Dataset Information

In Utero Exposure to Mercury Is Associated With Increased Susceptibility to Liver Injury and Inflammation in Childhood.

ABSTRACT:

Background and aims

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant-associated fatty liver disease.

Approach and results

We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother-child cohort with complementary in vitro experiments on monocyte cells that are known to play a key role in liver immune homeostasis and NAFLD. We used data from 872 mothers and their children (median age, 8.1 years; interquartile range [IQR], 6.5-8.7) from the European Human Early-Life Exposome cohort. We measured Hg concentration in maternal blood during pregnancy (median, 2.0 μg/L; IQR, 1.1-3.6). We also assessed serum levels of alanine aminotransferase (ALT), a common screening tool for pediatric NAFLD, and plasma concentrations of inflammation-related cytokines in children. We found that prenatal Hg exposure was associated with a phenotype in children that was characterized by elevated ALT (≥22.1 U/L for females and ≥25.8 U/L for males) and increased concentrations of circulating IL-1β, IL-6, IL-8, and TNF-α. Consistently, inflammatory monocytes exposed in vitro to a physiologically relevant dose of Hg demonstrated significant up-regulation of genes encoding these four cytokines and increased concentrations of IL-8 and TNF-α in the supernatants.

Conclusions

These findings suggest that developmental exposure to Hg can contribute to inflammation and increased NAFLD risk in early life.

SUBMITTER: Stratakis N

PROVIDER: S-EPMC8446089 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

In Utero Exposure to Mercury Is Associated With Increased Susceptibility to Liver Injury and Inflammation in Childhood.

Stratakis Nikos N Golden-Mason Lucy L Margetaki Katerina K Zhao Yinqi Y Valvi Damaskini D Garcia Erika E Maitre Léa L Andrusaityte Sandra S Basagana Xavier X Borràs Eva E Bustamante Mariona M Casas Maribel M Fossati Serena S Grazuleviciene Regina R Haug Line Småstuen LS Heude Barbara B McEachan Rosemary R C RRC Meltzer Helle Margrete HM Papadopoulou Eleni E Roumeliotaki Theano T Robinson Oliver O Sabidó Eduard E Urquiza Jose J Vafeiadi Marina M Varo Nerea N Wright John J Vos Miriam B MB Hu Howard H Vrijheid Martine M Berhane Kiros T KT Conti David V DV McConnell Rob R Rosen Hugo R HR Chatzi Lida L

Hepatology (Baltimore, Md.) 20210830 3

<h4>Background and aims</h4>Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant-associated fatty liver disease.<h4>Approach and results</h4>We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother-child cohort with complementary in vitro experiments on mono ...[more]

PMID: 33730435

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Project description:BackgroundLow-dose mercury (Hg) exposure has been associated with cardiovascular diseases, diabetes, and obesity in adults, but it is unknown the metabolic consequence of in utero Hg exposure. This study aimed to investigate the association between in utero Hg exposure and child overweight or obesity (OWO) and to explore if adequate maternal folate can mitigate Hg toxicity.MethodsThis prospective study included 1442 mother-child pairs recruited at birth and followed up to age 15 years. Maternal Hg in red blood cells and plasma folate levels were measured in samples collected 1-3 days after delivery (a proxy for third trimester exposure). Adequate folate was defined as plasma folate ≥ 20.4 nmol/L. Childhood OWO was defined as body mass index ≥ 85% percentile for age and sex.ResultsThe median (interquartile range) of maternal Hg levels were 2.11 (1.04-3.70) μg/L. Geometric mean (95% CI) of maternal folate levels were 31.1 (30.1-32.1) nmol/L. Maternal Hg levels were positively associated with child OWO from age 2-15 years, independent of maternal pre-pregnancy OWO, diabetes, and other covariates. The relative risk (RR = 1.24, 95% CI 1.05-1.47) of child OWO associated with the highest quartile of Hg exposure was 24% higher than those with the lowest quartile. Maternal pre-pregnancy OWO and/or diabetes additively enhanced Hg toxicity. The highest risk of child OWO was found among children of OWO and diabetic mothers in the top Hg quartile (RR = 2.06; 95% CI 1.56-2.71) compared to their counterparts. Furthermore, adequate maternal folate status mitigated Hg toxicity. Given top quartile Hg exposure, adequate maternal folate was associated with a 34% reduction in child OWO risk (RR = 0.66, 95% CI 0.51-0.85) as compared with insufficient maternal folate. There was a suggestive interaction between maternal Hg and folate levels on child OWO risk (p for interaction = 0.086).ConclusionsIn this US urban, multi-ethnic population, elevated in utero Hg exposure was associated with a higher risk of OWO in childhood, and such risk was enhanced by maternal OWO and/or diabetes and reduced by adequate maternal folate. These findings underscore the need to screen for Hg and to optimize maternal folate status, especially among mothers with OWO and/or diabetes.

