Abstract
ABSTRACT
Adolescents are uniquely vulnerable to endocrine‐disrupting chemicals (EDCs) due to the critical maturation of the hypothalamic–pituitary–gonadal (HPG) axis, yet current safety assessments overlook whole‐formulation risks during this developmental window. Using an adolescent zebrafish model, we established a biologically anchored screening threshold and elucidated the molecular mechanisms of formulation toxicity. Direct exposure to personal care products at unadjusted Scientific Committee on Consumer Safety (SCCS)–derived concentrations caused severe systemic overload (
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survival ≤ 16.87%). High‐dilution screening of a 17α‐ethinylestradiol (EE2)–spiked model lotion identified a 160× SCCS dilution as the no‐observed‐adverse‐effect level (NOAEL) for reproductive and neurodevelopmental endpoints. Ovarian metabolomics revealed a dichotomous threshold response: The 160× dilution induced focused, adaptive reprogramming of steroid hormone biosynthesis (modulating methionine, tyrosine, and histidine), whereas the 80× dilution triggered an energetic‐inflammatory crisis characterized by acylcarnitine accumulation, tricarboxylic acid cycle suppression, and oxidative stress. This metabolic disruption led to hypothalamic AMP‐activated protein kinase (AMPK)–mediated gonadotropin suppression and follicular atresia. Although the formulation matrix partially mitigated EE2‐induced ovarian failure, it failed to prevent
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neurobehavioral hypoactivity, implicating parallel thyroid and monoaminergic disruption. Commercial sunscreen validation confirmed product‐specific hazards at a 40× dilution, proving that whole‐formulation toxicity cannot be predicted from ingredient lists alone. These findings redefine risk assessment by advocating for whole‐formulation, mechanism‐informed screening. The 160× dilution threshold offers regulators a pragmatic, health‐protective benchmark to safeguard adolescent reproductive and neurodevelopmental health through molecular endocrinology–guided toxicology.