared with the exposome for incidence of dementias and breast, prostate and colorectal cancers, whereas the exposome explained a greater proportion of variation (5.5–49.4%) compared with polygenic risk for incidence of diseases of the lung, heart and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and incidence of common age-related diseases, suggesting that the exposome shapes distinct patterns of disease and mortality risk, irrespective of polygenic disease risk.

How does conception \<6 months after hysterosalpingography (HSG) with iodinated contrast media affect the neurodevelopment of the offspring compared to naturally-conceived peers at a school-age?Children conceived \<6 months after HSG with iodinated contrast media perform lower on intelligence tests and information processing and attention control compared to naturally-conceived peers.Tubal patency in subfertile women is commonly assessed using hysterosalpingography (HSG), but the potential risks of exposure to high iodine content in contrast media used remains unknown. Exposure to iodine excess can cause transient reduction in thyroid hormone synthesis due to the Wolff-Chaikoff effect. Thyroid hormone sufficiency in early pregnancy is vital for children's neurodevelopment. When conception occurs shortly after HSG with iodinated contrast, a temporary reduction of maternal and/or foetal thyroid hormone supply could jeopardize children's neurodevelopment.We evaluated neurodevelopmental outcomes of 6–9-year-old children conceived \<6 months after HSG with oil-based (iodine content: 480mg/ml) or water-based contrast (iodine content: 240-300mg/ml) in a nationwide randomised controlled trial (H2Oil trial; Netherlands; 2012-2014; NCT05168228). Naturally-conceived children (n = 44) with similar age, sex and parental education were used as a comparison group (NTR9574). We also compared children conceived \<4w, 4-12w, \>12w after HSG with those conceived naturally. The study took place January 2022 until November 2023.We contacted 140 mothers from the H2Oil trial, 69 children conceived \<6m after HSG participated, and parallelly we recruited 44 naturally-conceived children. Primary outcomes were intelligence (Wechsler's Intelligence Scale for Children V), behavioural functioning (SDQ and SWAN, administered to parents and teachers), and academic performance. Secondary outcomes were neurocognitive function assessed by a battery of computerized tests. We used linear regression adjusted for age, sex, and parental education and applied FDR correction.Compared to naturally conceived children, children conceived \<6m after HSG had lower performance on intelligence tests (-6.81; 95\%CI-10.97 to -2.65; p = 0.02) and the neurocognitive domain Processing \& Control (-0.52; 95\%CI-0.84 to -0.19; p = 0.02), with functions relating to information processing speed and consistency affected. No differences were found for other neurocognitive domains, behaviour or academic performance. Considering time between HSG and conception, intelligence scores were lower for children conceived \<4w after HSG compared to naturally-conceived peers (-11.47; 95\%CI-17.98 to -4.95; p = 0.03), while no significant differences were found for the groups of children conceived 4-12 weeks after HSG (-7.17; 95\%CI -12.28 to -2.06; p = 0.10) or \> 12 weeks after HSG (-4.20; 95\%CI -9.33 to 0.94; p = 0.52). The findings of this study warrant replication in larger independent samples in order to evaluate the long-term neurodevelopment of children conceived after HSG with iodinated contrast media.We aimed to recruit 64 children for each group, but our study was not sufficiently powered for small- and medium-sized differences. We did not collect information on the thyroid or iodine status of the mothers following HSG, and there is limited knowledge about pharmacokinetics of iodinated contrast media in humans.Replication studies with are needed to further evaluate the safety of iodinated contrast media use periconception, including their effects on thyroid function and children's neurodevelopment. Closer monitoring and treatment of thyroid dysfunction in the months following HSG may be warranted.NCT05168228

