Rapid resolution of variants of uncertain significance (VUS). A complementary role for zebrafish in the era of multi-million-dollar therapies.

Migraine is a common and disabling neurological disorder characterized by recurrent attacks of moderate to severe headache accompanied by neurological and systemic symptoms []. It ranks among the leading causes of years lived with disability worldwide [], affecting more than one billion individuals, with an estimated annual prevalence of approximately 15% []. A marked female predominance is observed [], with a female-to-male ratio of approximately 3:1, and heritability estimates of up to 57% highlight a substantial contribution of genetic susceptibility []. However, genetic factors alone do not fully explain disease risk, underscoring the important role of environmental influences and gene-environment interactions in migraine pathophysiology. Endocrine-disrupting chemicals (EDCs) have emerged as a growing environmental concern due to their ability to interfere with hormonal signaling pathways by mimicking or antagonizing endogenous hormones []. These compounds are widely present in industrial products, food packaging, personal care items, and pesticides, making exposure nearly ubiquitous. EDCs have been implicated in a range of adverse health outcomes, including reproductive dysfunction, metabolic disorders, and hormone-related cancers [–]. Increasing evidence also suggests that EDCs may affect the nervous system, with studies linking exposure to neurodevelopmental alterations, cognitive impairment, and behavioral changes []. Experimental studies further demonstrate that certain EDCs, such as bisphenol A (BPA) and octylphenol (OP), can disrupt calcium signaling and cellular differentiation, providing biological plausibility for their role in neurological disorders []. Migraine exhibits a strong hormonal component, as reflected by its sex-specific prevalence and sensitivity to fluctuations in sex hormones. Estrogen withdrawal is a key factor in triggering menstrual migraine, whereas a relatively stable hormonal environment, such as during pregnancy, exerts a protective effect [, ]. Other neuroendocrine factors, including progesterone, androgens, oxytocin and pituitary adenylate cyclase-activating polypeptide (PACAP), modulate migraine susceptibility by influencing nociceptive signaling, trigeminovascular activation, and neuroinflammatory responses [–]. Given that many EDCs possess estrogenic or anti-estrogenic activity, it is biologically plausible that environmental exposure to these chemicals may influence migraine susceptibility, potentially through interactions with genetically regulated molecular pathways.