The number of people diagnosed with cancer is rising across the globe. However, the cancer mortality rate has steadily declined due to technological advancements in diagnosis and therapeutics. For instance, the total number of cancer cases in the United States decreased by 26% from 1991 to 2015 [1], resulting in an increasing number of long-term cancer survivors. These survivors may be affected by therapy-related late effects such as endocrine disruption [2], making it more difficult for some cancer patients to conceive. One such advancement is the development of anticancer agents such as Epirubicin (EPI). EPI is an effective antineoplastic agent used to treat breast cancer [3]. EPI mechanisms of action involve DNA intercalation, while EPI-mediated toxicities are through the induction of enhanced oxidative and nitrosative stress and the orchestration of pro-inflammatory responses. EPI also poisons topoisomerase II, an enzyme that removes knots and tangles from DNA by generating temporary double-stranded DNA breaks [4,5]. These will culminate in cardiotoxicity, nephrotoxicity, hepatotoxicity, and reproductive system malfunction, limiting the drug's use in clinical practice [6,7]. More worrisome is the observation that prolonged exposure to EPI can alter the ovulation rate, induce ovarian atrophy, and impair the vascular morphogenesis of ovaries [1]. Due to these severe toxicities, some clinical modalities have been made, including dose moderation, combinatorial therapy, and nanoparticle-mediated liposomal drug encapsulation [8], to reduce the burden of EPI. In recent times, experimentalists have established novel and affordable options for ameliorating the toxic responses associated with EPI in cancer-treated patients [9,10]. One such method is chemopreventive agents capable of abating oxidative stress, resolving inflammation, and suppressing necrotic and apoptotic cell death in healthy tissues [11].

Tryptophan-derived 3-indolepropionic acid (3-IPA) is one of the products that ensues after tryptophan in the diet has been metabolised into indole by the gut microflora, Clostridium sporogenes [12]. 3-IPA possesses a structure similar to melatonin and is an effective radical scavenger for preventing oxidative damage-induced cell death [13]. 3-IPA also has anti-inflammatory, antioxidant, antimycobacterial and neuroprotective abilities and has been linked to a lower risk of type 2 diabetes [14]. In addition, 3-IPA has a significant amount of potential application because it reduces the adverse effects that are synergistically caused by antineoplastic medications. It removes peroxyl radicals, superoxide anion radicals, and hydrogen peroxide [14]. The ability of 3-IPA to protect male rats' reproductive system from toxic agents has been reported [15,16].

The hypothalamus is a crucial link in regulating endocrine and reproductive systems, determining the concentration of circulating hormones [17]. Precisely, the hypothalamus activates the gonadotropin-releasing hormones (GnRH) to produce GnRH, which binds to the pituitary gland and stimulates the biosynthesis and secretion of follicle-stimulating hormone (FSH) and luteinising hormone (LH). These hormones then act on the ovaries and regulate the activities of estrogen and other gonadotropin-releasing hormones [18]. In pathological conditions or exposure to certain drugs or toxicants (Fig. 1), the functionality and integrity of the hypothalamic-pituitary-gonadal system are impaired, leading to endocrine and reproductive disorders [19]. Based on this experimental discourse, we hypothesised that EPI could impair the functions of the hypothalamus via oxidative stress, inflammation, and apoptosis, leading to the impairment of the endocrine and reproductive system in female Wistar rats. Co-treatment with 3-IPA could mitigate these toxic responses by improving the ability of the hypothalamus to activate the GnRH, mediating the interaction of GnRH with the pituitary gland, and releasing copious circulating hormones needed to maintain the female productive health. Data generated from the study will serve as an experimental basis for monitoring the toxicity of EPI and canvasing for novel and affordable combination therapy against breast malignancy.