Disclosure: S. Keestra: None. C. Kooper: None. N. van Welie: None. K. Dreyer: Grant Recipient; Self; research grants from Guerbet. Speaker; Self; travel and speaker fees Guerbet. R. van Eekelen: None. T. Roseboom: None. J. Oosterlaan: None. B. Mol: Consulting Fee; Self; Organon Laboratories, Norgine, Merck. Grant Recipient; Self; Merck. Stock Owner; Self; ObsEva. M. Finken: None. V. Mijatovic: Grant Recipient; Self; Guerbet, Merck, Ferring Pharmaceuticals. Speaker; Self; Guerbet, Merck, Ferring Pharmaceuticals. M. Königs: None.Thyroid hormone sufficiency in pregnancy is vital for children's neurodevelopment. Exposure to iodine excess can cause transient disruption of thyroid hormone synthesis through the Wolff-Chaikoff effect. Iodinated contrast media are commonly utilized in hysterosalpingography (HSG) as part of female fertility work-up. When conception occurs shortly after HSG with iodinated contrast, a temporary reduction of maternal and/or foetal thyroid hormone synthesis could jeopardize children's neurodevelopment. We compared the neurodevelopmental outcomes of 6-9-year-old children (n=69) conceived \<6 months after HSG with 5-10 ml of oil-based contrast (iodine content: 480mg/ml) or water-based contrasts (iodine content: 250mg/ml) in the follow-up of a nationwide randomised controlled trial (H2Oil trial; Netherlands; 2012-2014; NCT05168228). A community sample of naturally-conceived children (n=44) with similar age, sex and parental education was used as a comparison group (NTR9574). Primary outcomes were intelligence (Wechsler's Intelligence Scale for Children V), behaviour questionnaires for parents and teachers (Strengths and Difficulties Questionnaire (SDQ); Strengths and Weaknesses of ADHD Symptoms And Normal behaviour (SWAN)), and academic performance. Secondary outcomes were neurocognitive domains assessed in computerized tasks focussing on Processing \& Control, Verbal Memory, Visual Memory, Verbal Working Memory, Visual Working Memory, and Visuomotor Integration (Emma Toolbox for Neurocognitive Functioning). We adjusted linear regression models for age, sex, and parental education, applying FDR correction for multiple comparisons. Additional analysis looked at children conceived within 4 weeks, 4-12 weeks, or \>12 weeks after HSG. Children conceived \<6 months after HSG had lower performance on intelligence tests (-6.81; 95\%CI -10.97 to -2.65; p=0.02) and the neurocognitive domain Processing \& Control (-0.52; 95\%CI-0.84 to -0.19; p=0.02), with processing speed and consistency affected. No differences were found for other neurocognitive domains, behaviour or academic performance. In comparison to naturally-conceived children, children conceived \<4 weeks after HSG had lower performance on intelligence tests, but there was no difference for children conceived 4-12 weeks and \>12 weeks after HSG. Replication studies with higher power are needed to further evaluate the safety of iodinated contrast media use periconception, including their effects on thyroid function and children's neurodevelopment. Closer monitoring and treatment of thyroid dysfunction in the months following HSG may be warranted.Presentation: 6/1/2024

