The sex matters: sex-biased stimulatory responses to contaminants

Hormetic regulation is a health hallmark determining susceptibility and lifespan, through which whole-animal performance is also stimulated by low doses of chemical contaminants. However, the sex-dependence of these stimulatory responses remains poorly understood. In this perspective, we highlight compelling evidence of sex-dependent stimulation by contaminants across diverse animal taxa. These responses occur at concentrations below (subNOAEL) or above (superNOAEL, sublethal) established toxicological thresholds, influencing traits such as growth, body mass, survival, and lifespan in a sex-dependent manner. The underlying mechanisms, including gene expression regulation and antioxidant capacity, often vary between sexes. While biphasic hormetic dose-response relationships are commonly observed, emerging evidence suggests that triphasic dose-response patterns may also occur and differ between sexes. The triphasic responses include the hormetic zone with stimulations, a sub-hormetic zone with potential negative effects, and a super-hormetic zone with adverse effects. Interestingly, the observed sex-biased responses often favor females, underscoring the need for further research. However, stimulations do not necessarily indicate beneficial effects and may introduce ‘hidden’ risks that warrant further long-term investigations integrating multiple dimensions such as resistance to disease or toxicity, metabolic efficiency and weight gain, and reproductive output. Understanding these phenomena is essential for improving ecological risk assessments, refining prevention and treatment strategies, and fostering resilience in affected organisms.