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Mixed "Antiandrogenic" Chemicals at Low Individual Doses Produce Reproductive Tract Malformations in the Male Rat.

ABSTRACT: Biomonitoring efforts have clearly shown that all humans are exposed to chemical mixtures. Of concern is whether or not exposure to mixtures during pregnancy contributes to congenital abnormalities in children even when each chemical is at an individual dose that does not affect the fetus. Here, we hypothesized that in utero exposure to a mixture of chemicals covering multiple "antiandrogenic" mechanisms of action at doses that individually have no adverse effect would result in permanent reproductive tract alterations in the male rat after birth. Pregnant dams were exposed to a range of dilutions (100%, 50%, 25%, 12.5%, 6.25%, or vehicle control) of a mixture containing pesticides, phthalates, and drugs (p, p'-DDE, linuron, prochloraz, procymidone, pyrifluquinazon, vinclozolin, finasteride, flutamide, simvastatin, and 9 phthalates [dipentyl, dicyclohexyl, di-2-ethylhexyl, dibutyl, benzyl butyl, diisobutyl, diisoheptyl, dihexyl, and diheptyl]). The top dose contained each chemical at 20% of its lowest observed adverse effect level (LOAEL) for the most sensitive male reproductive alteration following in utero exposure. We found that male rat offspring displayed a variety of neonatal, pubertal, and permanent adult effects across all dose levels. Even at the lowest dose (each chemical approximately 80-fold below lowest observed adverse effect level) there were permanent reductions in several reproductive tract tissue weights. In the top dose group, 100% of male offspring displayed permanent severe birth defects including genital malformations. Despite acting via 5 different molecular initiating events, a mixture of 18 chemicals can combine to produce additive effects even when each compound is at is at a relatively low dose.

SUBMITTER: Conley JM

PROVIDER: S-EPMC6677127 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Mixed "Antiandrogenic" Chemicals at Low Individual Doses Produce Reproductive Tract Malformations in the Male Rat.

Conley Justin M JM Lambright Christy S CS Evans Nicola N Cardon Mary M Furr Johnathan J Wilson Vickie S VS Gray Leon Earl LE

Toxicological sciences : an official journal of the Society of Toxicology 20180701 1

Biomonitoring efforts have clearly shown that all humans are exposed to chemical mixtures. Of concern is whether or not exposure to mixtures during pregnancy contributes to congenital abnormalities in children even when each chemical is at an individual dose that does not affect the fetus. Here, we hypothesized that in utero exposure to a mixture of chemicals covering multiple "antiandrogenic" mechanisms of action at doses that individually have no adverse effect would result in permanent reprod ...[more]

PMID: 29945228

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Project description:Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies.In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.We used U.S. EPA's animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA's in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features.A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network.Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s.Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050-1061;?http://dx.doi.org/10.1289/ehp.1510385.

Dataset Information

Mixed "Antiandrogenic" Chemicals at Low Individual Doses Produce Reproductive Tract Malformations in the Male Rat.

Publications

Mixed "Antiandrogenic" Chemicals at Low Individual Doses Produce Reproductive Tract Malformations in the Male Rat.

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