Transgenerational Effects of Arsenic Exposure on Learning and Memory in Rats: Crosstalk between Arsenic Methylation, Hippocampal Metabolism, and Histone Modifications.

Arsenic (As) is widely present in the natural environment, and exposure to it can lead to learning and memory impairment. However, the underlying epigenetic mechanisms are still largely unclear. This study aimed to reveal the role of histone modifications in environmental levels of arsenic (sodium arsenite) exposure-induced learning and memory dysfunction in male rats, and the inter/transgenerational effects of paternal arsenic exposure were also investigated. It was found that arsenic exposure impaired the learning and memory ability of F0 rats and down-regulated the expression of cognition-related genes Bdnf, c-Fos, mGlur1, Nmdar1, and Gria2 in the hippocampus. We also observed that inorganic arsenite was methylated to DMA and histone modification-related metabolites were altered, contributing to the dysregulation of H3K4me1/2/3, H3K9me1/2/3, and H3K4ac in rat hippocampus after exposure. Therefore, it is suggested that arsenic methylation and hippocampal metabolism changes attenuated H3K4me1/2/3 and H3K4ac while enhancing H3K9me1/2/3, which repressed the key gene expressions, leading to cognitive impairment in rats exposed to arsenic. In addition, paternal arsenic exposure induced transgenerational effects of learning and memory disorder in F2 male rats through the regulation of H3K4me2 and H3K9me1/2/3, which inhibited c-Fos, mGlur1, and Nmdar1 expression. These results provide novel insights into the molecular mechanism of arsenic-induced neurotoxicity and highlight the risk of neurological deficits in offspring with paternal exposure to arsenic.

Low Levels of Perfluorooctanoic Acid Exposure Activates Steroid Hormone Biosynthesis through Repressing Histone Methylation in Rats.

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant, which has endocrine-disrupting properties and can interfere with the synthesis and secretion of testicular steroid hormones, but the underlying molecular mechanisms are still not fully understood. In this study, we investigated the effects of low doses of PFOA exposure on testicular steroidogenesis in rats and revealed the role of histone modifications. It was found that the serum levels of progesterone, testosterone, and estradiol were significantly increased after 0.015 and 0.15 mg/kg of PFOA exposure, and the expression of Star, a key rate-limiting gene, was up-regulated, while other steroidogenic genes Cyp11a1, Hsd3b, Cyp17a1, and Hsd17b were down-regulated. In addition, the levels of multiple histone modifications (H3K9me1/2/3 and H3K9/18/23ac) were all significantly reduced by PFOA in rat testis. Histone H3K9 methylation is associated with gene silencing, while histone acetylation leads to gene activation. ChIP analysis further showed that H3K9me1/3 was significantly decreased in the promoter region of Star, while H3K18ac levels were down-regulated in other gene promoters. Accordingly, we suggest that low-level PFOA enhances StAR expression through the repression of H3K9me1/3, which stimulates steroid hormone production in rat testis. These results are expected to shed new light on the molecular mechanisms by which low-dose PFOA disturbs male reproductive endocrine from an epigenetic aspect and may be useful for human health risk assessment regarding environmental PFOA exposure.

Low-dose perfluorooctanoic acid stimulates steroid hormone synthesis in Leydig cells: Integrated proteomics and metabolomics evidence.

Perfluorooctanoic acid (PFOA), one of the well-known perfluoroalkyl substances (PFASs), has been widespread in the environment and associated with male reproductive toxicity. However, the molecular mechanism involved in low-level PFOA-induced male endocrine disruption remains to be elucidated. In this study, we performed a combined proteomics and metabolomics analysis to investigate the proteomic and metabolic alterations in MLTC-1 Leydig cells responsive to low levels of PFOA exposure. The results showed that PFOA significantly regulated the expressions of 67 proteins and 17 metabolites, among which 18 proteins and 7 metabolites were specifically tied to lipid and fatty acid metabolism as well as testicular steroidogenesis. It is further suggested that low-dose PFOA stimulates steroid hormone synthesis by accelerating fatty acid metabolism and steroidogenic process, which is involved in the repression of p38 and cAMP-dependent ERK signaling pathway. The animal studies also revealed that environmentally relevant levels of PFOA increased serum steroid hormone levels accompanied by the activated cAMP and inhibited p38/ERK pathway in testis, which confirmed our in vitro findings. Overall, the present study will provide novel insights into the toxicological mechanisms of low-level PFOA-mediated steroidogenic disturbance, and may implicate the reproductive health risk of humans with environmental PFOA exposure.