Does preconceptional exposure to oil-based iodinated contrast media during hysterosalpingography (HSG) impact children's neurodevelopment compared with exposure to water-based alternatives?Our study found no large-sized effects for neurodevelopment in children with preconceptional exposure to oil-based iodinated contrast media during HSG compared with water-based alternatives.HSG is widely used as a diagnostic tool in the female fertility work-up. Tubal flushing with oil-based iodinated contrast has been shown to enhance fertility outcomes in couples with unexplained infertility, increasing the chances of pregnancy and live birth compared with water-based alternatives. However, oil-based contrast contains higher doses of iodine and has a longer half-life, and concerns exist that iodinated contrast media can affect women's iodine status and cause temporary (sub)clinical hypothyroidism in mothers and/or foetuses. Considering that thyroid hormones are vital to embryonal and foetal brain development, oil-based contrast media use could increase the risk of impaired neurodevelopment in children conceived shortly after HSG. Here we examine neurodevelopmental outcomes in school-aged children conceived after HSG.This is a long-term follow-up of the H2Oil trial in which oil-based or water-based contrast was used during HSG (Netherlands; 2012–2014; NTR3270). Of 369 children born \<6 months after HSG in the study, we contacted the mothers of 140 children who gave consent to be contacted for follow-up. The follow-up study took place from January to July 2022 (NCT05168228).The study included 69 children aged 6–9 years who were conceived after HSG with oil-based (n = 42) or water-based contrast (n = 27). The assessments targeted intelligence (Wechsler Intelligence Scale for Children), neurocognitive outcomes (computerized neurocognitive tests), behavioural functioning (parent and teacher questionnaires), and academic performance. Linear regression models, adjusted for age, sex, and parental educational attainment were employed to compare groups.School-aged children born to mothers after oil-based contrast HSG did not significantly differ from children born to mothers after water-based contrast HSG, in regards to intelligence, neurocognitive functioning, behavioural functioning, or academic performance, with the exception of better performance for visuomotor integration functions in children exposed to oil-based contrast preconception. After exploratory correction for multiple comparisons, none of the group differences was statistically significant.The small sample size of this follow-up study limited statistical power. This study provides evidence for the absence of large-sized differences between preconceptional exposure to the two contrast media types but does not rule out more subtle effects on neurodevelopment compared to naturally conceived children without preconceptional exposure to HSG.This study contributes to our knowledge about the long-term effects of different types of iodinated contrast media used in fertility work-up, indicating that choosing oil-based over water-based iodinated contrast media is unlikely to have major effect on the long-term neurodevelopmental outcomes of children conceived shortly after HSG. However, further research should focus on the overall safety of iodine exposure during HSG, comparing children conceived after HSG to those conceived naturally as both types of contrast contain high amounts of iodine.The original H2Oil randomized controlled trial was an investigator-initiated study that was funded by the two academic hospitals now merged into the Amsterdam University Medical Centre. The current follow-up study (Neuro-H2Oil) is funded through a research grant awarded to the authors by the Amsterdam Reproduction \& Development (AR\&D) research institute. S.K. is funded by a AMC MD/PhD Scholarship from the Amsterdam UMC. S.K. reports holding voluntary roles in the civil society organizations Universities Allied for Essential Medicines and People's Health Movement. V.M. reports receiving travel and speaker fees as well as research grants from Guerbet, Merck and Ferring. K.D. reports receiving travel and speaker fees as well as research grants from Guerbet. BWM is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy, travel support and research funding from Merck, consultancy for Organon and Norgine, and holding stock from ObsEva. The other authors report no conflict of interest.NCT05168228

It has long been suggested that environmental exposures (i.e., the exposome) play a dominant role in shaping trajectories of human aging and premature mortality. Here we aimed to quantify the contribution of the exposome and genome to aging and mortality. We conducted an exposome-wide analysis in the UK Biobank (n=492,567) to systematically identify exposures associated with mortality while accounting for exposure correlation and mismeasurement. We found that the exposome is a major mortality determinant irrespective of genetic disease risk via shaping distinct biological and multimorbidity patterns. We identified 41 independent exposures associated with mortality, and demonstrate that most identified exposures are associated with a common signature of age-related multimorbidity, aging biomarkers, and major cardiometabolic risk factors. Compared with age and sex, polygenic risk for 22 major diseases and aging phenotypes explained an additional 2\% of mortality variation, whereas the exposome explained an additional 19\%. While genetics explained the majority of variation in dementias and breast, prostate, and colorectal cancers, the exposome explained the majority of variation for diseases of the lung, heart, and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and common age-related diseases.Competing Interest StatementThe authors have declared no competing interest.Funding StatementA.N-H. receives research funding from Novo Nordisk, GSK, and Ono Pharma. A.D. is supported by the Wellcome Trust [223100/Z/21/Z], Novo Nordisk, Swiss Re, the British Heart Foundation Centre of Research Excellence (grant number RE/18/3/34214), and Health Data Research UK, an initiative funded by UK Research and Innovation, Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities. C.M.vD. is supported by the common mechanisms and pathways in Stroke and Alzheimer{\textquoteright

