Biology subjects

Carrothers, S.

Publications and source records attributed to Carrothers, S..

3 recordsLinked to original sources

bioRxiv2025

In vitro evidence for bisphenol A as a human liver carcinogen: Environmentally relevant doses inhibit cancer protective ESR1 signaling in a human liver cell line

I.Several environmentally ubiquitous endocrine disrupting chemicals (EDCs) are suspected carcinogens, but their mechanism(s) of action are unknown. In this study, we test the potential for a model EDC, bisphenol A (BPA), to both initiate (via oxidative mutagenesis) and promote (via endocrine disruption) liver carcinogenesis. This study is motivated by our prior finding that developmental BPA exposure caused hepatocellular carcinoma (HCC) in mice. Here, we provide in vitro evidence supporting a mechanism for BPA as a non-genotoxic carcinogen. Using a highly sensitive, error-corrected sequencing method, we demonstrate that human population-relevant doses of BPA cause mutations that are consistent with oxidative DNA damage; however, overall mutation frequency does not differ substantially from controls. In contrast, we show that BPA inhibits cancer-protective, estrogen-induced transcription of estrogen receptor 1 (ESR1) target genes in the presence of pre-pubertal, but not post-pubertal, levels of estradiol. These results constitute strong initial evidence supporting BPA as a liver cancer promoting agent. This mechanism may be generalizable to a wide range of environmental EDCs that are weak agonists for ESR1. This finding is critically important to prevention of HCC, which is prevalent, lethal, and poorly responsive to therapy.

pharmacology and toxicology↗

bioRxiv2025

Epigenetic plasticity is a driver of heritable pollution tolerance in Atlantic killifish

Heritable epigenetic adaptation to environmental stressors is a compelling but highly contested possibility. Previously, we showed evidence of a generationally heritable epigenetic memory at the cytochrome P450 1a (cyp1a) gene in wild Atlantic killifish (Fundulus heteroclitus) with acquired tolerance to polycyclic aromatic hydrocarbons (PAHs). This memory leads to blunted induction of cyp1a by PAHs; this blunted response protects against PAH-induced cancer. Here, using Oxford Nanopore long-read sequencing in PAH-tolerant and -sensitive F. heteroclitus embryos, we show that PAH-tolerant embryos displayed reduced plasticity in DNA methylation response to PAH, as compared to PAH-sensitive embryos, that was not due to mutational loss of CpG sites. Notably, we observed population differences in DNA methylation of genes in pathways linked to the PAH tolerance phenotype, including aryl hydrocarbon receptor (ahr) and voltage-gated potassium channel signaling, as well as developmental processes and energy metabolism. Specifically, we observed PAH-induced loss of cyp1a gene body methylation in PAH-sensitive but not-tolerant embryos. We observed similar patterns at cyp1b1, cyp1c1, and the aryl hydrocarbon receptor repressor, ahrr, which show similarly blunted expression in response to PAH challenge. The reduced loss in genic methylation in tolerant embryos was correlated with greater induction of natural anti-sense RNA transcripts in cis (cis-NATs), which may regulate transcription of these genes. Our data support the existence of stable epigenetic responses to chronic environmental stressors in a natural experimental setting, with broad implications for natural or directed adaptation strategies for other populations.

genomics↗

bioRxiv2024

An epigenetic memory at the CYP1A gene in cancer-resistant, pollution-adapted killifish

Human exposure to polycyclic aromatic hydrocarbons (PAH) is a significant and growing public health problem. Frequent, high dose exposures are likely to increase due to a warming climate and increased frequency of large-scale wildfires. Here, we characterize an epigenetic memory at the cytochrome P450 1A (CYP1A) gene in a population of wild Fundulus heteroclitus that has adapted to chronic, extreme PAH pollution. In wild-type fish, CYP1A is highly induced by PAH. In PAH-tolerant fish, CYP1A induction is blunted. Since CYP1A metabolically activates PAH, this memory protects these fish from PAH-mediated cancer. However, PAH-tolerant fish reared in clean water recover CYP1A inducibility, indicating that blunted induction is a non-genetic memory of prior exposure. To explore this possibility, we bred depurated wild fish from PAH-sensitive and -tolerant populations, manually fertilized exposure-naive embryos, and challenged them with PAH. We observed epigenetic control of the reversible memory of generational PAH stress in F1 PAH-tolerant embryos. Specifically, we observed a bivalent domain in the CYP1A promoter enhancer comprising both activating and repressive histone post-translational modifications. Activating modifications, relative to repressive ones, showed greater increases in response to PAH in sensitive embryos, relative to tolerant, consistent with greater gene activation. Also, PAH-tolerant adult fish showed persistent induction of CYP1A long after exposure cessation, which is consistent with defective CYP1A shutoff and recovery to baseline. Since CYP1A expression is inversely correlated with cancer risk, these results indicate that PAH-tolerant fish have epigenetic protection against PAH-induced cancer in early life that degrades in response to continuous gene activation. SignificanceEpigenetic memory, or the inheritance across cell division within an organism or across generations, of environmental exposure response is a compelling phenomenon with limited understanding of mechanism. Here, we characterized an epigenetic memory at the CYP1A gene in pollution-adapted Fundulus heteroclitus. We found that the CYP1A promoter enhancer contains a bivalent domain, comprising both active and repressive histone modifications, that shows reduced function correlating with reduced gene induction by its pollutant activator. In early life, this memory protects fish against pollution-induced cancer. However, this reduced function carries a cost; adult fish show defective transcriptional recovery of CYP1A, which increases cancer risk later in life. These results provide an initial mechanism for a model epigenetic memory and highlight potential costs.

genomics↗