Fish models of obesity, test guidelines, and regulatory challenges of identifying non-EATS endocrine disruptors

Endocrine disrupting chemicals (EDCs) that interfere with estrogenic, androgenic, thyroidal and steroidogenic (EATS) pathways, as well as non-EATS pathways, should be identified and classified under EU chemical regulations. Identifying and classifying obesogenic EDCs is particularly challenging, as they are typically regulated through non-EATS mechanisms and lack standardized test methods and guidance for evaluation. This review evaluates fish models of obesity, synthesizes current evidence on chemical effects on fish adipogenesis, and discusses the regulatory challenges associated with EDC identification and classification. Diet-induced obesity (DIO) fish models have been developed in species such as zebrafish, medaka, tilapia, rainbow trout, and others. However, the composition and quantity of diets in these studies vary significantly. Notably, the high calorie diet used to induce obesity in one zebrafish experiment may be equivalent to the control diet in another. Fat accumulation in fish has been studied in pharmaceuticals, bioactive chemicals, biocides, pesticides, and industrial chemicals. Body weight, body mass index (BMI), condition factor, and various endpoints derived from adipose tissue are commonly used to investigate obesity-related effects in fish. However, body weight alone may not reliably indicate adiposity. Obesity in fish is not explicitly addressed in existing OECD test guidelines. A mode of action (MOA) analysis is needed to identify and classify obesogenic EDCs. Both EATS and non-EATS pathways should be evaluated to establish biological plausibility regarding effects on population relevant obesogenic endpoints in fish. The challenges of using fish models of obesity are discussed, along with recommendations for incorporating relevant obesity related endpoints into test guidelines.