5α-reductase-1 catalyzes production of various steroids, including neurosteroids. We reported previously that expression of its encoding gene, Srd5a1, drops in murine ovaries and hypothalamic preoptic area (POA) after early-life immune stress, seemingly contributing to delayed puberty and ovarian follicle depletion, and in the ovaries the first intron was more methylated at two CpGs. Here, we hypothesized that this CpG-containing locus comprises a methylation-sensitive transcriptional enhancer for Srd5a1. We found that ovarian Srd5a1 mRNA increased 8-fold and methylation of the same two CpGs decreased up to 75% between postnatal days 10 and 30. Estradiol (E2) levels rise during this prepubertal stage, and exposure of ovarian cells to E2 increased Srd5a1 expression. Chromatin immunoprecipitation in an ovarian cell line confirmed ESR1 binding to this differentially methylated genomic region and enrichment of the enhancer modification, H3K4me1. Targeting dCas9-DNMT3 to this locus increased CpG2 methylation 2.5-fold and abolished the Srd5a1 response to E2. In the POA, Srd5a1 mRNA levels decreased 70% between postnatal days 7 and 10 and then remained constant without correlation to CpG methylation levels. Srd5a1 mRNA levels did not respond to E2 in hypothalamic GT1-7 cells, even after dCas9-TET1 reduced CpG1 methylation by 50%. The neonatal drop in POA Srd5a1 expression occurs at a time of increasing glucocorticoids, and treatment of GT1-7 cells with dexamethasone reduced Srd5a1 mRNA levels; chromatin immunoprecipitation confirmed glucocorticoid receptor binding at the enhancer. Our findings on the tissue-specific regulation of Srd5a1 and its methylation-sensitive control by E2 in the ovaries illuminate epigenetic mechanisms underlying reproductive phenotypic variation that impact life-long health.

The forms of many species' vocal signals are shaped by their functions1–15. In humans, a salient context of vocal signaling is infant care, as human infants are altricial16,17. Humans often alter their vocalizations to produce "parentese", speech and song produced for infants that differ acoustically from ordinary speech and song18–35 in fashions that have been proposed to support parent-infant communication and infant language learning36–39; modulate infant affect33,40–45; and/or coordinate communicative interactions with infants46–48. These theories predict a form-function link in infant-directed vocalizations, with consistent acoustic differences between infant-directed and adult-directed vocalizations across cultures. Some evidence supports this prediction23,27,28,32,49–52, but the limited generalizability of individual ethnographic reports and laboratory experiments53 and small stimulus sets54, along with intriguing reports of counterexamples55–62, leave the question open. Here, we show that people alter the acoustic forms of their vocalizations in a consistent fashion across cultures when speaking or singing to infants. We collected 1,615 recordings of infant- and adult-directed singing and speech produced by 410 people living in 21 urban, rural, and small-scale societies. First, we analyzed their acoustic forms. We found cross-culturally robust regularities in the acoustics of infant-directed vocalizations, such that infant-directed speech and song were reliably classified from acoustic features found across the 21 societies studied. The acoustic profiles of infant-directedness differed across language and music, but in a consistent fashion worldwide. Then, we studied whether listeners are sensitive to these acoustic features, playing the recordings to 49,241 people recruited online, from many countries, who guessed whether each vocalization was infant-directed. Their intuitions were largely accurate, predictable in part by acoustic features of the recordings, and robust to the effects of linguistic relatedness between vocalizer and listener. By uniting rich cross-cultural data with computational methods, we show links between the production of vocalizations and cross-species principles of bioacoustics, informing hypotheses of the psychological functions and evolution of human communication.

