Daily exposure to phthalates and alkylphenols alters miR biogenesis and expression in mice ovaries

Abstract

Reproductive hormone imbalance in infertile women is correlated to high levels of phthalates and alkylphenols, which are among endocrine-disrupting chemicals (EDCs). Previous studies have shown that they interfere with gene expression by deregulating levels of microRNAs (miRs), small non-coding RNAs targeting mRNAs encoding enzymes in the hormone biosynthesis pathway. However, this effect depends on the target organ, dose and whether or not they are alone or in mixtures. Our goal was to study whether the biosynthesis, and a specific group of miRs targeting mRNAs encoding enzymes in steroid hormone biosynthesis, are deregulated in the ovaries of female mice chronically exposed to a mixture of three phthalates (DEHP+DBP+BBP) and two alkylphenols (NP+OP) at a human environmentally relevant dose. We performed qPCR and western blot assays along with a bioinformatics approach and found that this mixture modified the biogenesis machinery of miRs, inducing an increase in the mRNA levels of Drosha and Dicer1 and DROSHA protein levels. In addition, we found changes in the precursor and mature forms of miR-96-5p, miR-200b-3p, miR-365-3p, miR-378a-3p and miR-503-5p which target steroidogenic pathway enzymes. Finally, using primary granulosa cell culture, we confirmed that miR-200b-3p targets Cyp19a1, transcript encoding CYP19A1, the enzyme that produces estradiol (E2). These results indicate that chronic exposure to phthalates and alkylphenols mixture alters the biogenesis of ovary miRs and increases the expression of miRs implicated in the control of steroidal hormone synthesis in female mice, thus contributing to reproductive pathologies.

Sustained Morphine Delivery Suppresses Bone Formation and Alters Metabolic and Circulating miRNA Profiles in Male C57BL/6J Mice

“…It is reported that miR-125b-5p expression is decreased in polycystic ovary syndrome (PCOS) women, (59) whereas miR-200b-3p targets steroidogenic pathway enzyme (eg, CYP19A1) that produces estradiol. (60) These findings suggest that miR-125b-5p and -200b-3p might unveil potential mechanisms of how morphine may impact steroid production. Here, we have not explored circulating steroid hormone levels and their receptors in our mouse model to understand to what extent the changes in this sex hormone's levels influenced our bone phenotype, and we believe that such aspect should be considered moving forward.…”

“…It is reported that miR-125b-5p expression is decreased in polycystic ovary syndrome (PCOS) women (47) , whereas miR-200b-3p targets steroidogenic pathway enzyme (e.g. CYP19A1) that produces estradiol (48) . These findings suggest that miR-125b-5p and -200b-3p might unveil potential mechanisms of how morphine may impact steroids production.…”

“…miR‐125b‐5p expression is described to be sex‐dependent ( 37 ) and is downregulated in osteoporotic postmenopausal women compared with non‐osteoporotic ones. ( 38 ) Moreover, miR‐125b‐5p ( 59 ) and miR‐200b‐3p ( 60 ) are miRNAs described to be involved in steroidogenesis. It is reported that miR‐125b‐5p expression is decreased in polycystic ovary syndrome (PCOS) women, ( 59 ) whereas miR‐200b‐3p targets steroidogenic pathway enzyme (eg, CYP19A1) that produces estradiol.…”

Sustained morphine delivery suppresses bone formation and alters metabolic and circulating miRNA profiles in male C57BL/6J mice

“…miR-125b-5p expression is described to be gender-dependent (32) , and is downregulated in osteoporotic postmenopausal women compared to non-osteoporotic ones (33) . Moreover, miR-125b-5p (47) and miR-200b-3p (48) are miRNAs described to be involved in steroidogenesis. It is reported that miR-125b-5p expression is decreased in polycystic ovary syndrome (PCOS) women (47) , whereas miR-200b-3p targets steroidogenic pathway enzyme (e.g.…”

Nicotinamide mononucleotide restores oxidative stress‐related apoptosis of oocyte exposed to benzyl butyl phthalate in mice

“…Furthermore, animal experiments have demonstrated that exposure to phthalate and its metabolites can adversely damage the reproductive system and oestrogen‐sensitive tissues by affecting circulating hormones 3 . It was reported that chronic exposure to phthalates changed the biogenesis of ovarian miRNAs in mice, leading to upregulated expression of hormone synthesis‐related miRNAs, thus inducing reproductive dysfunction 8 . Dietary exposure to BBP generated significant systemic and reproductive toxicity in rats 9 .…”