India-Aldana Sandra, Midya Vishal, Betanzos-Robledo Larissa, Yao Meizhen, Alcalá Cecilia, Andra Syam S, Arora Manish, Calafat Antonia M, Chu Jaime, Deierlein Andrea, Estrada-Gutierrez Guadalupe, Jagani Ravikumar, Just Allan C, Kloog Itai, Landero Julio, Oulhote Youssef, Walker Ryan W, Yelamanchili Shirisha, Baccarelli Andrea A, Wright Robert O, Téllez Rojo Martha María, Colicino Elena, Cantoral Alejandra, Valvi Damaskini
Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico.
J Hepatol. 2025 Jun;82(6):956-966. doi: 10.1016/j.jhep.2024.11.050. Epub 2024 Dec 12.
BACKGROUND & AIMS: Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on steatotic liver disease limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver outcomes, and effect modification by folic acid (FA) supplementation in mother-child pairs.
We studied ∼200 mother-child pairs from the Mexican PROGRESS cohort, with 43 MDCs measured during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide metabolites), and serum liver enzymes (ALT, AST) at ∼9 years post-parturition. Outcomes included elevated liver enzymes in children and established clinical scores for steatosis and fibrosis in mothers (i.e.
, AST: ALT, FLI, HSI, FIB-4). Bayesian-weighted quantile sum regression assessed MDC-mixture associations with liver outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation.
In children, many MDC-mixtures were associated with liver injury. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95% CI 1.67%, 19.4%) and AST by 5.27% (95% CI 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations (p-interactions <0.05). In mothers, only the LMWP-mixture was associated with odds for steatosis (odds ratio = 1.53, 95% CI 1.01-2.28 for HSI >36, and odds ratio 1.62, 95% CI 1.05-2.49 for AST:ALT <1). In mothers and children, most associations were attenuated (null) at FA supplementation ≥600 μg/day (p-interactions <0.05).
Pregnancy MDC exposures may increase risk of liver injury and steatosis, particularly in children. Adequate FA supplementation and maternal cobalt levels may attenuate these associations.
The effects of environmental chemical exposures on steatotic liver diseases are not well understood. In a parallel investigation of mothers and children, we found that pregnancy exposures to metabolism-disrupting chemicals may increase the risk of liver injury and steatosis, especially in the child, and that these associations could be attenuated by higher folic acid and/or cobalt levels. These findings can inform policies to decrease environmental chemical pollution and contribute to the design of clinical interventions addressing the metabolic dysfunction-associated steatotic liver disease epidemic.
关于代谢干扰化学物质（MDCs）对脂肪性肝病影响的知识匮乏，限制了干预机会。我们评估了母婴对中孕期MDC混合物与肝脏结局的关联，以及叶酸（FA）补充剂的效应修正作用。
我们研究了来自墨西哥PROGRESS队列的约200对母婴，测量了孕期的43种MDCs（估计的空气污染物、血液/尿液中的金属或类金属、尿液中的高和低分子量邻苯二甲酸盐[HMWPs、LMWPs]以及有机磷农药代谢物），并在产后约9年测量了血清肝酶（ALT、AST）。结局包括儿童肝酶升高以及母亲脂肪变性和纤维化的既定临床评分（即AST:ALT、FLI、HSI、FIB-4）。贝叶斯加权分位数和回归评估了MDC混合物与肝脏结局的关联。我们进一步研究了化学物质之间的相互作用以及自我报告的FA补充剂的效应修正作用。
在儿童中，许多MDC混合物与肝损伤有关。HMWP混合物每增加一个四分位数，ALT升高10.1%（95%CI 1.67%，19.4%），AST升高5.27%（95%CI 0.80%，10.1%）。LMWP混合物和空气污染物混合物分别与较高的AST和ALT有关。空气污染物以及非必需金属/元素与肝酶的关联因母亲血液中的钴浓度而减弱（p相互作用<0.05）。在母亲中，只有LMWP混合物与脂肪变性的几率有关（对于HSI>36，比值比=1.53，95%CI 1.01-2.28；对于AST:ALT<1，比值比1.62，95%CI 1.05-2.49）。在母亲和儿童中，当FA补充剂≥600μg/天时，大多数关联减弱（无关联）（p相互作用<0.05）。
孕期接触MDCs可能增加肝损伤和脂肪变性的风险，尤其是在儿童中。充足的FA补充剂和母亲的钴水平可能减弱这些关联。
环境化学物质暴露对脂肪性肝病的影响尚不清楚。在一项对母亲和儿童的平行调查中，我们发现孕期接触代谢干扰化学物质可能增加肝损伤和脂肪变性的风险，尤其是在儿童中，并且这些关联可能因较高的叶酸和/或钴水平而减弱。这些发现可为减少环境化学污染的政策提供依据，并有助于设计针对与代谢功能障碍相关的脂肪性肝病流行的临床干预措施。
