Exposure to phthalates: germline dysfunction and aneuploidy.

Epidemiological studies continue to reveal the enduring impact of exposures to environmental chemicals on human physiology, including our reproductive health. Phthalates, a well characterized class of endocrine disrupting chemicals and commonly utilized plasticizers, are among one of the many toxicants ubiquitously present in our environment. Phthalate exposure has been linked to increases in the rate of human aneuploidy, a phenomenon that is detected in 0.3% of livebirths resulting in genetic disorders including trisomy 21, approximately 4% of stillbirths, and over 35% of miscarriages. Here we review recent epidemiological and experimental studies that have examined the role that phthalates play in germline dysfunction, including increases in apoptosis, oxidative stress, DNA damage, and impaired genomic integrity, resulting in aneuploidy. We will further discuss subject variability, as it relates to diet and polymorphisms, and the sexual dimorphic effects of phthalate exposure, as it relates to sex-specific targets. Lastly, we discuss some of the conserved effects of phthalate exposure across humans, mammalian models and nonmammalian model organisms, highlighting the importance of using model organisms to our advantage for chemical risk assessment and unveiling potential mechanisms that underlie phthalate-induced reproductive health issues across species.

Altered gene expression linked to germline dysfunction following exposure of Caenorhabditis elegans to DEET.

N,N-diethyl-meta-toluamide (DEET) is a commonly used synthetic insect repellent. Although the neurological effects of DEET have been widely investigated, its effects on the germline are less understood. Here, we show that exposure of the nematode Caenorhabditis elegans, which is highly predictive of mammalian reprotoxicity, resulting in internal DEET levels within the range detected in human biological samples, causes activation of p53/CEP-1-dependent germ cell apoptosis, altered meiotic recombination, chromosome abnormalities, and missegregation. RNA-sequencing analysis links DEET-induced alterations in the expression of genes related to redox processes and chromatin structure to reduced mitochondrial function, impaired DNA double-strand break repair progression, and defects during early embryogenesis. We propose that Caenorhabditis elegans exposure to DEET interferes with gene expression, leading to increased oxidative stress and altered chromatin structure, resulting in germline effects that pose a risk to reproductive health.

Erratum: Altered gene expression linked to germline dysfunction following exposure to DEET.

[This corrects the article DOI: 10.1016/j.isci.2023.108699.].

Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction.

The gut-microbe-derived metabolite trimethylamine N-oxide (TMAO) is increased by insulin resistance and associated with several sequelae of metabolic syndrome in humans, including cardiovascular, renal, and neurodegenerative disease. The mechanism by which TMAO promotes disease is unclear. We now reveal the endoplasmic reticulum stress kinase PERK (EIF2AK3) as a receptor for TMAO: TMAO binds to PERK at physiologically relevant concentrations; selectively activates the PERK branch of the unfolded protein response; and induces the transcription factor FoxO1, a key driver of metabolic disease, in a PERK-dependent manner. Furthermore, interventions to reduce TMAO, either by manipulation of the gut microbiota or by inhibition of the TMAO synthesizing enzyme, flavin-containing monooxygenase 3, can reduce PERK activation and FoxO1 levels in the liver. Taken together, these data suggest TMAO and PERK may be central to the pathogenesis of the metabolic syndrome.

IL-1ß inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization.

Lack of insight into mechanisms governing breast cancer metastasis has precluded the development of curative therapies. Metastasis-initiating cancer cells (MICs) are uniquely equipped to establish metastases, causing recurrence and therapeutic resistance. Using various metastasis models, we discovered that certain primary tumours elicit a systemic inflammatory response involving interleukin-1ß (IL-1ß)-expressing innate immune cells that infiltrate distant MIC microenvironments. At the metastatic site, IL-1ß maintains MICs in a ZEB1-positive differentiation state, preventing MICs from generating highly proliferative E-cadherin-positive progeny. Thus, when the inherent plasticity of MICs is impeded, overt metastases cannot be established. Ablation of the pro-inflammatory response or inhibition of the IL-1 receptor relieves the differentiation block and results in metastatic colonization. Among patients with lymph node-positive breast cancer, high primary tumour IL-1ß expression is associated with better overall survival and distant metastasis-free survival. Our data reveal complex interactions that occur between primary tumours and disseminated MICs that could be exploited to improve patient survival.