Project description:ImportanceAlthough maternal unintentional injury during pregnancy has shown negative impacts on the mother and fetus, the evidence on its long-term associations with children's neurodevelopment is limited.ObjectiveTo examine the association between maternal unintentional injury and cerebral palsy (CP) in offspring.Design, setting, and participantsThis was a population-based, longitudinal, cohort study of all in-hospital live births born between April 1, 2002, and March 31, 2017, in a publicly funded health care system setting of Ontario, Canada. Infants born more than 20 weeks' gestation were included and followed up until March 31, 2018. Excluded from the analysis were stillbirths, infants with missing or invalid records, and births with missing or invalid birth characteristics. Data were analyzed from March 1 to June 30, 2021.ExposuresMaternal unintentional injury during pregnancy ascertained based on inpatient or emergency department diagnoses.Main outcomes and measuresCP diagnosis between birth and the end of follow-up in 2018 with the CP case definition of a single inpatient or 2 or more outpatient diagnoses at least 2 weeks apart between birth and age 16 years.ResultsOf 2 110 177 children included in this study (mean [SD] gestational age, 38.8 [1.9] weeks; 1 082 520 male [51.3%]), 81 281 (3.9%) were exposed in utero to maternal unintentional injury. During a median (IQR) follow-up time of 8 (4-12) years, 5317 children (0.3%) were diagnosed with CP (292 CP cases [5.5%] were exposed to maternal unintentional injury). The mean incidence rates of CP were 4.36 and 2.93 per 10 000 child-years in the exposed and the unexposed group, respectively. Children exposed to maternal unintentional injury had a modest increase in the risk of CP, compared with those unexposed (hazard ratio [HR], 1.33; 95% CI, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics. Severe injuries that resulted in hospitalization and delivery within 1 week from the injury conferred higher risks of CP (adjusted HR, 2.18; 95% CI, 1.29-3.68 and adjusted HR, 3.40; 95% CI, 1.93-6.00, respectively). Results were robust in multiple bias analyses.Conclusions and relevanceIn this Canadian population-based birth cohort study, in utero exposure to maternal unintentional injury was associated with an increased risk of CP, with a higher risk with more severe injuries. These findings fill an important gap in knowledge on the potential role of maternal injury on children's neurodevelopment outcomes. Public health professionals and stakeholders should be aware of these potential long-term consequences on offspring when designing programs and providing recommendations about safety during pregnancy. Early monitoring and developmental assessment of children exposed to maternal injury might be warranted.

Project description:BackgroundThere is considerable discussion over the possible harm caused by fetal exposure to mercury, but evidence of such harm is contradictory at levels commonly found in populations with moderate intakes of fish. Further information is needed to inform debate and clarify policy recommendations.MaterialData were collected prospectively for the Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood taken in the first half of pregnancy was assayed for mercury. The outcomes were offspring behavioural assessments collected using the Strengths and Difficulties Questionnaire at seven time points between ages 4 and 16-17 years; five were completed by the mother and two by the teacher. Socioeconomic and biological confounders were first taken into account; further analyses added maternal blood selenium. Separate analyses compared the relationships between prenatal mercury levels and behaviour traits treated as continuous measures in women who ate fish with those who ate no fish in order to determine whether the relationships differed; the hypothesis was that fish consumption had benefits on the brain and masked any mercury effects. In order to prevent Type II errors, the P value for significance was set at 0.10.ResultsPrenatal mercury measurements and offspring behaviour results were available for between 2776 (at 47 months) to 1599 mother-child pairs (at 16-17 years). Even given a P value of 0.10, the number of significant results was no greater than expected apart from the relationships with peer problems at 4, 6 and 10-11 years where the relationships with prenatal mercury were negative (i.e. the greater the level of mercury the fewer the problems the child had with his/her peers). There were no significant differences between the associations with mercury found among the offspring of women who ate fish in pregnancy and those who did not, nor did adjustment for selenium make a difference.ConclusionsThere were no adverse effects of maternal prenatal mercury levels on the behaviour of the offspring. A similar lack of relationship was found when the analyses were confined to those offspring whose mothers had eaten fish in pregnancy, and no consistent differences were found between the fish and non-fish eaters.

Project description:Elevated blood pressure in childhood is an important risk factor for hypertension in adulthood. Environmental exposures have been associated with elevated blood pressure over the life course and exposure to mercury (Hg) has been linked to cardiovascular effects in adults. As subclinical vascular changes begin early in life, Hg may play a role in altered blood pressure in children. However, the evidence linking early life Hg exposure to altered blood pressure in childhood has been largely inconsistent. In the ongoing New Hampshire Birth Cohort Study, we investigated prenatal and childhood Hg exposure at multiple time points and associations with blood pressure measurements in 395 young children (mean age 5.5 years, SD 0.4). Hg exposure was measured in children's toenail clippings at age 3 and in urine at age 5-6 years, as well as in maternal toenail samples collected at ∼28 weeks gestation and 6 weeks postpartum, the latter two samples reflecting early prenatal and mid-gestation exposures, respectively. Five measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were averaged for each child using a standardized technique. In covariate-adjusted linear regression analyses, we observed that a 0.1 μg/g increase in child toenail Hg at age 3 or a 0.1 μg/L urine Hg at age 5-6 were individually associated with greater DBP (toenail β: 0.53 mmHg; 95% CI: -0.02, 1.07; urine β: 0.48 mmHg; 95% CI: 0.10, 0.86) and MAP (toenail β: 0.67 mmHg; 95% CI: 0.002, 1.33; urine β: 0.55 mmHg; 95% CI: 0.10, 1.01). Neither early prenatal nor mid-gestation Hg exposure, as measured by maternal toenails, were related to any changes to child BP. Simultaneous inclusion of both child urine Hg and child toenail Hg in models suggested a potentially stronger relationship of urine Hg at age 5-6 with DBP and MAP, as compared to toenail Hg at age 3. Our findings suggest that Hg exposure during childhood is associated with alterations in BP. Childhood may be an important window of opportunity to reduce the impacts of Hg exposure on children's blood pressure, and in turn, long-term health.

Dataset Information

In Utero Exposure to Mercury Is Associated With Increased Susceptibility to Liver Injury and Inflammation in Childhood.

Background and aims

Approach and results

Conclusions

Publications

In Utero Exposure to Mercury Is Associated With Increased Susceptibility to Liver Injury and Inflammation in Childhood.

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