The inter- and multi- generational epigenetic alterations induced by maternal cadmium exposure

Lawless, Lauren; Xie, Linglin; Zhang, Ke

doi:10.3389/fcell.2023.1148906

Cited by 8 publications

(4 citation statements)

References 88 publications

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“…Teratogenic and epigenetic effects of environmental Cd in humans and acute or chronic exposure (mainly subcutaneous or intraperitoneal injection of CdCl 2 ) in experimental animals have been recently reviewed (Jacobo-Estrada et al 2017 ; Geng and Wang 2019 ; Lawless et al 2023 ). Exposure to Cd exposure during human pregnancy induces damage to the mothers (e.g.…”

Section: Cadmium (Cd)mentioning

confidence: 99%

“…Furthermore, epigenetic alterations within germ cells pose multigenerational adverse effects on the reproductive system. Interestingly, sex-specific effects on epigenetic mechanisms also occur, such as gene hypermethylation in male offspring and hypomethylation in females, as demonstrated in humans exposed to environmental Cd (reviewed in (Lawless et al 2023 )).…”

Section: Cadmium (Cd)mentioning

confidence: 99%

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Cadmium transport by mammalian ATP-binding cassette transporters

Thévenod,

Lee

2024

Biometals

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Cellular responses to toxic metals depend on metal accessibility to intracellular targets, reaching interaction sites, and the intracellular metal concentration, which is mainly determined by uptake pathways, binding/sequestration and efflux pathways. ATP-binding cassette (ABC) transporters are ubiquitous in the human body—usually in epithelia—and are responsible for the transfer of indispensable physiological substrates (e.g. lipids and heme), protection against potentially toxic substances, maintenance of fluid composition, and excretion of metabolic waste products. Derailed regulation and gene variants of ABC transporters culminate in a wide array of pathophysiological disease states, such as oncogenic multidrug resistance or cystic fibrosis. Cadmium (Cd) has no known physiological role in mammalians and poses a health risk due to its release into the environment as a result of industrial activities, and eventually passes into the food chain. Epithelial cells, especially within the liver, lungs, gastrointestinal tract and kidneys, are particularly susceptible to the multifaceted effects of Cd because of the plethora of uptake pathways available. Pertinent to their broad substrate spectra, ABC transporters represent a major cellular efflux pathway for Cd and Cd complexes. In this review, we summarize current knowledge concerning transport of Cd and its complexes (mainly Cd bound to glutathione) by the ABC transporters ABCB1 (P-glycoprotein, MDR1), ABCB6, ABCC1 (multidrug resistance related protein 1, MRP1), ABCC7 (cystic fibrosis transmembrane regulator, CFTR), and ABCG2 (breast cancer related protein, BCRP). Potential detoxification strategies underlying ABC transporter-mediated efflux of Cd and Cd complexes are discussed.

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Section: Cadmium (Cd)mentioning

confidence: 99%

Section: Cadmium (Cd)mentioning

confidence: 99%

Cadmium transport by mammalian ATP-binding cassette transporters

Thévenod,

Lee

2024

Biometals

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“…Environmental effects on the mother are widely known to contribute to intergenerational inheritance and the underlying mechanisms have been extensively studied. For example, maternal obesity and hormonal imbalance can predispose the offspring to type 2 diabetes and obesity; or maternal zinc deficiency can impact offspring development reducing birth weight, altering the offspring's lipid metabolism or increasing their resistance to insulin; maternal gestational exposure to cadmium can lead to hormonal changes in the F2; and maternal stress can increase the levels of stress hormones in their grandchildren (Lawless et al., 2023; Lecoutre et al., 2021; Mbiydzenyuy et al., 2022; Şanlı & Kabaran, 2019; Santilli & Boskovic, 2023; Sanusi et al., 2021; Stäubli & Peters, 2021).…”

Section: Introductionmentioning

confidence: 99%

Paternal starvation affects metabolic gene expression during zebrafish offspring development and lifelong fitness