Real-world particulate matters induce lung toxicity in rats fed with a high-fat diet: Evidence of histone modifications.

Exposure to ambient particulate matters (PMs) has been associated with a variety of lung diseases, and high-fat diet (HFD) was reported to exacerbate PM-induced lung dysfunction. However, the underlying mechanisms for the combined effects of HFD and PM on lung functions remain poorly unraveled. By performing a comparative proteomic analysis, the current study investigated the global changes of histone post-translational modifications (PTMs) in rat lung exposed to long-term, real-world PMs. In result, after PM exposure the abundance of four individual histone PTMs (1 down-regulated and 3 up-regulated) and six combinatorial PTMs (1 down-regulated and 5 up-regulated) were significantly altered in HFD-fed rats while only one individual PTM was changed in rats with normal diet (ND) feeding. Histones H3K18ac, H4K8ac and H4K12ac were reported to be associated with DNA damage response, and we found that these PTMs were enhanced by PM in HFD-fed rats. Together with the elevated DNA damage levels in rat lungs following PM and HFD co-exposure, we demonstrate that PM exposure combined with HFD could induce lung injury through altering more histone modifications accompanied by DNA damage. Overall, these findings will augment our knowledge of the epigenetic mechanisms for pulmonary toxicity caused by ambient PM and HFD exposure.

Chronic low-level perfluorooctane sulfonate (PFOS) exposure promotes testicular steroidogenesis through enhanced histone acetylation.

Perfluorooctane sulfonate (PFOS), an artificial perfluorinated compound, has been associated with male reproductive disorders. Histone modifications are important epigenetic mediators; however, the impact of PFOS exposure on testicular steroidogenesis through histone modification regulations remains to be elucidated. In this study, we examined the roles of histone modifications in regulating steroid hormone production in male rats chronically exposed to low-level PFOS. The results indicate that PFOS exposure significantly up-regulated the expressions of StAR, CYP11A1 and 3ß-HSD, while CYP17A1 and 17ß-HSD were down-regulated, thus contributing to the elevated progesterone and testosterone levels. Furthermore, PFOS significantly increased the histones H3K9me2, H3K9ac and H3K18ac while reduced H3K9me3 in rat testis. It is known that histone modifications are closely involved in gene transcription. Therefore, to investigate the association between histone modifications and steroidogenic gene regulation, the levels of these histone marks were further measured in steroidogenic gene promoter regions by ChIP. It was found that H3K18ac was augmented in Cyp11a1 promoter, and H3K9ac was increased in Hsd3b after PFOS exposure, which is proposed to result in the activation of CYP11A1 and 3ß-HSD, respectively. To sum up, chronic low-level PFOS exposure activated key steroidogenic gene expression through enhancing histone acetylation (H3K9ac and H3K18ac), ultimately stimulating steroid hormone biosynthesis in rat testis.

Environmental pollutants exposure and male reproductive toxicity: The role of epigenetic modifications.

Male fertility rates have shown a progressive decrease in recent decades. There is a growing concern about the male reproductive dysfunction caused by environmental pollutants exposure, however the underlying molecular mechanisms are still not well understood. Epigenetic modifications play a key role in the biological responses to external stressors. Therefore, this review discusses the roles of epigenetic modifications in male reproductive toxicity induced by environmental pollutants, with a particular emphasis on DNA methylation, histone modifications and miRNAs. The available literature proposed that environmental pollutants can directly or cause oxidative stress and DNA damage to induce a variety of epigenetic changes, which lead to gene dysregulation, mitochondrial dysfunction and consequent male reproductive toxicity. However, future studies focusing on more kinds of epigenetic modifications and their crosstalk as well as epidemiological data are still required to fill in the current research gaps. In addition, the intrinsic links between pollutants-mediated epigenetic regulations and male reproduction-related physiological responses deserve to be further explored.