Prenatal exposure to chromium induces early reproductive senescence by increasing germ cell apoptosis and advancing germ cell cyst breakdown in the F1 offspring

Abstract

Hexavalent chromium (CrVI), one of the more toxic heavy metals, is widely used in more than 50 industries such as chrome plating, welding, wood processing and tanneries. As one of the world’s leading producers of chromium compounds, the U.S. is facing growing challenges in protecting human health against multiple adverse effects of CrVI. CrVI is rapidly converted to CrIII intracellularly, and can induce apoptosis through different mechanisms. Our previous studies demonstrated postnatal exposure to CrVI results in a delay or arrest in follicle development and puberty. Pregnant rats were treated with 25 ppm potassium dichromate (CrVI) from gestational day (GD) 9.5 to 14.5 through drinking water, placentae were removed on GD 20, and total Cr was estimated in the placentae; ovaries were removed from the F1 offspring on postnatal day (PND)-1 and various analyses were performed. Our results show that gestational exposure to CrVI resulted in (i) increased Cr concentration in the placenta, (ii) increased germ cell apoptosis by up-regulating p53/p27–Bax–caspase-3 proteins and by increasing p53–SOD-2 co-localization; (iii) accelerated germ cell cyst (GCC) breakdown; (iv) advanced primordial follicle assembly and primary follicle transition and (v) down regulation of p-AKT, p-ERK and XIAP. As a result of the above events, CrVI induced early reproductive senescence and decrease in litter size in F1 female progeny.

Chromium VI − Induced developmental toxicity of placenta is mediated through spatiotemporal dysregulation of cell survival and apoptotic proteins

“…Many types of cells are known to undergo apoptosis in a p53-dependent manner in response to cytotoxic stimuli [42,44–46]. Studies from our laboratory had clearly demonstrated potential roles for p53 pathway in CrVI-induced apoptosis through direct [39] and indirect [47] mechanisms in the ovary. A few studies have shown that more p53 protein is produced by the human placentas in abnormal pregnancies [48].…”

The role of BH3-only proteins in apoptosis within the ovary

“…The apoptotic elimination of germ cells ultimately results in a reduced number of oocytes stored as primordial follicles within the ovary at birth (Myers et al 2014). Once formed, primordial follicles may be lost from the ovarian reserve as a consequence of exposure to endogenous and exogenous stressors, such as chemotherapy, radiation and environmental toxicants (Kerr et al 2012a, Sobinoff et al 2013, Sivakumar et al 2014. These agents are known to activate apoptotic responses within the primordial follicle oocyte itself, as well as in the granulosa cells of growing follicles (Suh et al 2006) (reviewed in Morgan et al (2012)).…”

Edaravone Mitigates Hexavalent Chromium-Induced Oxidative Stress and Depletion of Antioxidant Enzymes while Estrogen Restores Antioxidant Enzymes in the Rat Ovary in F1 Offspring1

“…CrIII increased cleaved Casp3 in the ovary. Our recent report also indicated that prenatal exposure to 25 ppm CrVI during the organogenesis window (gestational day 8.5-12.5) significantly up regulated cleaved Casp3 and apoptosis of germ cells and somatic cells on PND 1, whereas, it is not detectable in the control ovary [48]. Therefore, Casp3 -mediated cell death may be one of the key mechanisms for CrIII-induced increase in apoptosis in the ovarian cells followed by follicle atresia.…”