Aversion towards bitter tastes evolved across vertebrate species to enable the recognition of harmful plant toxins. Most studies to date have investigated the variation in bitter taste sensitivity between human populations. However, there is a lack of research investigating phenotypic plasticity and the variation in bitter taste perception within the same population. Here we examined bitter taste perception among the Mbendjele BaYaka hunter-gatherers from Congo, a group of forest hunter-gatherers who exhibit a variation in their levels of market integration. We conducted an experiment using phenylthiocarbamide (PTC) and thiourea infused paper strips and compared the prevalence of bitter tasting phenotypes between the BaYaka who grew up in town and forest camps. We found that 45.1\% of BaYaka experience PTC as bitter, and 42.5\% experience thiourea as bitter. There were no sex and age differences in bitter taste perception. Despite a shared genetic background, we found that BaYaka who grew up in town were more sensitive to bitter taste than those living in the forest, suggesting a developmental component in taste perception. We suggest that a decreased use of traditional plant medicine in town-born BaYaka may underlie this variation in bitter taste perception.Competing Interest StatementThe authors have declared no competing interest.

Three hundred fifty million people worldwide suffer from underactive thyroid conditions, which can lead to infertility, obesity, heart disease, and impaired mental health when poorly managed. Although mobile health (mHealth) applications can be a useful solution for self-managing one's condition, the impact of digital solutions for improving the health of thyroid patients remains unknown. Methods: We used a mixed methods analysis to assess the ways in which a digital approach might benefit thyroid patients. A cross-sectional study was conducted among users of BOOST Thyroid, an mHealth application for patients with an underactive thyroid. We collected data using a modified Short Form 36 Health Survey Questionnaire to measure the impact of in the app on participants' perceived health and quality of life. Participants were asked to (1) score their quality of life before and after using the app, and (2) describe whether and how using the app helped them. Results: We enrolled 406 users (380 females and 26 males), aged 18–78 years. Most participants (95.8%) reported using the app was helpful; of which 68% reported it improved their quality of life and 70.8% reported it had a positive impact on their health. Participants who found the app useful experienced less symptoms and a lower intensity of remaining symptoms. A key factor reported by these participants as helping with managing their health is the information provided in the app. Conclusions: The results support the idea that a patient-centered treatment would benefit from including mHealth tools for a daily self-management of underactive thyroid condition, as it can increase health literacy and improve both one's health status and quality of life.

Abstract Background Adrenarche involves maturation of the hypothalamic-pituitary-adrenal axis and increased production of dehydroepiandrosterone and its sulfate ester, dehydroepiandrosterone-sulfate (DHEA-S). It occurs at ages 6 to 8 in industrialized populations, marking the transition from childhood to juvenility and cognitive development at middle childhood. Studies in subsistence level populations indicate a later age (8-9) for adrenarche, but only two such studies currently exist for comparison. Aims To investigate adrenarcheal age among Maya girls and its association with body composition and dietary variables. We hypothesized adrenarche would occur earlier given the current dual burden of nutrition in Mexico. Materials and Methods 25 Maya girls aged 7 to 9 from Merida, Mexico using ELISAs to measure salivary DHEA-S, standard anthropometry for height, weight, and skinfolds, bioelectrical impedance for body composition variables, as well as a food frequency questionnaire for dietary information. Results Our hypothesis was rejected—adrenarche occurred close to 9 years. While no measures of body composition were significantly associated with adrenarcheal status, girls eating meat and dairy products more frequently had significantly higher DHEA-S levels. Discussion Like other populations living in ecologically challenging environments, adrenarche occurred relatively late among Maya girls. Adrenarche has been linked to measures of body composition, particularly, the adiposity or body mass index rebound, but no relevant anthropometric measures were associated, possibly because of the small sample. Conclusion Further studies are required to illuminate how adrenarcheal variation relates to developmental plasticity, body composition, pubertal progression, and animal product consumption in other transitional populations.

