HBM4EU-MOM: Prenatal methylmercury-exposure control in five countries through suitable dietary advice for pregnancy - Study design and characteristics of participants.

BACKGROUND: Seafood is a major source of vital nutrients for optimal fetal growth, but at the same time is the main source of exposure to methylmercury (MeHg), an established neurodevelopmental toxicant. Pregnant women must be provided with dietary advice so as to include safely fish in their diet for nutrition and mercury control. The aim of this work is to present the design of a multicentre randomized control trial (RCT), which combines human biomonitoring (HBM) with dietary interventions using seafood consumption advice to pregnant women for MeHg control, and to collect information about other possible sources of exposure to mercury. It also presents the materials developed for the implementation of the study and the characteristics of the study participants, which were self-reported in the first trimester of pregnancy. METHODS: The "HBM4EU-MOM" RCT was performed in the frame of the European Human Biomonitoring Initiative (HBM4EU) in five coastal, high fish-consuming European countries (Cyprus, Greece, Spain, Portugal and Iceland). According to the study design, pregnant women (≥120/country, ≤20 weeks gestational age) provided a hair sample for total mercury assessment (THg) and personal information relevant to the study (e.g., lifestyle, pregnancy status, diet before and during the pregnancy, information on seafood and factors related to possible non-dietary exposures to mercury) during the first trimester of pregnancy. After sampling, participants were randomly assigned to "control" (habitual practices) or "intervention" (received the harmonized HBM4EU-MOM dietary advice for fish consumption during the pregnancy and were encouraged to follow it). Around child delivery, participants provided a second hair sample and completed another tailored questionnaire. RESULTS: A total of 654 women aged 18-45 years were recruited in 2021 in the five countries, primarily through their health-care providers. The pre-pregnancy BMI of the participants ranged from underweight to obese, but was on average within the healthy range. For 73% of the women, the pregnancy was planned. 26% of the women were active smokers before the pregnancy and 8% continued to smoke during the pregnancy, while 33% were passive smokers before pregnancy and 23% remained passively exposed during the pregnancy. 53% of the women self-reported making dietary changes for their pregnancy, with 74% of these women reporting making the changes upon learning of their pregnancy. Of the 43% who did not change their diet for the pregnancy, 74% reported that their diet was already balanced, 6% found it difficult to make changes and 2% were unsure of what changes to make. Seafood consumption did not change significantly before and during the first trimester of pregnancy (overall average ∼8 times per month), with the highest frequency reported in Portugal (≥15 times per month), followed by Spain (≥7 times per month). During the first-trimester of pregnancy, 89% of the Portuguese women, 85% of the Spanish women and <50% of Greek, Cypriot and Icelandic women reported that they had consumed big oily fish. Relevant to non-dietary exposure sources, most participants (>90%) were unaware of safe procedures for handling spillage from broken thermometers and energy-saving lamps, though >22% experienced such an incident (>1 year ago). 26% of the women had dental amalgams. ∼1% had amalgams placed and ∼2% had amalgams removed during peri-pregnancy. 28% had their hair dyed in the past 3 months and 40% had body tattoos. 8% engaged with gardening involving fertilizers/pesticides and 19% with hobbies involving paints/pigments/dyes. CONCLUSIONS: The study design materials were fit for the purposes of harmonization and quality-assurance. The harmonized information collected from pregnant women suggests that it is important to raise the awareness of women of reproductive age and pregnant women about how to safely include fish in their diet and to empower them to make proper decisions for nutrition and control of MeHg, as well as other chemical exposures.

An exposome connectivity paradigm for the mechanistic assessment of the effects of prenatal and early life exposure to metals on neurodevelopment.

The exposome paradigm through an integrated approach to investigating the impact of perinatal exposure to metals on child neurodevelopment in two cohorts carried out in Slovenia (PHIME cohort) and Greece (HERACLES cohort) respectively, is presented herein. Heavy metals are well-known neurotoxicants with well-established links to impaired neurodevelopment. The links between in utero and early-life exposure to metals, metabolic pathway dysregulation, and neurodevelopmental disorders were drawn through urinary and plasma untargeted metabolomics analysis, followed by the combined application of in silico and biostatistical methods. Heavy metal prenatal and postnatal exposure was evaluated, including parameters indirectly related to exposure and health adversities, such as sociodemographic and anthropometric parameters and dietary factors. The primary outcome of the study was that the identified perturbations related to the TCA cycle are mainly associated with impaired mitochondrial respiration, which is detrimental to cellular homeostasis and functionality; this is further potentiated by the capacity of heavy metals to induce oxidative stress. Insufficient production of energy from the mitochondria during the perinatal period is associated with developmental disorders in children. The HERACLES cohort included more detailed data regarding diet and sociodemographic status of the studied population, allowing the identification of a broader spectrum of effect modifiers, such as the beneficial role of a diet rich in antioxidants such as lycopene and ω-3 fatty acids, the negative effect the consumption of food items such as pork and chicken meat has or the multiple impacts of fish consumption. Beyond diet, several other factors have been proven influential for child neurodevelopment, such as the proximity to pollution sources (e.g., waste treatment site) and the broader living environment, including socioeconomic and demographic characteristics. Overall, our results demonstrate the utility of exposome-wide association studies (EWAS) toward understanding the relationships among the multiple factors that determine human exposure and the underlying biology, reflected as omics markers of effect on neurodevelopment during childhood.