Jimenez‐Gonzalez,

Ansaloni,

Nebendahl

et al. 2024

Molecular Ecology

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Dietary restriction in the form of fasting is a putative key to a healthier and longer life, but these benefits may come at a trade‐off with reproductive fitness and may affect the following generation(s). The potential inter‐ and transgenerational effects of long‐term fasting and starvation are particularly poorly understood in vertebrates when they originate from the paternal line. We utilised the externally fertilising zebrafish amenable to a split‐egg clutch design to explore the male‐specific effects of fasting/starvation on fertility and fitness of offspring independently of maternal contribution. Eighteen days of fasting resulted in reduced fertility in exposed males. While average offspring survival was not affected, we detected increased larval growth rate in F1 offspring from starved males and more malformed embryos at 24 h post‐fertilisation in F2 offspring produced by F1 offspring from starved males. Comparing the transcriptomes of F1 embryos sired by starved and fed fathers revealed robust and reproducible increased expression of muscle composition genes but lower expression of lipid metabolism and lysosome genes in embryos from starved fathers. A large proportion of these genes showed enrichment in the yolk syncytial layer suggesting gene regulatory responses associated with metabolism of nutrients through paternal effects on extra‐embryonic tissues which are loaded with maternal factors. We compared the embryo transcriptomes to published adult transcriptome datasets and found comparable repressive effects of starvation on metabolism‐associated genes. These similarities suggest a physiologically relevant, directed and potentially adaptive response transmitted by the father, independently from the offspring's nutritional state, which was defined by the mother.

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“…Epigenetic modi cation can change the synthesis and functional formation of placental associated proteins without changing the DNA nucleotide sequence. This function can be in uenced by external environmental factors, leading to the occurrence of placental related diseases by regulate placental development and adaptive changes(He et al, 2022;Lawless et al, 2023). DNA methylation may be more susceptible to environmental impact and is a potential prenatal planning mechanism in embryonic stage, which plays a very important role in gene expression, embryonic development and other life processes.…”

mentioning

confidence: 99%

Prenatal stress increases corticosterone levels in offspring by impairing placental glucocorticoid barrier function

Liu,

Wang,

Zhu

et al. 2023

Preprint

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Background: Exposure to high cortisol levels in fetus of prenatal stress (PS) has adverse effects on growth, which is related to placental glucocorticoid (GC) barrier. DNA methylation is a potential prenatal planning mechanism in embryonic stage, however, the epigenetic regulation of placental GC barrier related genes on the PS resulting higher GC is unclear. This study was to test the hypothesis that PS would elevate cortisol which was associated with GC-related placenta genes (11β-HSD2, P-gp, NR3C1, and FKBP5) based on the DNA methylation. Method: PS model was established by chronic unpredictable mild stress (CUMS). DNA methylation in GC-related genes was analyzed using reduced representation bisulfite sequencing (RRBS) and confirmed results using MethylTarget™ sequencing. The genes expression were subjected to qRT-PCR and Western blot. Results: Offspring of PS had increased plasma corticosterone levels. GC-related gene (P-gp(abcb1a) and FKBP5) were identified by RRBS. We further verified DNA methylation and gene expression, including 43 differentially methylated sites and 2 differentially methylated regions. We found P-gp was hypermethylation and low expression, FKBP5 was hypermethylation low translational and high transcriptional levels. The expressions of 11β-HSD2 decreased, the NR3C1 mRNA expression was inhibited, and the protein expression increased. Discussion:This study provides an exploratory result: PS disrupts the placental GC barrier through hypermethylation and aberrant expression of GC-related genes, resulting in high corticosterone level in offspring, affecting growth and development. However, the molecular mechanism by which PS regulates the placental GC barrier remains to be further determined.

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The inter- and multi- generational epigenetic alterations induced by maternal cadmium exposure

Cited by 8 publications

References 88 publications

Cadmium transport by mammalian ATP-binding cassette transporters

Cadmium transport by mammalian ATP-binding cassette transporters

Paternal starvation affects metabolic gene expression during zebrafish offspring development and lifelong fitness

Prenatal stress increases corticosterone levels in offspring by impairing placental glucocorticoid barrier function

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