Ethnographers frequently allude to alcoholism and related harms in Indigenous hunter-gatherer communities, but very few studies have quantified patterns of alcohol consumption or its health and social impacts. We present a case study of the Mbendjele BaYaka, a Congolese population undergoing socioeconomic transition. 83 adults answered questions about their frequency and quantity of alcohol consumption, underwent biometric measurements and reported whether they were currently experiencing a cough or diarrhoea; 56 participated in structured interviews about their experiences with alcohol. Based on WHO standards, we found 44.3% of the full sample, and 51.5% of drinkers (excluding abstainers), had a hazardous volume of alcohol consumption; and 35.1% of the full sample, and 40.9% of drinkers, engaged in heavy episodic drinking; consumption habits varied with sex and age. Total weekly consumption was a positive predictor of blood pressure and the likelihood of experiencing diarrhoea; associations with other biometric variables were not statistically significant. Interview responses indicated numerous other economic, mental and physical health harms of alcohol use, the prevalence of which demonstrate some variability between forest camps and permanent village settlements. These include high rates of drinking during pregnancy and breastfeeding (~40%); frequent alcohol-induced violence; and considerable exchange of foraged foods and engagement in exploitative labour activities to acquire alcohol or repay associated debts. Our findings demonstrate the prevalence of hazardous alcohol consumption among transitioning hunter-gatherers is higher than other segments of the Congolese population and indicate negative impacts on health and wellbeing, highlighting an urgent need for targeted public health interventions.

Over the past century autoimmune disease incidence has increased rapidly in (post-) industrialised, affluent societies, suggesting that changes in ecology and lifestyle are driving this development. Epidemiological studies show that (i) 80% of autoimmune disease patients are female, (ii) autoimmune diseases co-occur more often in women, and (iii) the incidence of some autoimmune diseases is increasing faster in women than in men. The female preponderance in autoimmunity is most pronounced between puberty and menopause, suggesting that diverging sex hormone levels during the reproductive years are implicated in autoimmune disease development. Using an evolutionary perspective, we build on the hypotheses that female immunity is cyclical in menstruating species and that natural selection shaped the female immune system to optimise the implantation and gestation of a semi-allogeneic foetus. We propose that cyclical immunomodulation and female immune tolerance mechanisms are currently out of balance because of a mismatch between the conditions under which they evolved and (post-)industrialised, affluent lifestyles. We suggest that current changes in autoimmune disease prevalence may be caused by increases in lifetime exposure to cyclical immunomodulation and ovarian hormone exposure, reduced immune challenges, increased reproductive lifespan, changed reproductive patterns, and enhanced positive energy balance associated with (post-)industrialised, affluent lifestyles. We discuss proximate mechanisms by which oestrogen and progesterone influence tolerance induction and immunomodulation, and review the effect of the menstrual cycle, pregnancy, and contraceptive use on autoimmune disease incidence and symptoms.

Cultures around the world are converging as populations become more connected. On the one hand this increased connectedness can promote the recombination of existing cultural practices to generate new ones, but on the other it may lead to the replacement of traditional practices and global WEIRDing. Here we examine the process and causes of changes in cultural traits concerning wild plant knowledge in Mbendjele BaYaka hunter–gatherers from Congo. Our results show that the BaYaka who were born in town reported knowing and using fewer plants than the BaYaka who were born in forest camps. Plant uses lost in the town-born BaYaka related to medicine. Unlike the forest-born participants, the town-born BaYaka preferred Western medicine over traditional practices, suggesting that the observed decline of plant knowledge and use is the result of replacement of cultural practices with the new products of cumulative culture.

Two hundred million people worldwide experience some form of thyroid disorder, with women being especially at risk. However, why human thyroid function varies between populations, individuals, and across the lifespan has attracted little research to date. This limits our ability to evaluate the conditions under which patterns of variation in thyroid function are best understood as 'normal' or 'pathological'. In this review, we aim to spark interest in research aimed at understanding the causes of variation in thyroid phenotypes. We start by assessing the biomedical literature on thyroid imbalance to discuss the validity of existing reference intervals for diagnosis and treatment across individuals and populations. We then propose an evolutionary ecological framework for understanding the phylogenetic, genetic, ecological, developmental, and physiological causes of normal variation in thyroid function. We build on this approach to suggest testable predictions for how environmental challenges interact with individual circumstances to influence the onset of thyroid disorders. We propose that dietary changes, ecological disruptions of co-evolutionary processes during pregnancy and with pathogens, emerging infections, and exacerbated stress responses can contribute to explaining the onset of thyroid diseases. For patients to receive the best personalized care, research into the causes of thyroid variation at multiple levels is needed.